Current Medicinal Chemistry

Irreversible Protein Kinase Inhibitors

Irreversible Protein Kinase Inhibitors, 2011, 18(20) Pp. 2981-2994
L. Garuti, M. Roberti and G. Bottegoni

Targeting cancer with small molecule irreversible inhibitors of kinases represents an emerging challenge in drug discovery. Irreversible inhibitors bind to kinase active site in a covalent and irreversible form, most frequently by reacting with a nucleophilic cysteine residue, located near the ATP binding pocket. The most common mechanism is the Michael reaction, that refers to the addition of a nucleophile, such as cysteine, to an α,β-unsaturated carbonyl. The nucleophile reacts at the electrophilic β-position to form an adduct; as a result the inhibitor irreversibly blocks binding of ATP to the kinase, rendering the kinase inactive. Different cysteine-reactive groups have been evaluated, an acrylamide or a substituted acrylamide moiety are the Michael acceptors of choice. There are some advantages for the irreversible kinase inhibition. These compounds are highly selective because they target a specific cysteine and only a limited number of kinases has a cysteine at the corresponding position. Another advantage is that covalent bond formation can overcome competition with the high endogenous concentration of ATP. A further motivation for designing irreversible inhibitors is their longer duration of action respect to conventional inhibitors. In fact, once bound to enzyme, these compounds do not readily dissociate and the inhibition continues even after the inhibitor leaves the circulation. Moreover, these inhibitors have the potential to overcome and prevent the emergence of acquired resistance conferred by mutations. In this review examples of irreversible inhibitors are reported, focusing on chemical structures, SAR and biological activities. The great potential of these compounds could open new and promising perspectives for a broader application of this approach

ATP-Competitive Inhibitors of mTOR: An Update

ATP-Competitive Inhibitors of mTOR: An Update, 2011, 18(20) Pp. 2995-3014
S. Schenone, C. Brullo, F. Musumeci, M. Radi and M. Botta

mTOR (mammalian target of rapamycin) is a serine-threonine kinase belonging to the PI3K/Akt/mTOR signalling pathway that is involved in several cell functions, including growth, proliferation, apoptosis and autophagy. mTOR hyperactivation has been detected in several human cancers, thus representing, together with its upstream effectors, an important target for cancer therapy. mTOR exists in two different complexes in cells, mTORC1 and mTORC2 which could both be targeted by potential anticancer agents. Rapamycin, the selective and allosteric inhibitor of mTOR, inhibits the enzyme in mTORC1, but not in mTORC2. In the last few years a number of mTOR ATP-competitive inhibitors has been reported acting on mTOR in both complexes and possessing a more complete anticancer activity in comparison with that of rapamycin and its derivatives. mTOR shares high sequence homology in the hinge-region with PI3K that is a lipid kinase upstream to mTOR in the same signalling pathway; for this reason some compounds originally developed as PI3K inhibitors later showed to also target mTOR. As indicated by preclinical and clinical studies, compounds acting on more than one target could result in a better biological response and in enhanced therapeutic potential and also dual PI3K/mTOR inhibitors result of great interest as potential antitumor agents. This review mainly reports the recently discovered mTOR ATP-competitive inhibitors in terms of medicinal chemistry, classified by their chemical structures, focusing on SAR and modelling studies that led to the discovery of very potent and selective agents, such as AZD- 8055, OSI-027 and INK128, already entered clinical trials, or WYE-132, Torin1 and others in preclinical studies. Also some examples of dual PI3K/mTOR inhibitors, including PI-103, GNE477, WJD008 and GSK2126458 are reported together with their biological and clinical data.

Targeting the Human DEAD-Box Polypeptide 3 (DDX3) RNA Helicase as a Novel Strategy to Inhibit Viral Replication

Targeting the Human DEAD-Box Polypeptide 3 (DDX3) RNA Helicase as a Novel Strategy to Inhibit Viral Replication, 2011, 18(20) Pp. 3015-3027
A. Garbelli, M. Radi, F. Falchi, S. Beermann, S. Zanoli, F. Manetti, U. Dietrich, M. Botta and G. Maga

Compounds currently used for the treatment of HIV-1 Infections are targeted to viral proteins. However, the high intrinsic mutation and replication rates of HIV-1 often lead to the emergence of drug resistant strains and consequent therapeutic failure. On this basis, cellular cofactors represent attractive new targets for HIV-1 chemotherapy, since targeting a cellular factor that is required for viral replication should help to overcome the problem of viral resistance. We and others have recently reported the identification of compounds suppressing HIV-1 replication by targeting the cellular DEAD-box helicase DDX3. These results provide a proof-of-principle for the feasibility of blocking HIV-1 infection by rendering the host cell environment less favorable for the virus. The rationale for such an approach and its implications in potentially overcoming the problem of drug resistance related to drugs targeting viral proteins will be discussed in the context of the known cellular functions of the DEAD-box helicase DDX3.

The Potential Role of Glycogen Synthase Kinase 3 Inhibitors as Amyotrophic Lateral Sclerosis Pharmacological Therapy

The Potential Role of Glycogen Synthase Kinase 3 Inhibitors as Amyotrophic Lateral Sclerosis Pharmacological Therapy, 2011, 18(20) Pp. 3028-3034
V. Palomo, D. I. Perez, C. Gil and A. Martinez

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons. Lately, this disease has often been related to the protein kinase called glycogen synthase kinase 3 (GSK-3), through the experimental evidence of alterations of this enzyme on ALS patients. Therefore, there have been several experimental studies using GSK-3 inhibitors, in cellular and animal models and also in clinical studies that showed the potential of the therapeutic role of these molecules. GSK-3 inhibitors might play a pivotal role in the pharmacology of ALS disease with no curative treatment nowadays. In this review we give an overview of the current research in the area, showing all the evidences of the implication of dysfunctional GSK-3 in this disease on one hand, and on the other presenting the potential role of the GSK-3 inhibitors as a future pharmacological ALS therapy.

Biological Potential and Structure-Activity Relationships of Most Recently Developed Vascular Disrupting Agents: An Overview of New Derivatives of Natural Combretastatin A-4

Biological Potential and Structure-Activity Relationships of Most Recently Developed Vascular Disrupting Agents: An Overview of New Derivatives of Natural Combretastatin A-4, 2011, 18(20) Pp. 3035-3081
M. Marrelli, F. Conforti, G. A. Statti, X. Cachet, S. Michel, F. Tillequin and F. Menichini

Tumor blood vessels are an important emerging target for anti-cancer therapy. The antimitotic agent combretastatin A-4 (CA- 4), a cis-stilbene natural product isolated from the South African tree Combretum caffrum Kuntze, is the lead compound of a new class of anti-cancer drugs that target tumor vasculature. CA-4 inhibits tubulin polymerization by interacting at the colchicine binding site on tubulin. This alters the morphology of endothelial cells and causes vascular shutdown and regression of tumor vasculature. Some tubulin-binding vascular-disrupting agents (VDAs) are currently in clinical trials for cancer therapy. As a consequence of the potential favorable applications of these compounds, several analogs projected to induce rapid and selective vascular shutdown in tumors have been synthesized during the last few years. Many of these molecules have already been tested for their effects on tubulin polymerization as well as for their antiproliferative activity and other biological properties, and possible mechanisms of action have been investigated. The aim of the present review is to offer an overview of most recently developed combretastatin derivatives, focusing on biological effects exerted by these compounds. The published data about new analogs are presented and compared, and a detailed investigation of structure-activity relationships is described.

Current Progress in Antifibroitcs

Current Progress in Antifibroitcs, 2011, 18(20) Pp. 3082-3092
S. A.A. El Bialy, K. F. Abd El Kader and M. B. El-Ashmawy

After years of viewing cirrhosis as the irreversible end-stage of liver fibrosis, it has been shown recently that the possibility of its reversal is no longer a dream. Several studies on experimental animal models showed possible spontaneous resolution of fibrosis after the removal of fibrogenic stimulus. Similar results were also observed in human patients with liver fibrosis due to autoimmune hepatitis and biliary etiology. However, the need for other means of treatment is urgent, especially when the removal of the causative factor is unlikely. Recent antifibrotic strategies were designed to target one or more of the three stages involved in the process of fibrosis. These are the triggering stage, fibrogenesis, and extracellular matrix accumulation. In this review, the classification of the current drugs or agents that showed inhibition of one or more of fibrosis stages with their chemical synthesis are presented.

Bone Metastatic Disease: Taking Aim at New Therapeutic Targets

Bone Metastatic Disease: Taking Aim at New Therapeutic Targets, 2011, 18(20) Pp. 3093-3115
F. Coluzzi, E. Di Bussolo, I. Mandatori and C. Mattia

Conventional treatment for metastatic bone pain requires a multidisciplinary approach (medical therapy, surgery, and radiation), but is primarily palliative. Biphosphonates introduced the concept of disease-modifying therapy, by effectively reducing bone pain and skeletal related events in patients suffering from bone metastatic cancer. In the past decade, the growing knowledge of bone biology and our understanding of the molecular mechanisms at the basis of the interaction between cancer cells and bone matrix led to the identification of new therapeutic targets for innovative “smart drugs”. The most investigated is the RANK/RANKL/OPG pathway, and denosumab, among novel targeted therapies, is the molecule that is in the most advanced development phase. Additional targets have been identified and potential novel therapeutic interventions, classified as inhibitors of bone resorption or stimulators of bone formation, are under preclinical and clinical evaluation. These promising targets include cathepsin K, the Src tyrosine kinases, integrins, chloride channels, the parathyroid hormone-related peptide, endotelin-1, sclerostin, and TGF-beta. Other pathways or molecules expressed by bone cells and cancer cells, such as CXCR4, GPNMB, EGF-family ligands, Wnt/DKK1, and MIP-1 alpha have recently emerged as potential targets. The aim of this review is to discuss the molecular mechanisms behind these emerging therapeutic targets in bone metastases and to give an overview of results from those in advanced clinical phases.

Managing the Liabilities Arising from Structural Alerts: A Safe Philosophy for Medicinal Chemists

Managing the Liabilities Arising from Structural Alerts: A Safe Philosophy for Medicinal Chemists, 2011, 18(20) Pp. 3116-3135
P. J. Edwards and C. Sturino

Bioactivation of xenobiotics can, in certain circumstances, result in the formation of reactive electrophilic species. These reactive metabolites may covalently modify proteins and macromolecules and it has been suggested that protein modification is a key initial step in provoking idiosyncratic adverse drug reactions. Understanding these bioactivation pathways is critical in order to rationally design drug candidates with a lower propensity to form reactive intermediates. Herein, we provide an overview of the importance of Structural Alerts and bioactivation pathways and describe the creation of an in-house database as a tool aimed at informing medicinal chemists about these potential liabilities.

Editorial [Hot Topic: Protein Kinases in Cancer: Recent Findings (Guest Editor: Silvia Schenone)]

Editorial [Hot Topic: Protein Kinases in Cancer: Recent Findings (Guest Editor: Silvia Schenone)], 2011, 18(19) Pp. 2826-2826
Silvia Schenone

Protein kinases are responsible for key events in the cells, and their hyperactivation, overexpression or mutations have been detected in several human cancers. Kinase inhibitors are currently one of the most important classes of anticancer drugs, and both one-target-selective and dual or politargeted compounds have been approved for therapy of haematological or solid malignancies in the last decade, representing new important tools for the fight against cancer. Inhibition of a single kinase (Bcr-Abl in chronic myeloid leukemia and Kit in gastrointestinal stromal tumors) led to the discovery of fundamental drugs, such as imatinib, that can cure these diseases. However several cases of drug resistance have been reported and prompted the search for new compounds able to act on mutated enzymes and/or in the real tumor microenvironment that is characterized by marked gradients in drug concentration and by regions of hypoxia and acidity, all of which can influence tumor cell sensitivity to drug treatment. Moreover systems-wide analyses of tumors have recently identified receptor tyrosine kinase (RTK) coactivation as an important mechanism by which cancer cells achieve chemoresistance and for this reason also the research of multitargeted kinase inhibitors that might target both receptor and cytoplasmatic kinases, is very active. Indeed experiments and clinical data in different tumors show that a better cancer therapy can be obtained with a polypharmacology approach, by blocking several tumor cell biochemical pathways at once, accurately selecting critical targets and adjusting drug dosages for the best results. A great debate also exists whether to use peptides or small molecules, being the field of cyclin-dependent kinases (CDKs) an important example. Peptides are more selective being derived by the linear protein sequences, indeed they should mimic the catalytic or the regulatory subunits of the cell cycle controller complexes, but on the other side they usually present poorer pharmacokinetic characteristics. In contrast, small molecules have better pharmacokinetic features but lower specificity because many protein kinases show high sequence similarity within the active site. Kinases are also involved in HIV-1 replication cycle at the nuclear level, both directly through their catalytic activity on viral proteins and indirectly being activated by the virus. Alternatively, kinases may act indirectly such as in the case of DNA repair factors activated following HIV-1 infection and demonstrated to regulate the viral life cycle. Finally, inhibition of cellular kinases interacting with HIV-1 at the nuclear level has been shown to severely affect the viral replication cycle, thus suggesting potential new therapeutic approaches. The ever-deepening study of kinome addressed the interest also in kinases not yet targeted until now for the synthesis of potential drugs, such as protein kinase CK2, an ubiquitous and constitutively active protein kinase, that catalyzes the phosphorylation of more than 300 substrates or two other cytoplasmatic kinases, Fes and Fyn, both involved in cancer development and the latter also in CNS degenerative pathologies, such as Alzheimer's disease. The common problems faced by the antiviral and anticancer fields needs the integration of structural, biochemical and in silico modelling approaches for the development of novel highly active kinase inhibitors. Particularly the knowledge of protein kinase three-dimensional structure is of great help in the rational design of specific ligands and kinase homology modeling techniques have been widely diffused. The research in the field of kinase inhibition is extremely active, also due the high number of protein kinases identified, as evidenced by the increasing number of publications that appear in the literature daily. For these reasons new updates are always needed and in this special issue some of the most exciting studies on this topic are reported.

Cancer Multitarget Pharmacology in Prostate Tumors: Tyrosine Kinase Inhibitors and Beyond

Cancer Multitarget Pharmacology in Prostate Tumors: Tyrosine Kinase Inhibitors and Beyond, 2011, 18(19) Pp. 2827-2835
M. Bologna, C. Vicentini, P. Muzi, G. Pace and A. Angelucci

Tyrosine kinase inhibitors are currently one of the most important classes of cancer drugs, essentially because many kinases and regulators are molecules related to frequently mutated oncogenes and tumor suppressors. Many experiments and clinical data in different tumors show that better cancer therapy can be obtained by blocking several tumor cell biochemical pathways at once, accurately selecting critical targets and adjusting drug dosages for the best results. Through our direct experience in experimental models of prostate cancer (PCa), we discuss in this review the issues of tyrosine kinase inhibition in neoplastic cells and illustrate the opportunities to extend cancer proliferation control to other key biological targets of clinical interest, aiming at the realization of better polypharmacology applications in cancer chemotherapy. Briefly, in this review the main experimental evidences on the efficacy of tyrosine kinase inhibitors (TKIs) on PCa are described, together with a reasoned analysis of biological data which may be useful for a general extension to other clinical areas of cancer multitargeted and possibly individualized polychemotherapy.

Overcoming the Drug Resistance Problem with Second-Generation Tyrosine Kinase Inhibitors: From Enzymology to Structural Models

Overcoming the Drug Resistance Problem with Second-Generation Tyrosine Kinase Inhibitors: From Enzymology to Structural Models, 2011, 18(19) Pp. 2836-2847
E. Crespan, E. Zucca and G. Maga

Protein phosphorylation is one of the major pathways used by eukaryotic cells to propagate signals to the final effectors, regulating multiple aspects of the living cell, such as metabolism, growth, differentiation, adhesion, motility, genome stability and death. In this context, tyrosine kinases (TKs) play a central role in signal transduction and their overexpression or disregulated activity has been implicated in tumor onset and malignancy progression. To date, eight TKs inhibitors have been approved by FDA for the treatment of specific tumors. In spite of their efficacy, insurgence of resistance is a common feature after prolonged administration. The selective pressure by these drugs, in fact, induces clonal expansion of subsets of cancer cells harboring TKs mutations, leading to decreased inhibition potency. Alternatively, resistance to TK inhibitors can be acquired through the activation of others, often unrelated, TKs. For this reason, while stringent target selectivity of TKs inhibitors has been always considered a desirable feature in order to limit toxicity, molecules targeting different TKs have been recently shown to be promising anti-cancer agents as well. Understanding the molecular mechanisms that confer resistance to TK inhibitors, through a combination of enzymatic, structural and cellular studies, is essential in the development of second generation inhibitors active also towards drug resistant tumors.

Protein Kinase Homology Models: Recent Developments and Results

Protein Kinase Homology Models: Recent Developments and Results, 2011, 18(19) Pp. 2848-2853
T. Tuccinardi and Adriano Martinelli

Protein kinases are key regulators of cell function that constitute one of the largest and most functionally diverse gene families, and knowledge of their three-dimensional structure could be of great help in the rational design of specific ligands. However, only about one quarter of human protein kinase structures has been experimentally defined; thus, kinase homology modeling techniques have been widely diffused. In this review, the most recent kinase homology models are reported, together with the most recent approaches and the main validation methods.

Peptides or Small Molecules? Different Approaches to Develop More Effective CDK Inhibitors

Peptides or Small Molecules? Different Approaches to Develop More Effective CDK Inhibitors, 2011, 18(19) Pp. 2854-2866
D. Cirillo, F. Pentimalli and A. Giordano

Cell cycle regulation involves processes crucial to the survival of a cell, including the detection and repair of genetic damage as well as the prevention of uncontrolled cell division. The molecular events that control cell cycle are ordered and directional. Cyclins and cyclin-dependent kinases (CDKs), determine cell progression through the cycle ensuring the orderly coordination of cellular events. Alterations of cell cycle controllers are among the main causes of cancer onset. In the past decades many efforts have been made to develop kinase inhibitors that are able to modulate cyclin and CDK complexes, either by mimicking the function of natural CDK inhibitors, such as p21, p16 and p27, or by modulating the cyclin-CDK complexes or their targets directly. The great debate is whether to use peptides or small molecules. Peptides are more selective being derived by the linear protein sequences, indeed they should mimic the catalytic or the regulatory subunits of the cell cycle controller complexes, but on the other side they usually present poorer pharmacokinetic characteristics. In contrast, small molecules have better pharmacokinetic features but lower specificity because many protein kinases show high sequence similarity within the active site. The purpose of this review article is to provide an overview of the main classes of CDK inhibitors focusing on structure-activity relationship (SAR) studies and discussing the pharmacological and therapeutic implications.

The Dark Side of Protein Kinase CK2 Inhibition

The Dark Side of Protein Kinase CK2 Inhibition, 2011, 18(19) Pp. 2867-2884
G. Cozza, F. Meggio and S. Moro

Casein kinase 2 (CK2) is a ubiquitous, highly pleiotropic and essential protein kinase whose abnormally high constitutive activity has been implicated in several human diseases. In the last decade, several ATP competitive inhibitors of CK2, characterized by an in vitro activity that ranges from micromolar to nanomolar, have been discovered. However, until now only one drug candidate has been entered in Phase I clinical trial as a potential anticancer drug. Why this constitutively active kinase is so undruggable? Can ATP competitive inhibitors be considered the most promising drug candidates for the near future? In this review, we would like to underline how targeting binding sites outside the conventional ATP-binding could represent a new promising strategy to inhibit CK2 activity and, consequently, bear a great potentiality in discovering new drug candidates.

Role of the Hypoxic Microenvironment in the Antitumor Activity of Tyrosine Kinase Inhibitors

Role of the Hypoxic Microenvironment in the Antitumor Activity of Tyrosine Kinase Inhibitors, 2011, 18(19) Pp. 2885-2892
I. Filippi, A. Naldini and F. Carraro

The tumor microenvironment is characterized, not only by marked gradients in drug concentration, but also by gradients in the rate of cell proliferation and by regions of hypoxia and acidity, all of which can influence tumor cell sensitivity to drug treatment. Hypoxia is also an important environmental factor in chronic myeloid leukemia (CML), because bone marrow is intrinsically hypoxic in nature. Systems-wide analyses of tumors have recently identified receptor tyrosine kinase coactivation as an important mechanism by which cancer cells achieve chemoresistance. Recent work suggests that Src activation might play a prominent role in the response to hypoxia to promote cell survival, progression, and metastasis of a variety of human cancer. Other studies also established a functional link between Bcr-Abl and the Src family tyrosine kinases. It is well known that mutations can also cause some tyrosine kinases to become constitutively active, a nonstop functional state that may contribute to initiation or progression of cancer as in CML. Leukemic cells carrying chromosomal alteration, are sensitive to imatinib that induces complete remission in most patients. This inhibitor is a highly selective Bcr-Abl tyrosine kinase inhibitor (TKI). There is a considerable interest in understanding how activated signaling pathways enhance tumor cell survival under hypoxia, because this might lead to the introduction of more effective treatments to target these resistant subpopulations. For all these reasons it is important to identify new TKIs which are also active in hypoxia, the real tumor microenvironment, as possible alternative therapy.

Receptor Tyrosine Kinase Kit and Gastrointestinal Stromal Tumours: An Overview

Receptor Tyrosine Kinase Kit and Gastrointestinal Stromal Tumours: An Overview, 2011, 18(19) Pp. 2893-2903
S. Sartini, B. Dario, M. Morelli, F. Da Settimo and C. La Motta

Kit is a growth factor receptor of the type III tyrosine kinase family, whose gain-of-function mutations have been identified as driving causes of different kinds of tumours. It thus represents a viable drug target, and the development of Kit inhibitors has been shown to be a promising therapeutic concept. This review will focus on structural and signalling properties of both wild-type and mutant Kit, as well as its role in the development of human cancers. Special attention will be dedicated to gastrointestinal stromal tumours, GISTs. Progress in research on the aetiopathogenesis of GISTs and their therapeutic approaches will be fully discussed, focusing on the latest tendencies for the treatment of these kinds of tumours.

Role of Phosphorylation in the Nuclear Biology of HIV-1

Role of Phosphorylation in the Nuclear Biology of HIV-1, 2011, 18(19) Pp. 2904-2912
A. C. Francis, C. Di Primio, A. Allouch and A. Cereseto

The central events of HIV-1 life cycle occur at the nuclear level where the viral genome is integrated into the host cellular DNA in order to be expressed and replicated. The viral pre-integration complexes (PICs) are actively transported in the nuclear compartment where integration occurs in specific regions of the cellular chromatin. Similar to all viruses, HIV-1 encodes for a limited number of proteins that are insufficient to produce new viral progenies. Several cellular pathways are thus hijacked by HIV-1 to efficiently complete the replication cycle. The majority of viral proteins are substrates for cellular kinases indicating a pivotal role of these cellular enzymes at multiple steps of the HIV-1 life cycle. The nuclear biology of the cell is highly controlled by kinases (nuclear transport, DNA replication, repair and transcription) and many of these kinases also sustain the viral nuclear events. This review summarizes our current knowledge on kinases that are involved in HIV-1 replication cycle at the nuclear level, both directly through their catalytic activity on viral proteins and indirectly being activated by the virus. Among viral proteins directly modified by kinases is integrase (IN) the factor that catalyzes the integration of HIV-1 in the cellular genome. Notably, this recent discovery may shed light onto mechanisms underlying the different susceptibility of the main cell types targeted by HIV-1 (CD-4+ T-cell) depending on their activation status. Alternatively, kinases may act indirectly such as in the case of DNA repair factors activated following HIV-1 infection and demonstrated to regulate the viral life cycle. Finally, inhibition of cellular kinases interacting with HIV-1 at the nuclear level has been shown to severely affect the viral replication cycle, thus suggesting potential new therapeutic approaches.

Role of the Non-Receptor Tyrosine Kinase Fes in Cancer

Role of the Non-Receptor Tyrosine Kinase Fes in Cancer, 2011, 18(19) Pp. 2913-2920
F. Condorelli, E. Stec-Martyna, J. Zaborowska, L. Felli, I. Gemmi, M. Ponassi and C. Rosano

Non receptor protein tyrosine kinases are targets in the treatment of a number of diseases. This review focuses on the role of Fes tyrosine kinase and on the design of inhibitors of this protein. Fes and its homologously related protein Fer are the only two members of a distinct class of non receptor tyrosine kinases and they seem to play a role in cytoskeletal rearrangements and inside-out signalling associated with receptor-ligand, cell-matrix and cell-cell interactions. The knowledge of the three dimensional structure of this protein, in fact, has informed drug design, while at the same time it has helped to shed some light on the molecular mechanism at the basis of kinase activation and functions.

Fyn Kinase in Brain Diseases and Cancer: The Search for Inhibitors

Fyn Kinase in Brain Diseases and Cancer: The Search for Inhibitors, 2011, 18(19) Pp. 2921-2942
S. Schenone, C. Brullo, F. Musumeci, M. Biava, F. Falchi and M. Botta

Fyn is a non-receptor tyrosine kinase belonging to the Src family kinases. It has been shown to play important roles in neuronal functions, including myelination and oligodendrocytes formation, and in inflammatory processes. It has also demonstrated its involvement in signaling pathways that lead to severe brain pathologies, such as Alzheimer's and Parkinson's diseases. Moreover, Fyn is upregulated in some malignancies. Experimental studies demonstrated that Fyn inhibition could be useful in the disruption of metabolic processes involved in cancer and in neurodegenerative diseases. Unfortunately no specific Fyn inhibitor has been discovered so far, being the reported compounds active also on other members of Src family or on different tyrosine kinases. However, multitargeted inhibitors might be endowed with therapeutic potential. Indeed, as increasingly reported, also a not completely selective inhibitor of a specific protein could be therapeutically useful, affecting a number of cell pathways involved especially in cancer development. In this review, we report some examples of small molecule tyrosine kinase inhibitors for which data on Fyn inhibition, both in enzymatic and in cell assays, have been reported, with the aim of giving information as starting point for the researchers working in this field.

BCR-ABL Inhibitors in Chronic Myeloid Leukemia: Process Chemistry and Biochemical Profile

BCR-ABL Inhibitors in Chronic Myeloid Leukemia: Process Chemistry and Biochemical Profile, 2011, 18(19) Pp. 2943-2959
F. Leonetti, A. Stefanachi, O. Nicolotti, M. Catto, L. Pisani, S. Cellamare and A. Carotti

Chronic myeloid leukemia (CML) is a myeloproliferative disease originating from a constitutively active tyrosine kinase, called BCR-ABL, expressed by an oncogene resulting from a reciprocal translocation between chromosome 9 and chromosome 22, coded as (t[9,22][q34;q11]). Inhibition of BCR-ABL with tyrosine kinase inhibitors (TKI) proved to be an efficient targeted therapy of Philadelphia-positive (Ph+) CML in the chronic phase. This review mainly addresses the synthetic pathways and process chemistry leading to the large scale preparation for pre-clinical demands and clinical supply of the three TKIs approved for Ph+ CML, i.e., imatinib, dasatinib and nilotinib and three more investigational drugs, i.e., bosutinib, ponatinib and bafetinib. Recent progress on the biochemical profiling of the six examined TKIs has been also reported.

Targeting mTOR Signaling Pathway in Ovarian Cancer

Targeting mTOR Signaling Pathway in Ovarian Cancer, 2011, 18(19) Pp. 2960-2968
S. Mabuchi, T. Hisamatsu and T. Kimura

The mammalian target of rapamycin (mTOR) is frequently activated in epithelial ovarian cancer, and is regarded as an attractive therapeutic target for therapy. Preclinical investigations using rapamycin and its analogs have demonstrated significant growthinhibitory effects on the growth of ovarian cancer both in the setting of monotherapy and in combination with cytotoxic agents. Based on promising preclinical data, mTOR inhibitors are currently being evaluated in several phase I/II trials in patients with ovarian cancer. In an effort to overcome resistance to rapamycin and its analogs, the novel ATP-competitive mTOR inhibitors have recently been developed. In this report, we review the scientific rationale and evidence for the potential clinical benefits provided by mTOR inhibitor therapy for patients with epithelial ovarian cancer.

An Original Deal for New Molecule: Reversal of Efflux Pump Activity, A Rational Strategy to Combat Gram-Negative Resistant Bacteria

An Original Deal for New Molecule: Reversal of Efflux Pump Activity, A Rational Strategy to Combat Gram-Negative Resistant Bacteria, 2011, 18(19) Pp. 2969-2980
J.-M. Pages, L. Amaral and S. Fanning

The worldwide dissemination of ‹multi-drug resistant› (MDR) pathogens has severely reduced the efficacy of our antibiotic arsenal and increased the frequency of therapeutic failure. MDR bacteria over-express efflux pumps and this active mechanism can extrude all classes of antibiotics from the cell. It is necessary to clearly decipher the genetic, structural and functional aspects of this transport system in order to combat this polyselective mechanism. By understanding how efflux pumps work we may be able to develop a new group of antibacterial agents, collectively termed efflux reversals, including membrane permeabilisers, efflux pump inhibitors and flux-competitive agents, specific blockers, energy poisons, etc. Several chemical families of efflux pump inhibitors have been described and characterized. Among them several inhibitor compounds demonstrate efficient blocking of the efflux pump activity involved in the MDR phenotype as observed in many Gram-negative clinical isolates. This new family of molecules represents the first antibacterial class of compound specifically targeting active transport in the bacterial cell.

Editorial [Hot Topic: Phosphoinositide 3-Kinase Pathway Inhibitors: Pharmacology, Metabolism & Drug Development (Guest Editor: Marco Falasca)]

Editorial [Hot Topic: Phosphoinositide 3-Kinase Pathway Inhibitors: Pharmacology, Metabolism & Drug Development (Guest Editor: Marco Falasca)], 2011, 18(18) Pp. 2673-2673
Marco Falasca

The enzyme phosphoinositide 3-kinase (PI3K) plays a central role in the cellular response to growth factors and receptor activation through activation of downstream effectors such as Akt and mTOR [1]. PI3K is involved in protein synthesis, cell proliferation, survival and multiple drug resistance mechanisms in cancer cells [2,3]. Several signalling molecules in the PI3K/Akt pathways are frequently mutated, deleted or amplified in human cancer including PI3K, PTEN, and Akt [3]. Treatment with PI3K inhibitors as single agents can inhibit cancer cell proliferation and induce apoptosis and cell death. The combination of PI3K inhibitors with other therapeutic agents has often synergistic effects on tumor growth inhibition in experimental models and in some clinical trials [4]. The inhibition of PI3K signalling therefore provides a strong lead to improve cancer treatment. Currently, there are promising PI3K inhibitors in clinical trials to treat human cancer [5]. The immediate future challenge is to determine whether or how these PI3K inhibitors can be applied in a highly tumour-specific way with little adverse effects and how to select the most sensitive patients among different genetic backgrounds. The increasing importance of PI3K-dependent signalling as a cancer target has generated a large number of therapeutics targeting the PI3K/Akt pathways. Despite the surge of expectations elicited by their promising preclinical data, preliminary clinical results obtained so far with PI3K pathway inhibitors have not fulfilled their promises especially if considered as single-agent. Among the different explanations it is possible that this is due to insufficient inhibition of the target or to the fact that PI3K inhibition is simply not sufficient to stop tumor growth. Nevertheless, the clinical testing of PI3K pathway inhibitors is still in its infancy and requires a concerted tuning of strategies and approaches. On this basis, novel aspects of pharmacology and drug development of PI3K pathway inhibitors are the focus of this Hot Topic issue of Current Medicinal Chemistry. This is a timely topic, as there is tremendous interest in the therapeutic development of PI3K inhibitors. As a consequence of the increasing interest around PI3K pathways, during the last few years, there have been several reviews on PI3K signaling and on PI3K pathway inhibitors. Therefore, to avoid inevitable overlapping and repetitions I decided to concentrate the attention of this Hot Topic on the ultimate challenges that lay ahead in this scientific field. In order to distinguish themselves, Ciraolo et al., have focused on describing the pharmacology of the developmental compounds, preliminary clinical findings and potential side effects based on research mainly from genetic studies [6]. Shuttleworth et al. provide a comprehensive review of the recent development of compounds targeting the class I PI3Ks and also compounds that target both the class I PI3-Ks and mTOR [7]. Much of the data that the authors summarize is from patents and meeting abstracts and therefore absent from the general scientific literature. The cancer stem cell hypothesis is generating a great deal of interest because of its potential clinical implications, as it indicates that the route for cancer eradication will require the use of strategies which expunge the root cause of the tumour [8]. The findings reviewed in one article of this Hot Topic, strongly suggest that increased PI3K/Akt/mTOR signalling activity is important to regulate some of the cancer stem cells properties, including resistance to chemotherapy and radiotherapy [9]. Finally, three articles focused their attention on key downstream targets of PI3K, namely Akt, mTOR and PDK1, discussing strategies used to develop novel kinase inhibitors [10-12]. Overall, I hope the articles of this Hot Topic can represent a useful instrument for the broad readership of Current Medicinal Chemistry to become acquainted with signal transduction pathways that have emerged as important therapeutic targets in the context of cancer and the exciting and promising small molecule discovery research in the PI3K field.

Present and Future of PI3K Pathway Inhibition in Cancer: Perspectives and Limitations

Present and Future of PI3K Pathway Inhibition in Cancer: Perspectives and Limitations, 2011, 18(18) Pp. 2674-2685
E. Ciraolo, F. Morello and E. Hirsch

Phosphoinositide 3-kinases (PI3Ks) control key signaling pathways in cancer cells, leading to cell proliferation, survival, motility and angiogenesis. In several human cancers, activation of PI3Ks results from gain-of-function or over-expression of PI3Ks and/or hyperactivity of up- or downstream players in the pathway. As inhibition of PI3Ks and downstream targets such as mammalian target of rapamycin (mTOR) has been shown to reduce tumor growth in vitro and in preclinical models, several small molecule inhibitors of PI3Ks are currently undergoing clinical trial as novel agents in cancer therapy. These drugs include inhibitors targeting all class I PI3Ks (α, β, γ, δ isoforms), compounds blocking selective PI3K isoforms and dual inhibitors active on both PI3Ks and mTOR. Herein, we summarize the pharmacology and preliminary clinical data of the main PI3K inhibitors undergoing clinical trial. We will also review the preclinical studies documenting the major effects of systemic PI3K inhibition on non-cancer tissues, which have shed light on potential side effects, caveats and limitations for PI3K blockade in patients.

Progress in the Preclinical Discovery and Clinical Development of Class I and Dual Class I/IV Phosphoinositide 3-Kinase (PI3K) Inhibitors

Progress in the Preclinical Discovery and Clinical Development of Class I and Dual Class I/IV Phosphoinositide 3-Kinase (PI3K) Inhibitors, 2011, 18(18) Pp. 2686-2714
S. J. Shuttleworth, F. A. Silva, A. R.L. Cecil, C. D. Tomassi, T. J. Hill, F. I. Raynaud, P. A. Clarke and P. Workman

The phosphoinositide 3-kinases (PI3Ks) constitute an important family of lipid kinase enzymes that control a range of cellular processes through their regulation of a network of signal transduction pathways, and have emerged as important therapeutic targets in the context of cancer, inflammation and cardiovascular diseases. Since the mid-late 1990s, considerable progress has been made in the discovery and development of small molecule ATP-competitive PI3K inhibitors, a number of which have entered early phase human trials over recent years from which key clinical results are now being disclosed. This review summarizes progress made to date, primarily on the discovery and characterization of class I and dual class I/IV subtype inhibitors, together with advances that have been made in translational and clinical research, notably in cancer.

Targeting the Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin Signaling Network in Cancer Stem Cells

Targeting the Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin Signaling Network in Cancer Stem Cells, 2011, 18(18) Pp. 2715-2726
A. M. Martelli, C. Evangelisti, M. Y. Follo, G. Ramazzotti, M. Fini, R. Giardino, L. Manzoli, J. A. McCubrey and L. Cocco

Cancer stem cells (CSCs) comprise a subset of hierarchically organized, rare cancer cells with the ability to initiate cancer in xenografts of genetically modified murine models. CSCs are thought to be responsible for tumor onset, self-renewal/maintenance, mutation accumulation, and metastasis. The existence of CSCs could explain the high frequency of neoplasia relapse and resistance to all of currently available therapies, including chemotherapy. The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is a key regulator of physiological cell processes which include proliferation, differentiation, apoptosis, motility, metabolism, and autophagy. Nevertheless, aberrantly upregulated PI3K/Akt/mTOR signaling characterizes many types of cancers where it negatively influences prognosis. Several lines of evidence indicate that this signaling system plays a key role also in CSC biology. Of note, CSCs are more sensitive to pathway inhibition with small molecules when compared to healthy stem cells. This observation provides the proof-of-principle that functional differences in signaling transduction pathways between CSCs and healthy stem cells can be identified. Here, we review the evidence which links the signals deriving from the PI3K/Akt/mTOR network with CSC biology, both in hematological and solid tumors. We then highlight how therapeutic targeting of PI3K/Akt/mTOR signaling with small molecule inhibitors could improve cancer patient outcome, by eliminating CSCs.

Novel Inhibitors of AKT: Assessment of a Different Approach Targeting the Pleckstrin Homology Domain

Novel Inhibitors of AKT: Assessment of a Different Approach Targeting the Pleckstrin Homology Domain, 2011, 18(18) Pp. 2727-2742
E. J. Meuillet

Protein kinase B/AKT plays a central role in cancer. The serine/threonine kinase is over-expressed or constitutively active in many cancers and has been validated as a therapeutic target for cancer treatment. However, targeting the kinase activity has revealed itself to be a challenge due to non-selectivity of the compounds towards other kinases. This review summarizes other approaches scientists have developed to inhibit the activity and function of AKT. They consist of targeting the pleckstrin homology (PH) domain of AKT. Indeed, upon the generation of 3-phosphorylated phosphatidylinositol phosphates (PI3Ps) by PI3-kinase (PI3K), AKT translocates from the cytosol to the plasma membrane and binds to the PI3Ps via its PH domain. Thus, several analogs of PI3Ps (PI Analogs or PIAs), alkylphospholipids (APLs), such as edelfosine, and inositol phosphates (IPs) have been described that inhibit the binding of the PH domain to PI3Ps. Recently allosteric inhibitors and small molecules that do not bind the kinase domain but affect the kinase activity of AKT, presumably by interacting with the PH domain, have also been identified. Finally, several drug screening studies spawned novel chemical scaffolds that bind the PH domain of AKT. Together, these approaches have been more or less successful in vitro and to some extent translated in preclinical studies. Several of these new AKT PH domain inhibitors exhibit promising anti-tumor activity in mouse models and some of them show synergy with ionizing radiation and chemotherapy. Early clinical trials have started and results will attest to the validity and efficacy of such approaches in the near future.

mTOR Inhibitors: Facing New Challenges Ahead

mTOR Inhibitors: Facing New Challenges Ahead, 2011, 18(18) Pp. 2743-2762
I. Mavrommati and T. Maffucci

The enzyme mammalian target of rapamycin (mTOR) is a master kinase that regulates several critical intracellular processes. It is now well established that this enzyme has a key role in cancer and its inhibition as therapeutic anti-cancer strategy is well recognised. Several clinical trials using mTOR inhibitors have been and are currently being performed. A huge scientific literature exists not only reporting the results of these trials but also discussing the reasons for the limited efficacy of strategies used so far and the need for new strategies to overcome the problem of resistance. The aim of this review is mainly to reflect on how the complexity of the mTOR-dependent signalling pathway and our difficulty to untangle it can ultimately affect the development of proper strategies to fully exploit the potential benefits of mTOR inhibition as anti-cancer strategy.

Targeting PDK1 in Cancer

Targeting PDK1 in Cancer, 2011, 18(18) Pp. 2763-2769
C. Raimondi and M. Falasca

Abnormal activation of phosphoinositide 3-kinase (PI3K) signalling is very common in cancer, leading to deregulation of several intracellular processes normally controlled by this enzyme, including cell survival, growth, proliferation and migration. Mutations in the gene encoding the tumour suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which leads to uncontrolled activation of the PI3K pathway, are reported in different cancers. Among the downstream effectors of PI3Ks, 3- phosphoinositide-dependent protein kinase 1 (PDK1) and protein kinase B (PKB)/Akt have a key role in several cancer types. More recent data indicate that alteration of PDK1 is a critical component of oncogenic PI3K signalling in breast cancer, suggesting that inhibition of PDK1 can inhibit breast cancer progression. PDK1 has an essential role in regulating cell migration especially in the context of PTEN deficiency. Downregulation of PDK1 levels inhibits migration and experimental metastasis of human breast cancer cells. PDK1 activates a large number of proteins, including Akt, some PKC isoforms, S6K and SGK. Data also reveal that PDK1 is oncogenic and this is dependent on PI3K pathway. Therefore, accumulating evidence demonstrates that PDK1 is a valid therapeutic target and suggests that PDK1 inhibitors may be useful to prevent cancer progression and abnormal tissue dissemination. This review will focus on published data on the role of PDK1 in cancer and approaches used to inhibit PDK1.

Novel Circular, Cyclic and Acyclic ψ(CH2O) Containing Peptide Inhibitors of SKI- 1/S1P: Synthesis, Kinetic and Biochemical Evaluations

Novel Circular, Cyclic and Acyclic ψ(CH2O) Containing Peptide Inhibitors of SKI- 1/S1P: Synthesis, Kinetic and Biochemical Evaluations, 2011, 18(18) Pp. 2770-2782
S. Majumdar, A. Chen, H. Palmer-Smith and A. Basak

Background: Subtilisin Kexin Isozyme-1 (SKI-1)/Site1Protease (S1P) is a Ca+2-dependent membrane bound pyrolysin-type serine protease of mammalian subtilase super family Proprotein Convertases (PCs)/Proprotein Convertase Subtilisin Kexins (PCSKs). It cleaves precursor proteins at the carboxy terminus of a non basic amino acid characterized by the sequence Arg/Lys--Φ-Leu/Ser/Thr↓, where = any amino acid except Cys, Φ = the alkyl side chain containing hydrophobic amino acid. SKI-1 cleaves pro-BDNF, pro- SREBP2, pro-ATF6, pro-somatostatin and viral glycoproteins to generate their active forms. As a result SKI-1 plays important roles in cartilage development, bone mineralization, cholesterol metabolism, fatty acid synthesis and infections caused by Arina viruses of hemorrhagic type. Interest has grown to develop inhibitors of SKI-1 that may find useful therapeutic and biochemical applications. Objective: Our objective is to develop small molecule inhibitors of SKI-1/S1P and study their kinetic and biochemical properties. Results: Peptide analogs were designed by inserting a protease resistant methylene-oxy (-CH2-O-) pseudoamide function at the cleavage site of 251Asp-Ile-Tyr-Ile-Ser-Arg-Arg-Leu-Leu↓Gly-Thr-Phe-Thr263, derived from SKI-1 processing site of Lassa virus glycoprotein. The synthesis was conducted by substituting Leu-Gly with previously made Leu-CH2-O-Gly. Flexible linear and conformationally constrained circular and disulphide bridged cyclic peptides were prepared by solid phase method. Circular and cyclic peptides inhibited SKI-1 more potently (Ki∼14-20 μM) than the corresponding acyclic peptide (Ki7sim;51 μM). They also blocked SKI-1-mediated processing of pro-h(human)SREBP2 into its mature form in HepG2 cells. Circular pseudopeptides designed from hATF6 and hSREBP2 also inhibited SKI-1. This is the first report of circular and cyclic Ψ(CH2-O) containing peptides as SKI-1 inhibitors with potential therapeutic applications in cholesterol synthesis.

Serotonin Receptors of Type 6 (5-HT6): What can we Expect from them?

Serotonin Receptors of Type 6 (5-HT6): What can we Expect from them?, 2011, 18(18) Pp. 2783-2790
D. Marazziti, S. Baroni, M. Catena Dell'Osso, F. Bordi and F. Borsini

The serotonin (5-HT) receptors of type 6 (5-HT6) are relatively new. They are quite different from all other 5-HT receptors, as they are characterized by a short third cytoplasmatic loop and a long C-terminal tail, and contain one intron located in the middle of the third cytoplasmatic loop. After some initial controversies, the available findings are now apparently more congruent. Nevertheless, discrepancies still exist, such as those in binding affinity, effects of 5-HT6 ligands on brain catecholamines and behavioral syndromes mediated by them. Much interest in 5-HT6 receptors was triggered by the evidence that some antipsychotics could bind to them. Subsequently, despite the lack of complete information on metabolic patterns of the various compounds, some of 5-HT6 receptor ligands entered the clinical development as potential anti-dementia, antipsychotic and anti-obese drugs. In any case, the available information on the pharmacology of 5-HT6 receptors is still quite scant. Therefore, with the present paper we aimed at reporting a comprehensive review on the status of art of the 5-HT6 receptors, while highlighting the potential clinical applications of 5-HT6 receptor agonists/antagonists.

Adenosine in the Inflamed Gut: A Janus Faced Compound

Adenosine in the Inflamed Gut: A Janus Faced Compound, 2011, 18(18) Pp. 2791-2815
A. B. Estrela and W.-R. Abraham

The purine ribonucleoside adenosine (Ado) has been recognized for its regulatory functions in situations of cellular stress like ischemia, hypoxia and inflammation. The importance of extracellular Ado as a modulator in the immune system is a theme of great appreciation and the focus of recent increasing interest in the field of gastrointestinal inflammation. In this review, the different aspects of Ado signaling during inflammatory responses in the gut are discussed, considering the contribution of the four known Ado receptors (ARs; A1, A2A, A2B, and A3), their mechanisms and expression patterns. Activation of these receptors in epithelial cells as well as in immune cells recruited to the inflamed intestinal mucosa determines the overall effect, ranging from a protective, anti-inflammatory modulation to a strong pro-inflammatory induction. Here we present the current advances in agonists and antagonists development and their potential therapeutic application studied in animal models of intestinal inflammation. In addition, alternative complementary approaches to manipulate such a complex signaling system are discussed, for example, the use of AR allosteric modulators or interference with Ado metabolism. Special features of the gut environment are taken into account: the contribution of diet components; the involvement of Ado in intestinal infections; the interactions with the gut microbiome, particularly, the recent exciting finding that an intestinal bacterium can directly produce extracellular Ado in response to host defense mechanisms in an inflammation scenario. Understanding each component of this dynamic system will broaden the possibilities for applying Ado signaling as a therapeutic target in gut inflammation.

Molecular Chaperone Hsp90 as a Target for Oxidant-Based Anticancer Therapies

Molecular Chaperone Hsp90 as a Target for Oxidant-Based Anticancer Therapies, 2011, 18(18) Pp. 2816-2825
R. Beck, N. Dejeans, C. Glorieux, R. C. Pedrosa, D. Vasquez, J. A. Valderrama, P. B. Calderon and J. Verrax

Hsp90 is a molecular chaperone involved in the stabilization of many oncoproteins that are required for the acquisition and maintenance of the so-called six major hallmarks of cancer cells. Various strategies have, therefore, been developed to inhibit the chaperone activity of Hsp90 and induce cancer cell death through the destabilization of its client proteins. Among these strategies, we have shown that generation of oxidative stress leads to the cleavage and deactivation of Hsp90. Because cancer cells are often deficient in antioxidant enzymes and exhibit higher basal levels of reactive oxygen species (ROS) than their normal counterparts, inducing a selective oxidative stress may be a promising approach for cancer treatment. Thus, many redox-modulating agents have, therefore, been developed or are undergoing clinical trials and Hsp90 represents a new target for oxidative stress-generating agents. The purpose of this article is to review the current state of knowledge about Hsp90 and the use of oxidative stress-generating agents in cancer treatment. We will illustrate the review with some of our results concerning the effects of oxidative stress on Hsp90 using various oxidative stress-generating systems based on different quinones in combination with a well-known reducing agent (i.e., ascorbate). Our results show that oxidative stress provokes the cleavage of Hsp90 in CML cells, as well as the degradation of its client protein Bcr-Abl and the deactivation of its downstream signaling pathways, namely MAPK and STAT5. Overall, these results highlight the potential interest of using oxidative stress to target Hsp90.

Editorial [Hot Topic:Methodologies and Applied Strategies in the Rational Drug Design (Guest Editor: T. Mavromoustakos)]

Editorial [Hot Topic:Methodologies and Applied Strategies in the Rational Drug Design (Guest Editor: T. Mavromoustakos)], 2011, 18(17) Pp. 2516-2516
T. Mavromoustakos

This special issue is dedicated to my former and inspired director of Institute of Organic and Pharmaceutical Chemistry of the National Hellenic Research Foundation Dr. N. Oikonomakos who left this short life early. It is also dedicated to the scientists who use the research amour for advancing our knowledge in the treatment of major diseases and rationalize the drug design. Both experimentalists and theoreticians join their efforts in a complementary and hopefully in a successful way to achieve a common research aim: to develop newer, safer and more effective drugs. Various interesting topics related to the rational drug design are covered in this special issue including: the use of multitarget drugs specifically on the cardiovascular system; the future of aldo-keto reductase AKRIC1-AKRIC4, CRF and PLA2 inhibitors; the develop of pharmacophore modeling and virtual screening strategies as well as the combination of x-ray diffraction, molecular docking and 3D QSAR methodologies for the advancement of rational drug design. I believe that this issue covers interesting approaches in the drug discovery and provides valuable information for those scientists working in the field of drug rational design. In addition, the reader will find interesting information in a condensed matter for the trends to tackle major diseases such as cardiovascular, cancer, inflammation,diabetes,depression and anxiety.

Strategies in the Rational Drug Design

Strategies in the Rational Drug Design, 2011, 18(17) Pp. 2517-2530
T. Mavromoustakos, S. Durdagi, C. Koukoulitsa, M. Simcic, M. G. Papadopoulos, M. Hodoscek and S. Golic Grdadolnik

Rational design is applied in the discovery of novel lead drugs. Its rapid development is mainly attributed to the tremendous advancements in the computer science, statistics, molecular biology, biophysics, biochemistry, medicinal chemistry, pharmacokinetics and pharmacodynamics experienced in the last few decades. The promising feature that characterizes the application of rational drug design is that it uses for developing potential leads in drug discovery all known theoretical and experimental knowledge of the system under study. The utilization of the knowledge of the molecular basis of the system ultimately aims to reduce human power cost, time saving and laboratory expenses in the drug discovery. In this review paper various strategies applied for systems which include: (i) absence of knowledge of the receptor active site; (ii) the knowledge of a homology model of a receptor, (iii) the knowledge of the experimentally determined (i.e. X-ray crystallography, NMR spectroscopy) coordinates of the active site of the protein in absence and (iv) the presence of the ligand will be analyzed.

Multitarget Cardiovascular Drugs

Multitarget Cardiovascular Drugs, 2011, 18(17) Pp. 2531-2542
U. Trstenjak and D. Kikelj

Cardiovascular disease is the number one cause of death globally. Design of cardiovascular drugs based on new paradigms is therefore a prominent goal of medicinal chemistry. Designed multiple ligands, targeting two or more proteins involved in pathogenesis of disease have become a viable concept in drug discovery. Although adjustment of the activities ratio at the different targets is a demanding and challenging task, modulation of two or more targets involved in a cardiovascular disease may be more successful for therapeutic application than treatment directed against each target alone, because of improved pharmacodynamic and pharmacokinetic properties of designed multitarget drugs. The article reviews the applications of multitarget approach to cardiovascular drug design, covering angiotensin-converting enzyme/neutral endopeptidase inhibitors, neutrale endopeptidase/endothelin-converting enzyme inhibitors, angiotensin-converting enzyme/neutral endopeptidase/endothelin-converting enzyme inhibitors, dual angiotensin/endothelin receptor and angiotensin1/angotensin2 receptor antagonists and angiotensin receptor antagonist/neutral endopeptidase inhibitors.

Pharmacophore Modelling: A Forty Year Old Approach and its Modern Synergies

Pharmacophore Modelling: A Forty Year Old Approach and its Modern Synergies, 2011, 18(17) Pp. 2543-2553
F. Caporuscio and A. Tafi

A pharmacophore represents a simple and intuitive concept that can be used in many different drug discovery applications. Ligand-based and structure-based pharmacophore models continue to play a pivotal role in hit discovery and may guide lead optimization. Moreover, owing to the versatility of the pharmacophore concept, pharmacophore modelling has been routinely used in combination with other molecular modelling techniques. The synergistic use of different tools in drug discovery workflows may allow to fully exploit the advantages, while compensating for some of the intrinsic limitations, of each methodology. This review will focus on the synergistic combination of pharmacophore modelling with other molecular modelling approaches such as the hot spot analysis of protein binding sites, molecular dynamics, and docking.

Inhibitors of Aldo-Keto Reductases AKR1C1-AKR1C4

Inhibitors of Aldo-Keto Reductases AKR1C1-AKR1C4, 2011, 18(17) Pp. 2554-2565
P. Brozic, S. Turk, T. Lanisnik Rizner and S. Gobec

The AKR1C aldo-keto reductases (AKR1C1-AKR1C4) are enzymes that interconvert steroidal hormones between their active and inactive forms. In this manner, they can regulate the occupancy and trans-activation of the androgen, estrogen and progesterone receptors. The AKR1C isoforms also have important roles in the production and inactivation of neurosteroids and prostaglandins, and in the metabolism of xenobiotics. They thus represent important emerging drug targets for the development of agents for the treatment of hormone-dependent forms of cancer, like breast, prostate and endometrial cancers, and other diseases, like premenstrual syndrome, endometriosis, catamenial epilepsy and depressive disorders. We present here the physiological roles of these enzymes, along with their structural properties and an overview of the recent developments regarding their inhibitors. The most important strategies of inhibitor design are described, which include the screening of banks of natural compounds (like cinnamic acids, flavonoids, jasmonates, and related compounds), the screening of and structural modifications to non-steroidal anti-inflammatory drugs, the substrate-inspired design of steroidal and nonsteroidal inhibitors, and computer-assisted structure-based inhibitor design.

The Application of Rational Design on Phospholipase A2 Inhibitors

The Application of Rational Design on Phospholipase A2 Inhibitors, 2011, 18(17) Pp. 2566-2582
V. D. Mouchlis, E. Barbayianni, T. M. Mavromoustakos and G. Kokotos

The phospholipase A2 (PLA2) superfamily consists of different groups of enzymes which are characterized by their ability to catalyze the hydrolysis of the sn-2 ester bond in a variety of phospholipid molecules. The products of PLA2s activity play divergent roles in a variety of physiological processes. There are four main types of PLA2s: the secreted PLA2s (sPLA2s), the cytosolic PLA2s (cPLA2s), the calcium-independent PLA2s (iPLA2) and the lipoprotein-associated PLA2s (LpPLA2s). Various potent and selective PLA2 inhibitors have been reported up to date and have provided outstanding support in understanding the mechanism of action and elucidating the function of these enzymes. The current review focuses on the implementation of rational design through computer-aided drug design (CADD) on the discovery and development of new PLA2 inhibitors.

Members of CRF Family and their Receptors: From Past to Future

Members of CRF Family and their Receptors: From Past to Future, 2011, 18(17) Pp. 2583-2600
G. Liapakis, M. Venihaki, A. Margioris, D. Grigoriadis and K. Gkountelias

Corticotropin releasing factor (CRF), originally isolated from the mammalian hypothalamus, is a 41 amino acid peptide that plays an important physiological role and is implicated in the pathophysiology of various diseases. In addition to CRF and its related peptides, a large number of small non-peptide CRF analogs have been recently synthesized, some currently in clinical trials having considerable therapeutic potential in the treatment of CRF-related illnesses. CRF and its related peptides exert their multiple actions by interacting with two types of plasma membrane G-protein coupled CRF receptors, the type 1 (CRF1) and type 2 (CRF2). These receptors, like all GPCRs consist of an amino-terminal extracellular region, a carboxyl-terminal intracellular tail and seven, membrane-spanning segments, connected by alternating intracellular and extracellular loops. This review describes the functional role of CRF receptors and their ligands emphasizing the structural elements that are important for their function and could potentially contribute in the development of future target-based approaches to design new CRF-related drugs which will enrich the pharmaceutical armoire against serious diseases.

Atomistic Models for Free Energy Evaluation of Drug Binding to Membrane Proteins

Atomistic Models for Free Energy Evaluation of Drug Binding to Membrane Proteins, 2011, 18(17) Pp. 2601-2611
S. Durdagi, C. Zhao, J. E. Cuervo and S. Y. Noskov

The binding of various molecules to integral membrane proteins with optimal affinity and specificity is central to normal function of cell. While membrane proteins represent about one third of the whole cell proteome, they are a majority of common drug targets. The quest for the development of computational models capable of accurate evaluation of binding affinities, decomposition of the binding into its principal components and thus mapping molecular mechanisms of binding remains one of the main goals of modern computational biophysics and related drug development. The primary scope of this review will be on the recent extension of computational methods for the study of drug binding to membrane proteins. Several examples of such applications will be provided ranging from secondary transporters to voltage gated channels. In this mini-review, we will provide a short summary on the breadth of different methods for binding affinity evaluation. These methods include molecular docking with docking scoring functions, molecular dynamics (MD) simulations combined with post-processing analysis using Molecular Mechanics/Poisson Boltzmann (Generalized Born) Surface Area (MM/PB(GB)SA), as well as direct evaluation of free energies from Free Energy Perturbation (FEP) with constraining schemes, and Potential of Mean Force (PMF) computations. We will compare advantages and shortcomings of popular techniques and provide discussion on the integrative strategies for drug development aimed at targeting membrane proteins.

Ligand and Structure Based Virtual Screening Strategies for Hit-Finding and Optimization of Hepatitis C Virus (HCV) Inhibitors

Ligand and Structure Based Virtual Screening Strategies for Hit-Finding and Optimization of Hepatitis C Virus (HCV) Inhibitors, 2011, 18(17) Pp. 2612-2619
G. Melagraki and A. Afantitis

Virtual Screening (VS) has experienced increased attention into the recent years due to the large datasets made available, the development of advanced VS techniques and the encouraging fact that VS has contributed to the discovery of several compounds that have either reached the market or entered clinical trials. Hepatitis C Virus (HCV) nonstructural protein 5B (NS5B) has become an attractive target for the development of antiviral drugs and many small molecules have been explored as possible HCV NS5B inhibitors. In parallel with experimental practices, VS can serve as a valuable tool in the identification of novel effective inhibitors. Different techniques and workflows have been reported in literature with the goal to prioritize possible potent hits. In this context, different virtual screening strategies have been deployed for the identification of novel Hepatitis C Virus (HCV) inhibitors. This work reviews recent applications of virtual screening in an effort to identify novel potent HCV inhibitors.

From Structure Based to Knowledge Based Drug Design Through X-Ray Protein Crystallography: Sketching Glycogen Phosphorylase Binding Sites

From Structure Based to Knowledge Based Drug Design Through X-Ray Protein Crystallography: Sketching Glycogen Phosphorylase Binding Sites, 2011, 18(17) Pp. 2620-2629
E. D. Chrysina, A. Chajistamatiou and M. Chegkazi

The knowledge derived from the three-dimensional structure of a macromolecular receptor either in the native form or in complex with different ligands has given new insights to the development of improved drug candidates contributing to the drug development pipeline. The structure-based drug design approach has been tested on a number of macromolecular targets implicated in various diseases such as hypertension, glaucoma, HIV and influenza. This approach has also been employed for the development of new antidiabetic agents targeting glycogen phosphorylase (GP), an enzyme that modulates glucose levels in blood circulation. The key role of x-ray protein crystallography in the structure-based inhibitor design process is presented by the case of rabbit muscle GP (RMGPb) that shares increased homology with the liver isoenzyme. The properties of the allosteric binding sites of RMGPb are revealed by filing the interactions formed upon binding of characteristic functional groups and documenting the changes induced in the residues lining the site of interest.

Aluminum Vaccine Adjuvants: Are they Safe?

Aluminum Vaccine Adjuvants: Are they Safe?, 2011, 18(17) Pp. 2630-2637
L. Tomljenovic and C. A. Shaw

Aluminum is an experimentally demonstrated neurotoxin and the most commonly used vaccine adjuvant. Despite almost 90 years of widespread use of aluminum adjuvants, medical science's understanding about their mechanisms of action is still remarkably poor. There is also a concerning scarcity of data on toxicology and pharmacokinetics of these compounds. In spite of this, the notion that aluminum in vaccines is safe appears to be widely accepted. Experimental research, however, clearly shows that aluminum adjuvants have a potential to induce serious immunological disorders in humans. In particular, aluminum in adjuvant form carries a risk for autoimmunity, long-term brain inflammation and associated neurological complications and may thus have profound and widespread adverse health consequences. In our opinion, the possibility that vaccine benefits may have been overrated and the risk of potential adverse effects underestimated, has not been rigorously evaluated in the medical and scientific community. We hope that the present paper will provide a framework for a much needed and long overdue assessment of this highly contentious medical issue.

Amphiphilic Polysaccharide-Hydrophobicized Graft Polymeric Micelles for Drug Delivery Nanosystems

Amphiphilic Polysaccharide-Hydrophobicized Graft Polymeric Micelles for Drug Delivery Nanosystems, 2011, 18(17) Pp. 2638-2648
Y. Liu, J. Sun, P. Zhang and Z. He

Self-assembled amphiphilic graft copolymers in aqueous solution to form polymeric micelles, have received growing scientific attention over the years. Among the polymeric micelles, hydrophobicized polysaccharides have currently become one of the hottest researches in the field of drug delivery nanosystems. It is attributable to such appealing properties as small particle size and narrow size distribution, distinctive core-shell structure, high solubilization capacity and structural stability, tumor passive localization by enhanced permeability and retention (EPR) effect, active targeting ability via tailored targeting promoiety, long-circulation property and facile preparation. The polymeric micelles self-assembled by hydrophobicized polysaccharides can be employed as targeted drug delivery nanosystem by including thermo- or pH-sensitive components or by attaching specific targeted moieties to the outer hydrophilic surface. Beside encapsulation of water-insoluble drugs, hydrophobicized polysaccharide polymeric micelles can complex with charged proteins or peptide drugs through electrostatic force or hydrogen bond, and serve as an effective non-viral vector for gene delivery. In the latter case, polymeric micelles can not only markedly protect these macromolecules from degradation by protease or ribozymes, but also increase the gene transfection efficiency. This review will highlight the state of the art self-assembled mechanism, characterization, preparation methods and surface modification of hydrophobicized polysaccharide polymeric micelles and their recent rapid applications as drug delivery nanosystems.

Retroviral Restriction Factors TRIM5α: Therapeutic Strategy to Inhibit HIV-1 Replication

Retroviral Restriction Factors TRIM5α: Therapeutic Strategy to Inhibit HIV-1 Replication, 2011, 18(17) Pp. 2649-2654
Jing Zhang, Weiying Ge, Peng Zhan, Erik De Clercq and Xinyong Liu

Tripartite motif protein 5-alpha (TRIM5α) is a cytoplasmic protein that efficiently recognizes the incoming capsid (CA) protein of retroviruses and potently inhibits virus infection in a species-specific manner. Through directly recognizing and interacting with HIV CA, TRIM5α is capable of disrupting the ordered process of viral uncoating, eventually interfering with HIV-1 reverse transcription and virus replication. TRIM5α protein contains four domains: RING domain, B-box 2 domain, coiled-coil domain, and B30.2 domain (SPRY) domain. All of the domains are necessary for efficient retrovirus restriction and the B30.2 domain has been shown to be the determinant of the specificity of restriction. Species-specific innate resistance against viral infections offers novel avenues for antiviral therapeutics. Various mutants of TRIM5α have been described which differently affect the HIV-1 reverse transcription process. This makes the establishment of new and improved models for HIV replication and AIDS pathogenesis by monitoring endogenous TRIM5α an attractive approach. TRIM5α-mediated restriction is modulated by the host protein Cyclophilin A (Cyp A) which could effectively interact with the CA of HIV-1. Here we will review the structure and roles of TRIM5α protein, the interaction between Cyp A and TRIM5α, as well as gene therapy strategies associated with TRIM5α to inhibit HIV-1 infection.

Genetic Bases of Progressive Supranuclear Palsy: The MAPT Tau Disease

Genetic Bases of Progressive Supranuclear Palsy: The MAPT Tau Disease, 2011, 18(17) Pp. 2655-2660
Barbara Borroni, Chiara Agosti, Enrico Magnani, Monica Di Luca and Alessandro Padovani

Progressive Supranuclear Palsy (PSP) is a progressive neurodegenerative syndrome characterized by supranuclear palsy, postural instability, and mild dementia. Neuropathologically, PSP is a four-repeat tauopathy, defined by the accumulation of neurofibrillary tangles and tufted astrocytes. Etiology remains elusive, but genetic background has a key-role in the disease pathogenesis. Recent studies have reported high familial aggregation in PSP patients, and it has been widely demonstrated that Microtuble Associated Protein Tau (MAPT) gene mutations are causative of monogenic autosomal dominant PSP. In sporadic cases, genetic advances have further confirmed the role of MAPT in increasing disease risk, and the H1 MAPT haplotype has been consistently associated with PSP, while the H2 haplotype seems protective. Conversely, no major environmental risk factors have been reported so far. A proper evaluation of known susceptibility factors related to PSP pathogenesis may help in defining neuroprotective therapeutic approaches.

Flavonoids as Promising Lead Compounds in Type 2 Diabetes Mellitus: Molecules of Interest and Structure-Activity Relationship

Flavonoids as Promising Lead Compounds in Type 2 Diabetes Mellitus: Molecules of Interest and Structure-Activity Relationship, 2011, 18(17) Pp. 2661-2672
E. Nicolle, F. Souard, P. Faure and A. Boumendjel

There is evidence that hyperglycemia results in the generation of reactive oxygen species, leading to oxidative stress in various tissues, including vascular system. An important link between oxidative stress, inflammatory response and insulin activity is now well established. The ability of antioxidants to protect against the deleterious effects of hyperglycemia and also to improve glucose metabolism and intake must be considered as leads of choice in diabetes treatment. In addition to their antioxidative activity, many flavonoids were demonstrated to act on biological targets involved in type 2 diabetes mellitus such as: α-glycosidase, glucose cotransporter or aldose reductase. In this context, flavonoids behaving as antioxidants were studied as potential drugs by acting as biological targets involved in diabetes development. In this review, we propose to shed light on antioxidants flavonoids investigated as antidiabetics. A special focus was made to address the structure-activity relationship related to the effect of these naturally occurring molecules on different targets involved in diabetes development.

STAT-3 Inhibitors: State of the Art and New Horizons for Cancer Treatment

STAT-3 Inhibitors: State of the Art and New Horizons for Cancer Treatment, 2011, 18(16) Pp. 2359-2375
A. Lavecchia, C. Di Giovanni and E. Novellino

The signal transducers and activators of transcription (STATs) include a class of cytoplasmic signaling proteins whose role in the regulation of cell growth and survival is mediated by phosphorylation of a critical tyrosine residue within the STAT protein. This occurs in response to cytokines and growth factors modulating the expression of specific target genes. In particular, phosphorylation induces STAT:STAT dimer formation between two monomers, via reciprocal phosphoTyr (pTyr)-SH2 domain interactions. To date, seven members of the STAT family, all with different roles, have been identified in mammals. After dimerization, phosphorylated STATs enter the nucleus and, working co-ordinately with other transcriptional co-activators and transcription factors, induce increased transcriptional initiation. In healthy human and animal cells, ligand-dependent activation of STATs is a transient process, lasting for several minutes to several hours. In contrast, in many cancerous cell lines and tumors, where growth factor dysregulation is frequently at the heart of cellular transformation, the STAT proteins (in particular STAT1, 3 and 5) are persistently tyrosine-phosphorylated or activated; abnormal levels of STAT3 activation have been observed in breast, ovarian, prostate, hematological and head and neck cancer cell lines. Thus, in this review, we examine the most important classes of agents designed to disrupt STAT3 signaling, with particular regard to STAT3 dimerization inhibitors, which could play a significant role in the future of cancer and adjuvant cancer therapies.

Recent Advances in the DABOs Family as Potent HIV-1 non-Nucleoside Reverse Transcriptase Inhibitors

Recent Advances in the DABOs Family as Potent HIV-1 non-Nucleoside Reverse Transcriptase Inhibitors, 2011, 18(16) Pp. 2376-2385
Mingyan Yu, Erkang Fan, Jingde Wu and Xinyong Liu

HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind to an allosteric site on reverse transcriptase (RT) and are a key component of highly active anti-retroviral therapy (HAART) combination regimen for clinical treatment of HIV/AIDS. However, the rapid emergence of drug resistance has limited NNRTIs' clinical option. Therefore, there is an urgent need for the design and development of new and safe NNRTIs that are specifically active against drug-resistant viral strains. DABOs family is one representative of the reported potent HIV-1 NNRTIs, with robust anti-HIV-1 activity against both the wild-type (wt) and drug-resistant isolates carrying multiple RT gene mutations. Three generations of DABO analogues have been studied up to now, i.e.: dihydroalkyloxybenzyloxopyrimidines (O-DABOs), dihydroalkylthiobenzyloxopyrimidines (S-DABOs) and dihydroalkylaminodifluorobenzyloxopyrimidines (N-DABOs), from which many promising DABOs are under developed. The recent research of the DABOs family in antiviral activity, structure activity relationships (SAR), and interaction model with the HIV-1 RT are reviewed in this paper.

Interactions Between Clopidogrel and Proton Pump Inhibitors: A Review of Evidence

Interactions Between Clopidogrel and Proton Pump Inhibitors: A Review of Evidence, 2011, 18(16) Pp. 2386-2400
C. Munoz-Esparza, E. Jover, D. Hernandez-Romero, D. Saura, M. Valdes, G. Y.H. Lip and F. Marin

Clopidogrel is a thienopyridine, which inhibits the platelet P2Y adenosine diphosphate (ADP) receptor termed P2Y12. It is taken as a prodrug that requires biotransformation to an active metabolite by cytochrome P450 (CYP) isoenzymes. In addition, esterases shunt the majority of clopidogrel to an inactive pathway, whilst the remaining prodrug requires two separate CYP-dependent oxidative steps. PPIs might diminish the antiplatelet effects and the clinical effectiveness of clopidogrel possibly through inhibition of CYP2C19 and CYP3A4 isoenzymes. Treatment with clopidogrel and aspirin decreases recurrent cardiovascular events after an acute coronary syndrome. However, an inherent increment of major bleeding is also associated with antiplatelet therapy, as well as dyspepsia with aspirin. Also, major bleeding has been associated with high risk for ischemic events and mortality. For this reason, a proton pump inhibitor (PPI) is often co-prescribed to reduce the risk of gastrointestinal tract bleeding, but its concomitant use might reduce the inhibitory effect of clopidogrel on platelet aggregation. Nevertheless, doubts exist about the possible interaction of concomitant PPI use that may reduce the inhibitory effect of clopidogrel on platelet aggregation. Indeed, there is some controversy with regard to the true risk of cardiovascular adverse events arising from a potential drug-drug interaction between clopidogrel and PPI. In this article, we will review the current status and controversies in relation to a possible interaction between clopidogrel and PPIs.

Aspartic Protease Inhibitors as Potential Anti-Candida albicans Drugs: Impacts on Fungal Biology, Virulence and Pathogenesis

Aspartic Protease Inhibitors as Potential Anti-Candida albicans Drugs: Impacts on Fungal Biology, Virulence and Pathogenesis, 2011, 18(16) Pp. 2401-2419
L. A. Braga-Silva and A. L.S. Santos

Mycoses are still one of the most problematic illnesses worldwide, especially affecting immunocompromised individuals. The development of novel antifungal drugs is becoming more demanding every day, since existing drugs either have too many side effects or they tend to lose effectiveness due to the resistant fungal strains. In this scenario, Candida albicans is still the main fungal pathogen isolated in hospitals. Pathogenicity results essentially from modifications of the host defense mechanisms that secondarily initiate transformations in the fungal behavior. The pathogenesis of C. albicans is multifactorial and different virulence attributes are important during the various stages of infection. Some virulence factors, like the secreted aspartic proteases (Saps), play a role in several infection stages and the inhibition of one of the many stages may contribute to the containment of the pathogen and thus should help in the treatment of disease. Therefore, Saps are potential targets for the development of novel anti-C. albicans drugs. Herein, we review the beneficial properties of pepstatin A and aspartic-type protease inhibitors used in the anti-human immunodeficiency virus chemotherapy on C. albicans, with particular emphasis in the effects on Sap activity, proliferation, morphogenesis (yeasts into mycelia transformation), ultrastructural architecture, adhesion to mammalian cells and abiotic materials, modulation of unrelated virulence factors (e.g., surface glycoconjugates, lipases and sterol), experimental candidiasis infection as well as synergistic properties when conjugated with classical antifungals. Collectively, these positive findings have stimulated the search for novel natural and/or synthetic pharmacological compounds with anti-aspartic protease properties against the human opportunistic fungus C. albicans.

Non-Peptidic α-Helical Mimetics as Protein-Protein Interaction Inhibitors

Non-Peptidic α-Helical Mimetics as Protein-Protein Interaction Inhibitors, 2011, 18(16) Pp. 2420-2428
M. B. Dewal and S. M. Firestine

Protein-protein interactions play a major role in almost all biological pathways and thus, these interactions have a profound impact on the pathogenesis of diseases. The ability to modulate protein-protein interactions with small molecules is an important and rapidly growing area in the field of medicinal chemistry. One of the most common secondary protein structures that are involved in protein-protein interactions are α-helices. Thus, a common approach towards developing inhibitors of protein-protein interactions is to design non-peptidic small molecules that mimic the spatial orientations of the side chains of an α-helix. In this review, we will discuss a variety of small molecules including terephenyls, terephthalamides, benzamides, enaminones, benzoylureas, pyridines, imidazoles, thiazoles, pyridazines, piperazines, oxopiperazines and diphenylindanes that have been published from 2005-2010 as small molecule α- helical mimetics.

Branched Peptides for the Modulation of Protein-Protein Interactions: More Arms are Better than One?

Branched Peptides for the Modulation of Protein-Protein Interactions: More Arms are Better than One?, 2011, 18(16) Pp. 2429-2437
M. Ruvo, A. Sandomenico, L. Tudisco and S. De Falco

Combinatorial peptide libraries from synthetic or biological sources have been largely used in the last two-decades with the aim of identifying bioactive peptides that specifically bind proteins and modulate their interactions with other protein partners. Differently from biological libraries, synthetic methods allow the development of different kinds of libraries based on two main characteristics: i) the use of building blocks and chemical bonds different from those naturally occurring and ii) the possibility of designing scaffolds with non-linear shapes, as cyclic and branched structures. These two features, alone or in combination, have increased the chemical and structural diversity of peptide libraries expanding the offer of collections for the screenings. Here we describe our and other experiences with branched peptides and the results obtained in the last fifteen years. These clearly indicate how the use of short multimerized peptides can represent a successful approach for different applications ranging from affinity chromatography to the modulation of protein-protein interactions in different biological contexts.

Recent Developments in the Synthesis and Biological Activity of Muramylpeptides

Recent Developments in the Synthesis and Biological Activity of Muramylpeptides, 2011, 18(16) Pp. 2438-2451
K. Dzierzbicka, A. Wardowska and P. Trzonkowski

Derivatives of muramyl dipeptide (MDP) are considered as immunostimulants and adjuvants in the immunotherapy of cancer and infections. The interest in these compounds is mainly related to a high variety of their structure and biological properties. Here, we describe the synthesis and biological activity of several recently developed classes of MDP analogues. We also report potential of these analogues in the treatment of cancer and infectious diseases in experimental systems and cancer patients.

Regional Grey Matter Loss and Brain Disconnection Across Alzheimer Disease Evolution

Regional Grey Matter Loss and Brain Disconnection Across Alzheimer Disease Evolution, 2011, 18(16) Pp. 2452-2458
M. Bozzali, A. Padovani, C. Caltagirone and B. Borroni

It is becoming increasingly clearer that the clinical manifestations of Alzheimer's disease (AD) are not only associated with regional grey matter (GM) damage, but also with abnormal integration between cortical brain regions by disconnection mechanism. This concept comes from the evidence that white matter (WM) damage (as assessed by diffusion MR imaging) can be observed in patients with AD since the early clinical stages, and it correlates with clinical measures of cognitive disability. In this perspective, several functional imaging studies, based on PET and resting state fMRI, have provided evidence that brain hypometabolism/disconnection may precede the occurrence of GM atrophy in certain regions of AD brains, such as the cingulate cortex. The cingulum represents the most prominent WM tract of the limbic system, being directly connected to the medial temporal lobe structures. Therefore, this structure likely contributes to changes in functional connectivity observed within the so called default-mode network of AD patients, and its damage is likely to play a remarkable role in the conversion from mild cognitive impairment (MCI) to dementia. Nowadays, the combination of several neuroimaging techniques that provide both, measures of regional GM loss and measures of functional and structural connectivity offer the opportunity to investigate in vivo the pathophysiological changes of brain tissue modifications across the clinical evolution of AD. This paper reviews the main MR based methods of investigation of brain tissue involvement in patients with AD and MCI, and the role they have played in clarifying the differential contribution of GM damage and brain disconnection to AD pathophysiology. This subject seems to be relevant for both, speculative aspects of neurology and application to clinical trials.

Removing Protein Aggregates: The Role of Proteolysis in Neurodegeneration

Removing Protein Aggregates: The Role of Proteolysis in Neurodegeneration, 2011, 18(16) Pp. 2459-2476
D. A.T. Nijholt, L. De Kimpe, H. L. Elfrink, J. J.M. Hoozemans and W. Scheper

A common characteristic of neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD) is the accumulation of protein aggregates. This reflects a severe disturbance of protein homeostasis, the proteostasis. Here, we review the involvement of the two major proteolytic machineries, the ubiquitin proteasome system (UPS) and the autophagy/lysosomal system, in the pathogenesis of neurodegenerative diseases. These proteolytic systems cooperate to maintain the proteostasis, as is indicated by intricate cross talk. In addition, the UPS and autophagy are regulated by stress pathways that are activated by disturbed proteostasis, like the unfolded protein response (UPR). We will specifically discuss how these proteolytic pathways are affected in neurodegenerative diseases. We will show that there is a differential involvement of the UPS and autophagy in different neurodegenerative disorders. In addition, the proteolytic impairment may be primary or secondary to the pathology. These differences have important implications for the design of therapeutic strategies. The opportunities and caveats of targeting the UPS and autophagy/lysosomal system as a therapeutic strategy in neurodegeneration will be discussed.

Posttranslational Modifications as Versatile Regulators of Parkin Function

Posttranslational Modifications as Versatile Regulators of Parkin Function, 2011, 18(16) Pp. 2477-2485
E. Rubio de la Torre, P. Gomez-Suaga, M. Martnez-Salvador and S. Hilfiker

Parkin functions as an E3 ubiquitin ligase that monoubiquitylates and polyubiquitylates proteins to regulate a variety of cellular processes. It appears that parkin functions as a multipurpose neuroprotectant in a number of toxic paradigms, and loss of parkin's E3 ligase activity seems to play a pathogenic role in both inherited and sporadic Parkinson's disease (PD). Increasing evidence indicates that posttranslational modifications play a major role in regulating parkin's catalytic activity, solubility, substrate selection or subcellular localization. As some of these modification events are subject to pharmacological interventions, these findings may allow for new approaches in preventing or delaying PD onset and/or progression. Here, we review how posttranslational modifications can regulate this unique multifaceted ubiquitin ligase which plays a crucial role for the survival of dopaminergic neurons.

Mechanisms of Resistance to Photodynamic Therapy

Mechanisms of Resistance to Photodynamic Therapy, 2011, 18(16) Pp. 2486-2515
A. Casas, G. Di Venosa, T. Hasan and Al. Batlle

Photodynamic therapy (PDT) involves the administration of a photosensitizer (PS) followed by illumination with visible light, leading to generation of reactive oxygen species. The mechanisms of resistance to PDT ascribed to the PS may be shared with the general mechanisms of drug resistance, and are related to altered drug uptake and efflux rates or altered intracellular trafficking. As a second step, an increased inactivation of oxygen reactive species is also associated to PDT resistance via antioxidant detoxifying enzymes and activation of heat shock proteins. Induction of stress response genes also occurs after PDT, resulting in modulation of proliferation, cell detachment and inducing survival pathways among other multiple extracellular signalling events. In addition, an increased repair of induced damage to proteins, membranes and occasionally to DNA may happen. PDT-induced tissue hypoxia as a result of vascular damage and photochemical oxygen consumption may also contribute to the appearance of resistant cells. The structure of the PS is believed to be a key point in the development of resistance, being probably related to its particular subcellular localization. Although most of the features have already been described for chemoresistance, in many cases, no cross-resistance between PDT and chemotherapy has been reported. These findings are in line with the enhancement of PDT efficacy by combination with chemotherapy. The study of cross resistance in cells with developed resistance against a particular PS challenged against other PS is also highly complex and comprises different mechanisms. In this review we will classify the different features observed in PDT resistance, leading to a comparison with the mechanisms most commonly found in chemo resistant cells.

Editorial [Hot Topic: IDO1, Cancer and Cancer-Associated Inflammation (Guest Editor: Sergio Rutella)]

Editorial [Hot Topic: IDO1, Cancer and Cancer-Associated Inflammation (Guest Editor: Sergio Rutella)], 2011, 18(15) Pp. 2204-2204
Sergio Rutella

Indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan-catabolizing enzyme expressed by professional antigen presenting cells such as dendritic cells (DC) or by a variety of cell types at sites of inflammation. IDO1 has been implicated in the development of immune tolerance to tumors. It is likely that IDO1 is not the only immune regulatory molecule but it is part of a more complex network of interactions and regulatory pathways that are operational in the DC compartment and possibly in other cell types. The biochemical properties of IDO1 are addressed in the first article, from Dr. Lancellotti and co-workers, which extensively covers the structural and functional properties of the enzyme, with a view to the development of novel inhibitor molecules. They also provide a thorough discussion of the ”ideal” inhibitor of IDO1, based on our current knowledge of the structural elements responsible for the optimal interaction with the catalytic site of IDO1. Dr. Fallarino and Dr. Grohmann discuss the contribution of IDO1 to the generation of regulatory T cells (Treg), a T-cell subset with remarkable plasticity that has attracted much attention over the last years. They also address the relative contribution of tryptophan starvation and kynurenine production to the amplification of Treg cells and, even more intriguingly, they focus on the inter-relations and interconversions between Treg cells and Th17, a recently described T-cell subset with pro-inflammatory actions. These data open a fascinating scenario and point to IDO1 as a molecular mechanism controlling the adaptability of Treg cells and ultimately dictating the balance between immunity and tolerance. Articles in this Issue also impart essential information on IDO1 expression and regulation in the antigen-presenting cell compartment. Dr. Heitger and Dr. Trabanelli provide us with an overview of the mechanisms that control IDO1 transcription and expression in human DC. The Authors also discuss the implications of the pharmacological manipulation of IDO1 activity in pertinent clinical scenarios such as cancer, hematopoietic stem cell transplantation and autoimmunity. Dr. Munn reviews the current evidence interconnecting the IDO pathway with Treg biology. As clearly stated in this paper, IDO is likely to represent a crucial regulatory checkpoint that controls the differentiation of nave T cells into Treg cells, the activation of mature, preexisting Treg cells and the inflammation-induced conversion of Treg cells into pro-inflammatory T helper-like cells, a phenomenon termed “reprogramming”. These are important advances in our understanding of Treg-mediated suppression in cancer, also in view of the successful application of IDO-inhibitor drugs to the clinic. Moving to the role of IDO1 in infectious diseases, Dr. Boasso provides a close analysis of the down-stream effects of IDO over-activation on the immune alterations that characterize HIV disease. This review examines the mechanisms of IDO1 induction during HIV infection and discusses how IDO1 contributes to HIV immunopathogenesis through the inhibition of T-cell responses, the alteration of the Th1/Th2 balance, and the generation of Treg cells at sites of active viral replication. This knowledge opens exciting therapeutic perspectives aimed at inhibiting the IDO pathway in HIV-infected patients. Dr. Prendergast and co-workers present a discussion on IDO1 as a regulator of cancer-associated inflammation rather than simply a suppressor of immune function. IDO1 can also be viewed as a candidate molecule to define cancer-associated inflammation as it is distinguished from chronic inflammatory states that are not associated with cancer. The Authors offer a new perspective whereby IDO1 activity defines a state that can support, or in some cases antagonize, disease development and progression. On a related point, Dr. Cesario and co-workers discuss the inter-connections between IDO1 and cyclooxygenase (COX)-2, an enzyme involved in the biosynthesis of prostanoids. COX-2-derived prostaglandins contribute to inflammation and induce IDO1 as well as Treg activity, potentially driving cancer-associated immune suppression. Selective COX-2 inhibitors reduce IDO1 protein levels and augment the efficacy of anti-tumor DC-based vaccines, thus pointing to this class of drugs as potential modulators of IDO1 function in vivo. In conclusion, this Issue introduces the most recent findings and advances on IDO1 expression and regulation in diverse clinical settings, including chronic inflammation, HIV infection and cancer. Importantly, IDO inhibitor drugs have now entered the clinical arena and are being offered to patients with advanced cancer. This will hopefully become a viable therapeutic option also for patients with HIV infection and with certain inflammatory and autoimmune conditions.

Biochemical Properties of Indoleamine 2,3-dioxygenase: From Structure to Optimized Design of Inhibitors

Biochemical Properties of Indoleamine 2,3-dioxygenase: From Structure to Optimized Design of Inhibitors, 2011, 18(15) Pp. 2205-2214
S. Lancellotti, L. Novarese and R. De Cristofaro

The enzyme indoleamine 2,3-dioxygenase (IDO, EC 1.13.11.42) belongs to the family of heme-containing oxidoreductases and catalyzes the first and rate-limiting step in the kynurenine pathway, the major pathway of tryptophan metabolism. IDO is folded into one large and one small distinct α-helical domains, with the heme prosthetic ring positioned between them. The enzyme, through the oxidative properties of the Fe3+ atom present at the centre of the heme ring, catalyses the oxidative cleavage of the pyrrole ring of L-Trp to generate N-formyl-kynurenine. The active IDO conformer exists only in the presence of reducing cofactors (such as cytochrome b5), requiring the single electron reduction of ferric-to-ferrous iron (Fe3+ Fe2+), which facilitates binding of L-Trp and O2 to the enzyme active site. IDO, through production of kynurenine and other downstream metabolites, can regulate immune responses, suppressing effector T-cell function and favouring the differentiation of regulatory T cells. Local expression of the enzyme during inflammation is another self-protection mechanism, which limits antigen-specific immune responses, especially in some organs, as the central nervous system. The detailed knowledge of the structural and functional properties of IDO, was a fundamental step to design and develop new molecules for the pharmacological inhibition of IDO activity in several clinical settings.

Using an Ancient Tool for Igniting and Propagating Immune Tolerance: IDO as an Inducer and Amplifier of Regulatory T Cell Functions

Using an Ancient Tool for Igniting and Propagating Immune Tolerance: IDO as an Inducer and Amplifier of Regulatory T Cell Functions, 2011, 18(15) Pp. 2215-2221
F. Fallarino and U. Grohmann

Although most CD4+CD25+ regulatory T (Treg) cells develop in the thymus (i.e., natural Treg or nTreg), accumulating evidence suggests that they can also develop in the periphery (adaptive/induced Treg or iTreg). Both types of cells are functionally associated with the expression of Foxp3, a transcription factor that is constitutively expressed in nTreg cells and inducible during iTreg cell generation from CD4+CD25 T lymphocytes. Multiple factors are involved in the generation and function of Treg cells, but a major role seems to be played by indoleamine 2,3-dioxygenase (IDO). IDO can both deplete tryptophan in local tissue microenvironments and generate immunoregulatory catabolites, known as kynurenines. Tryptophan starvation and presence of kynurenines can induce the conversion of nave CD4+CD25 T cells into highly suppressive CD4+CD25+Foxp3+ Treg cells. In turn, Treg cells induce IDO in dendritic cells (DCs) and convert inflammatory into regulatory DCs, which can further expand the Treg cell compartment by tryptophan catabolism. Evidence suggests that the modulation of IDO activity favors the interconversion between Treg cells and T helper type 17 (TH17) inflammatory cells. Thus, in the periphery, tolerogenic immune responses mediated by Treg cells can be induced and amplified by IDO, a tryptophan catabolizing enzyme that also contributes to the plasticity of the Treg cell lineage.

Regulation of Expression and Function of IDO in Human Dendritic Cells

Regulation of Expression and Function of IDO in Human Dendritic Cells, 2011, 18(15) Pp. 2222-2233
A. Heitger

In the human immune system, IDO expression and activity (IDO competence), are preferentially found in the antigenpresenting cell population, of which dendritic cells (DCs) represent an essential part. As will be comprehensively reviewed, IDO competence in human DCs, in general, is induced by molecules such as interferon-γ, which otherwise initiate immunity. IDO activity therefore, can be interpreted as a negative feedback pathway that limits uncontrolled immune responses. Because of its potent immunosuppressive effects (down-regulation of T cell responses or the expansion of T cell regulatory activity), IDO competence in human DCs is tightly regulated, at the transcriptional, translational and post-translational levels. I will critically discuss the experimental prerequisites and limits of attributing IDO competence to a mechanism of immunosuppression and examine, whether IDO competence itself can be viewed as mediating immunosuppression, or as representing one component among other immunosuppressive factors, involved in tolerogenic function of DCs. Finally, the newly emerging concepts of manipulating IDO competence as a therapy for either augmenting immune responses, such as in cancer, or down-regulating immune responses, such as in transplantation, will be summarized.

Induction of Regulatory T Cells by Dendritic Cells through Indoleamine 2,3- dioxygenase: A Potent Mechanism of Acquired Peripheral Tolerance

Induction of Regulatory T Cells by Dendritic Cells through Indoleamine 2,3- dioxygenase: A Potent Mechanism of Acquired Peripheral Tolerance, 2011, 18(15) Pp. 2234-2239
S. Trabanelli, D. Ocadlikova, C. Evangelisti, S. Parisi and A. Curti

Indoleamine 2,3-dioxygenase (IDO) is an intracellular heme-containing enzyme that catalyzes the initial rate-limiting step in tryptophan degradation along the kynurenine pathway. Recent works have demonstrated a crucial role for IDO in the induction of immune tolerance during infections, pregnancy, transplantation, autoimmunity, and neoplasias. IDO is widely expressed in human tissues and cell subsets, including dendritic cells, where it modulates their function by increasing tolerogenic capacities. The aim of the present paper is to highlight the most recent data about IDO expression in dendritic cells and its role as a potent inducer of T regulatory cells.

Indoleamine 2,3-dioxygenase, Tregs and Cancer

Indoleamine 2,3-dioxygenase, Tregs and Cancer, 2011, 18(15) Pp. 2240-2246
D. H. Munn

The IDO pathway is implicated in a number of settings which lead to acquired peripheral tolerance. One such setting may be the functional tolerance displayed by tumor-bearing hosts toward tumor-associated antigens. Foxp3+ Tregs are now recognized as a major contributor to tumor-induced immune suppression and functional tolerance. Emerging evidence links the IDO pathway with Treg biology at several points. The first is the ability of IDO-expressing DCs to drive the differentiation of naive CD4+ T cells toward a Foxp3+ (inducible Treg) phenotype. The second link is the ability of IDO-expressing DCs to directly activate mature, pre-existing Tregs for markedly enhanced suppression of target cells. And the third link is the ability of IDO to prevent the inflammation-induced conversion (“reprogramming”) of Tregs into pro-inflammatory T-helper-like cells in vivo. Taken together, these findings suggest that IDO may represent an important regulatory checkpoint influencing Treg activity: both by stabilizing and augmenting the suppressive phenotype, and by preventing Treg reprogramming into non-suppressive helper-like cells.

Wounding the Immune System with its Own Blade: HIV-Induced Tryptophan Catabolism and Pathogenesis

Wounding the Immune System with its Own Blade: HIV-Induced Tryptophan Catabolism and Pathogenesis, 2011, 18(15) Pp. 2247-2256
A. Boasso

Indoleamine 2,3-dioxygenase (IDO) is an immunoregulatory enzyme which plays a key role in maintaining the physiologic immune balance between the efficient responses to insulting pathogens and the control of harmful autoimmune reactions. During HIV infection, multiple mechanisms involving both viral and cellular components, contribute to enhance IDO expression and activity in an uncontrolled manner. The downstream effects of IDO overactivation collectively contribute to the immune alterations which characterize HIV disease. This review explores the cellular and molecular pathways which result in IDO upregulation during HIV infection and considers the consequences of IDO hyperactivity on the immune system, their relevance in the context of HIV immunopathogenesis and the potential for specific therapeutic intervention.

Indoleamine 2,3-dioxygenase as a Modifier of Pathogenic Inflammation in Cancer and other Inflammation-Associated Diseases

Indoleamine 2,3-dioxygenase as a Modifier of Pathogenic Inflammation in Cancer and other Inflammation-Associated Diseases, 2011, 18(15) Pp. 2257-2262
G. C. Prendergast, M. Y. Chang, L. Mandik-Nayak, R. Metz and A. J. Muller

Chronic inflammation underlies the basis for development and progression of cancers and a variety of other disorders, but what specifically defines its pathogenic nature remains largely undefined. Recent genetic and pharmacological studies in the mouse suggest that the immune modulatory enzyme indoleamine 2,3-dioxygenase (IDO), identified as an important mediator of immune escape in cancer, can also contribute to the development of pathology in the context of chronic inflammatory models of arthritis and allergic airway disease. IDO-deficient mice do not display spontaneous disorders of classical inflammation and small molecule inhibitors of IDO do not elicit generalized inflammatory reactions. Rather, in the context of a classical model of skin cancer that is promoted by chronic inflammation, or in models of inflammation-associated arthritis and allergic airway disease, IDO impairment can alleviate disease severity. Here we offer a survey of preclinical literature suggesting that IDO functions as a modifier of inflammatory states rather than simply as a suppressor of immune function. We propose that IDO induction in a chronically inflamed tissue may shape the inflammatory state to support, or in some cases retard, pathogenesis and disease severity.

The Interplay between Indoleamine 2,3-Dioxygenase 1 (IDO1) and Cyclooxygenase (COX)-2 In Chronic Inflammation and Cancer

The Interplay between Indoleamine 2,3-Dioxygenase 1 (IDO1) and Cyclooxygenase (COX)-2 In Chronic Inflammation and Cancer, 2011, 18(15) Pp. 2263-2271
A. Cesario, B. Rocca and S. Rutella

The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) degrades the essential amino acid tryptophan into kynurenine and other downstream metabolites that suppress effector T-cell function and favor the differentiation of regulatory T cells. IDO1 is traditionally viewed as a general suppressor of T-cell activation and mediator of immune escape in cancer. Recently, evidence has emerged to support a greater functional complexity of IDO1 as modifier of pathogenic inflammation. For instance, IDO1 activity may sustain autoantibody production by B cells, and elicit the development of cancer in the context of chronic inflammation. Cyclooxygenase (COX)-2 metabolizes the first enzymatic step in the conversion of arachidonic acid into prostanoids. In particular, prostaglandin (PG)E2 generated at sites of inflammation and/or immune response is mainly COX-2-derived and has pro-inflammatory and immune regulatory activities. Pharmacological blockade of COX-2 in animal models of cancer translates into down-regulation of IDO1 expression at tumor sites and decreased levels of kynurenine in the circulation, underpinning the view that IDO1 might be downstream of COX-2. This article reviews preclinical studies focusing on IDO1 and COX-2 as inter-related molecular targets for therapeutic intervention in chronic inflammation and cancer. COX-2 inhibition might, in principle, be pursued in cancer-associated inflammation characterized by IDO1 hyper-activity, with the foreseeable aim at altering the immune response within the tumor microenvironment.

Contribution of Catecholamine Reactive Intermediates and Oxidative Stress to the Pathologic Features of Heart Diseases

Contribution of Catecholamine Reactive Intermediates and Oxidative Stress to the Pathologic Features of Heart Diseases, 2011, 18(15) Pp. 2272-2314
V. M. Costa, F. Carvalho, M. L. Bastos, R. A. Carvalho, M. Carvalho and F. Remiao

Pathologic heart conditions, particularly heart failure (HF) and ischemia-reperfusion (I/R) injury, are characterized by sustained elevation of plasma and interstitial catecholamine levels, as well as by the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Despite the continuous and extensive research on catecholamines since the early years of the XXth century, the mechanisms underlying catecholamine-induced cardiotoxicity are still not fully elucidated. The role of catecholamines in HF, stress cardiomyopathy, I/R injury, ageing, stress, and pheochromocytoma will be thoroughly discussed. Furthermore and although the noxious effects resulting from catecholamine excess have traditionally been linked to adrenoceptors, in fact, several evidences indicate that oxidative stress and the oxidation of catecholamines can have important roles in catecholamine-induced cardiotoxicity. Accordingly, the reactive intermediates formed during catecholamine oxidation have been associated with cardiac toxicity, both in in vitro and in vivo studies. An insight into the influence of ROS, RNS, and catecholamine oxidation products on several heart diseases and their clinical course will be provided. In addition, the source and type of oxidant species formed in some heart pathologies will be referred. In this review a special focus will be given to the research of cardiac pathologies where catecholamines and oxidative stress are involved. An integrated vision of these matters is required and will be provided along this review, namely how the concomitant surge of catecholamines and ROS occurs and how they can be interconnected. The concomitant presence of these factors can elicit peculiar and not fully characterized responses on the heart. We will approach the existing data with new perspectives as they can help explaining several controversial results regarding cardiovascular diseases and the redox ability of catecholamines.

Anticancer Antioxidant Regulatory Functions of Phytochemicals

Anticancer Antioxidant Regulatory Functions of Phytochemicals, 2011, 18(15) Pp. 2315-2338
J. M. Mates, J. A. Segura, F. J. Alonso and J. Marquez

Plant foods are not only a main source of nutrients, but they are also rich in physiologically bioactive bionutrients or phytochemicals. Consumption of fruit and vegetables is associated with a decreased risk of pathological status, including cancer. Reactive oxygen species play a key role in the genesis and development of cancer. Therefore, antioxidant functions of phytonutrients have been thoroughly investigated in the last years in relation to their crucial effect in the pathophysiology associated with neoplasia. This review discusses current knowledge on phytochemicals in relation to their potential as chemopreventive and/or chemotherapeutic molecule against human cancers. Finally, we will outline the use of bioactive phytochemicals on synergistic actions involved in the prevention and treatment of cancer as well as its future prospects.

Recent Insights on the Medicinal Chemistry of Sickle Cell Disease

Recent Insights on the Medicinal Chemistry of Sickle Cell Disease, 2011, 18(15) Pp. 2339-2358
J. L. dos Santos and C. M. Chin

Sickle Cell Disease (SCD) is one of the most prevalent hematological diseases in the world. SCD is a genetic disease characterized by punctual mutation that basis on the exchange of glutamic acid to valine in a beta chain of hemoglobin. In deoxygenated state, the interaction among the beta chains leads to hemoglobin polymerization carrying out to deformation of cytoskeleton structure of red blood cells to a sickle shape. Currently, the treatment is performed with the antineoplasic drug hydroxyurea. This review summarizes current knowledge about possible targets and the approaches to discover new compounds to treat the SCD symptoms. Drug design based on therapeutical application and molecular modifications strategies will be discussed.

Editorial [Hot Topic:Impacts of Nanotechnology on Medicinal Chemistry and Drug Discovery (Guest Editor: Bing Yan)]

Editorial [Hot Topic:Impacts of Nanotechnology on Medicinal Chemistry and Drug Discovery (Guest Editor: Bing Yan)], 2011, 18(14) Pp. 2044-2044
Bing Yan

Drug discovery is constantly stimulated by new technologies and new paradigms. Nanotechnology has already had unprecedented impacts on every area of modern technologies, from energy to materials to medicine [1-3], and more impacts and discoveries are still to come. The term “nanomedicine” appeared in the literature only a decade ago, and now it has already become a rapidly advancing research field with focus on developing novel therapy and imaging approaches for various diseases, particularly cancer [4-9]. In this special issue of Current Medicinal Chemistry, leading experts in the interdisciplinary areas of nanomedicine and nanobiotechnology critically review the impacts of nanotechnology on drug discovery and medicine, particularly in areas previously affected by the limitations of traditional drug design and delivery methods. An ideal drug should enter cells and selectively inhibit the disease target while possessing suitable solubility, blood pool retention time, metabolic stability, and pharmacokinetic/ pharmacodynamic properties, and with no evident toxicity. Traditional small-molecule drugs have to incorporate all these functions into a single molecule with a molecular weight around 500. This is a tremendous challenge! However, nanoparticles with dimensions less than hundreds of nanometers are approximately 0.01-1.0% of the size of human cells. They can easily enter cells or pass through the leaky vasculature in tumors. On the other hand, they are bigger than small molecules, so they can be built into a nanoplatform that easily integrates targeting molecules, drugs, imaging moiety, and biocompatible side chains on a single nanoparticle, taking advantage of their large surface areas. In this special issue, articles by Sun, Huang, Kanwar, and their coworkers describe several typical nanoplatforms with the aims of overcoming difficulties in conventional drug design and formulation, “sugar code” on cell surfaces for cell targeting, and oral delivery of peptides and proteins. Articles by Boppart, Yan, and their coworkers describe research into nanomedicinal constructs with imaging or with integrated imaging, therapy, and targeting functions. Absorption, distribution, metabolism, and excretion, as well as toxicity, are important concerns for nanomedicine candidates, as for small molecule drugs. Nanotoxicology has evolved into a research discipline of its own. Wick and coworkers describe research in this aspect on a promising nanoplatform called carbon nanotubes. With rapid development in nanotechnology and nanomedicine, this collection can only provide a glimpse of this dynamic field. We expect that nanomedicine research will soon provide new clinical approaches to diagnosing disease, delivering therapy, and monitoring therapeutic effects quickly and non-invasively.

Fullerenes for Applications in Biology and Medicine

Fullerenes for Applications in Biology and Medicine, 2011, 18(14) Pp. 2045-2059
P. Anilkumar, F. Lu, L. Cao, P. G. Luo, J.-H. Liu, S. Sahu, K. N. Tackett II, Y. Wang and Y.-P. Sun

Fullerenes as a unique class of carbon allotropes have been studied extensively for their distinctive material properties and potential technological applications, including those in biology and medicine. Since a major focus in the latter has been on drug development and formulation, in this paper we highlight some representative studies related to such a focus, including the use of fullerenes for drug-like functions and for their improving the formulation of established drugs. Also discussed are some other potential medically relevant applications of fullerenes, such as their serving as potent agents in photodynamic therapy and magnetic imaging.

Glyco-Nanomaterials: Translating Insights from the “Sugar-Code” to Biomedical Applications

Glyco-Nanomaterials: Translating Insights from the “Sugar-Code” to Biomedical Applications, 2011, 18(14) Pp. 2060-2078
Kheireddine El-Boubbou and Xuefei Huang

Over the past decade, diagnostics and therapeutics have changed gradually towards the use of more specific and targeted approaches. The most profound impact has been in the nanotechnology sectors, where an explosion in directing biomolecules to specific biomarkers has illustrated great potentials not only in detection but also in targeted therapy. Increased knowledge of the diseases at the molecular level catalyzed a shift towards identifying new biological indicators. In particular, carbohydrate-mediated molecular recognitions using nano-vehicles are likely to increasingly affect medicine opening a new area of biomedical applications. This article provides an overview of the recent progress made in recruiting the “sugar code” functionalized on various nano-platforms to decipher cellular information for both in vitro and in vivo applications. Today's glyco-technologies are enabling better detection with great therapeutic potentials. Tomorrow they are likely to bring a full understanding of the “cell-glyconanomaterial bio-conversation” where major biomedical problems will be overcome translating insights from the “glyco-nanoworld” into clinical practice.

The Use of Cyclodextrins Nanoparticles for Oral Delivery

The Use of Cyclodextrins Nanoparticles for Oral Delivery, 2011, 18(14) Pp. 2079-2085
J. R. Kanwar, B. M. Long and R. K. Kanwar

This review aims to highlight many of the difficulties encountered in trying to achieve the task of delivering proteins and peptides through oral administration. The necessity of controlled protein and peptide release, protection and stability in the gastrointestinal tract, and ability to target specific areas are only a handful of the many problems associated with trying to engineer a useful solution. Current research gives strong indication that both cyclodextrins and nanoparticles could be highly useful in the search for a suitable method for such successful oral delivery of proteins and peptides. This review focuses on the use of cyclodextrins in pharmaceuticals, aiming to discuss the use of cyclodextrins in conjunction with nanoparticles for oral delivery of proteins. Both classical applications and more advanced “nanomedical” approaches are discussed. In order to achieve a complete overview this review will include background information about cyclodextrins, nanomedicine and their role in oral delivery systems. The use of absorption enhancers like cyclodextrins, bile salts and surfactants was used to facilitate bio-availability into the system. The state-of-the-art technology and challenges in this area are discussed, with typical examples.

Cancer-Targeting Multifunctionalized Gold Nanoparticles in Imaging and Therapy

Cancer-Targeting Multifunctionalized Gold Nanoparticles in Imaging and Therapy, 2011, 18(14) Pp. 2086-2102
P. F. Jiao, H. Y. Zhou, L. X. Chen and B. Yan

Nanotechnology has provided many promising nanoplatforms for targeted cancer imaging and therapy. Among these platforms, gold nanoparticles (GNPs) play a unique role in medicine because of their excellent physical and chemical properties. To expand the applications of GNPs in medicine, amounts of targeting moieties, imaging labels, and therapeutic agents have been integrated into these particles to form multifunctionalized GNPs. In this review, we highlight recent advances of the fabrication of cancer-targeting multifunctionalized GNPs and their applications in imaging and therapy.

Magnetomotive Molecular Nanoprobes

Magnetomotive Molecular Nanoprobes, 2011, 18(14) Pp. 2103-2114
Renu John and Stephen A. Boppart

Tremendous developments in the field of biomedical imaging in the past two decades have resulted in the transformation of anatomical imaging to molecular-specific imaging. The main approaches towards imaging at a molecular level are the development of high resolution imaging modalities with high penetration depths and increased sensitivity, and the development of molecular probes with high specificity. The development of novel molecular contrast agents and their success in molecular optical imaging modalities have lead to the emergence of molecular optical imaging as a more versatile and capable technique for providing morphological, spatial, and functional information at the molecular level with high sensitivity and precision, compared to other imaging modalities. In this review, we discuss a new class of dynamic contrast agents called magnetomotive molecular nanoprobes for molecular-specific imaging. Magnetomotive agents are superparamagnetic nanoparticles, typically iron-oxide, that are physically displaced by the application of a small modulating external magnetic field. Dynamic phase-sensitive position measurements are performed using any high resolution imaging modality, including optical coherence tomography (OCT), ultrasonography, or magnetic resonance imaging (MRI). The dynamics of the magnetomotive agents can be used to extract the biomechanical tissue properties in which the nanoparticles are bound, and the agents can be used to deliver therapy via magnetomotive displacements to modulate or disrupt cell function, or hyperthermia to kill cells. These agents can be targeted via conjugation to antibodies, and in vivo targeted imaging has been shown in a carcinogeninduced rat mammary tumor model. The iron-oxide nanoparticles also exhibit negative T2 contrast in MRI, and modulations can produce ultrasound imaging contrast for multimodal imaging applications.

Carbon Nanotubes Curse or Blessing

Carbon Nanotubes Curse or Blessing, 2011, 18(14) Pp. 2115-2128
J.-P. Kaiser, M. Roesslein, T. Buerki-Thurnherr and P. Wick

Although nanotechnology is a relatively new scientific field, quite many different products are already introduced in the market containing nanosized particles. A special class of nanosized materials namely the carbon nanotubes (CNT) possesses outstanding new properties and extraordinary potential for creating new products. Carbon nanotubes are already used in various consumer products, industrial applications and science. It is not as this time clear how CNT are able to affect human health since most types of CNTs differ significantly in terms of structural characteristics (morphology, size, shape and length), surface properties (surface chemistry and surface charge) and chemical composition. This review provides an overview about contradicting reports that are found in the literature. We summarize the studies that report about nontoxic as well as toxic effects of CNT in-vitro and in-vivo. We describe how carbon nanotubes can readily be degraded under certain conditions. Another phenomenon is that despite the observed toxic effects which may occur to cells, organs and animals after uptake of CNT, intensive research investigations were undertaken in order to use these outstanding materials in medical applications. The second part of this review starts with a short description of the main principles in metrology. Observed conflicts were discussed in CNT toxicity assays into terms of measurement science or metrology issues. It was demonstrated that any specification of a measurand is only valid within the given framework. This means that many of the published results are within their measurement framework correct, but there are no means to compare them outside this framework.

Antimicrobial Strategies Effective Against Infectious Bacterial Biofilms

Antimicrobial Strategies Effective Against Infectious Bacterial Biofilms, 2011, 18(14) Pp. 2129-2145
Manuel Simoes

Bacteria are able to adapt to undesirable changes in nutrient availability, environmental conditions and presence of antimicrobial products, as well as to immunological defenses. One particularly important example of bacterial adaptation is the ability to grow as part of a sessile community, commonly referred to as biofilm. It is a natural tendency of microorganisms to attach to biotic or abiotic surfaces, to multiply and to embed themselves in a slimy matrix, resulting in biofilms. Biofilms are the leading example of physiological adaptation and are one of the most important sources of bacterial resistance to antimicrobials. It is now recognized that most bacterial-associated infections, including endocarditis, dental caries, middle ear infections, osteomyelitis, medical device-related infections and chronic lung infections in cystic fibrosis patients are problematic because of biofilms. Bacteria in biofilms demonstrate intrinsic resistance to antimicrobial stress more effectively than the planktonic counterparts. Antimicrobial concentrations necessary to inhibit bacterial biofilms can be up to 10-1000 times higher than those needed to inhibit the same bacteria grown planktonically. Thus, in the presence of therapeutically available antibiotic concentrations biofilms remain viable after treatment. Therefore, the identification of new antimicrobials that inhibit or destroy biofilms is needed. The aim of this review is to cover the recent advances on the studies of antimicrobial strategies effective against infectious bacterial biofilms, including the current developments in the structure-activity relationship of those effective antimicrobials.

Recent Developments in the Third Generation Inhibitors of Bcr-Abl for Overriding T315I Mutation

Recent Developments in the Third Generation Inhibitors of Bcr-Abl for Overriding T315I Mutation, 2011, 18(14) Pp. 2146-2157
X. Y. Lu, Q. Cai and K. Ding

In the treatment of chronic myeloid leukemia (CML) with Bcr-Abl kinase inhibitors, the T315I gatekeeper mutant has emerged as resistant to all currently approved agents, such as imatinib, nilotinib and dasatinib, by discrupting important contact interactions between the inhibitors and the enzyme. To overcome this particular resistance, several different strategies have been explored and many molecules have been investigated as capable of potently inhibiting Bcr-Abl T315I. Herein, this review reports on some predominant examples of third generation inhibitors of Bcr-Abl active against the T315I mutation, and special attentions are paid to the “hybrid-design” strategy for creating type-II class ATP-competitive inhibitors.

Virtual Screening Against Obesity

Virtual Screening Against Obesity, 2011, 18(14) Pp. 2158-2173
P. Markt, S. Herdlinger and D. Schuster

The development of novel drugs against obesity is one of the top priorities of worldwide drug research. In recent years, it has been facilitated by the application of virtual screening methods. In this review, we give a short introduction into obesity-related protein targets and computer-aided drug design techniques. Furthermore, we highlight the most successful virtual screening studies, outline their results, and provide suggestions for future anti-obesity drug development.

Filariasis: Current Status, Treatment and Recent Advances in Drug Development

Filariasis: Current Status, Treatment and Recent Advances in Drug Development, 2011, 18(14) Pp. 2174-2185
D. Katiyar and L. K. Singh

Lymphatic filariasis, onchocerciasis and loiasis caused by human filarial nematodes are diseases of tropical and subtropical countries causing considerable morbidity. The available control strategies have significant limitations such that current drugs are ineffective against macrofilariae (adult worms), require repeated and prolonged treatment over years and are threatened by emergence of drug resistance. Due to this concern, these diseases are the focus of renewed scientific interest and much has been done in filariasis research in the past decade. This review summarizes the current status of filariasis, different control strategies, recent advances in antifilarial chemotherapy including currently used drugs, their pros and cons, their mechanism of action, and recently discovered targets and prototypes.

Twenty Years of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: Time to Reevaluate their Toxicity

Twenty Years of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: Time to Reevaluate their Toxicity, 2011, 18(14) Pp. 2186-2195
A. Blas-Garcia, J. V. Esplugues and N. Apostolova

Twenty years of effective clinical application have consolidated non-nucleoside reverse transcriptase inhibitors (NNRTI) as essential components of the Highly Active Antiretroviral Therapy (HAART) employed in the treatment of Human Immunodeficiency Virus (HIV). However, as the disease has come under control, there has been growing emphasis on the long-term adverse effects induced by this chronic pharmacological therapy. Although traditionally considered to be safe and well-tolerated drugs, there is mounting evidence that associates NNRTI with the onset of cutaneous reactions, neuropsychiatric symptoms, hepatotoxicity, metabolic disturbances and gastrointestinal toxicity. Though the clinical manifestations of these detrimental events are increasingly recognised, the cellular and molecular mechanisms underlying them have received little attention. This review revaluates the toxicities associated with the use of NNRTI by analysing data from both clinical trials and recent in vitro studies. Particular emphasis is placed on the specific characteristics of each of the compounds that comprise this class of anti-HIV drugs, including some that are currently in clinical development. A deeper understanding of the causes of NNRTI-induced side effects would greatly help to improve existing anti-HIV-1 therapies and to develop safer and better tolerated drugs in the future, thus increasing the long term efficacy of NNRTI-containing regimens.

Ankylosing Spondylitis, Late Osteoarthritis, Vascular Calcification, Chondrocalcinosis and Pseudo Gout: Toward a Possible Drug Therapy

Ankylosing Spondylitis, Late Osteoarthritis, Vascular Calcification, Chondrocalcinosis and Pseudo Gout: Toward a Possible Drug Therapy, 2011, 18(14) Pp. 2196-2203
S. Mebarek, E. Hamade, C. Thouverey, J. Bandorowicz-Pikula, S. Pikula, D. Magne and R. Buchet

In this review we consider diseases associated with pathological mineralization/ossification, namely, ankylosing spondylitis (AS), osteoarthritis (OA), generalized artery calcification of infancy (GACI), vascular calcification as well as chondrocalcinosis (CC) and pseudo gout. Deciphering the key enzymes implicated in the calcification process is an objective of prime importance and the ultimate goal is to synthesize inhibitors of these enzymes in order to provide efficient alternate therapeutic strategies that will slow down the pathologic mineralization and complement the arsenal of anti-inflammatory drugs. One of the difficulties in the definition of diseases associated with pathologic mineralization/ossification lies in the controversial relationship between the type of calcification and the nature of the disease. Here, we propose to clarify this relationship by making a distinction between diseases associated with hydroxyapatite (HA) and calcium pyrophosphate dihydrate (CPPD) deposits. AS, OA, GACI and vascular calcification are usually characterized by mineralization/ossification associated with HA deposits, while CC and pseudo gout are mostly characterized by CPPD deposits. Although both HA and CPPD deposits may occur concomitantly, as in chronic pyrophosphate arthritis or in OA with CPPD, they are formed as a result of two antagonistic processes indicating that treatment of distinct diseases can be only achieved by diseasespecific drug therapies. The hydrolysis of PPi, an inhibitor of HA formation, is mostly controlled by tissue non-specific alkaline phosphatase TNAP, while PPi production in the extracellular medium is controlled by ANK, a PPi transporter, and/or NPP1 which generates PPi from nucleotide triphosphates. Low PPi concentration may lead to a preferential deposition of HA while high PPi concentration will favor the formation of CPPD deposits. Thus, HA and CCPD deposition cannot occur concomitantly because they are determined by the Pi/PPi ratio which, in turn, depends on the relative activities of antagonistic enzymes, TNAP hydrolyzing PPi or ANK and NPP1 producing PPi. TNAP inhibitors could prevent HA formation in AS, in late OA, in GACI, as well as in vascular calcifications, while ANK or NPP1 inhibitors could slow down CCPD deposition in CC and pseudo gout.

Editorial [Hot Topic: NAD and its Role in Biology and Medicine (Guest Editor: Krzysztof W. Pankiewicz)]

Editorial [Hot Topic: NAD and its Role in Biology and Medicine (Guest Editor: Krzysztof W. Pankiewicz)], 2011, 18(13) Pp. 1890-1890
Krzysztof W. Pankiewicz

This special issue of Current Medicinal Chemistry focuses on the chemistry and biology of nicotinamide adenine dinucleotide (NAD and NADP). In recent years, NAD(P)-utilizing enzymes have been extensively investigated and implicated in a wide variety of diseases. Thus, understanding of the role of NAD(P) in medical disorders may lead to potential NAD(P)-based therapeutics. NAD(P) is not only a key component of redox reactions but also participates in a diverse range of cellular processes that are crucial for the cell health and replication. There is a growing interest in identification of small molecules as modulators of NAD(P)-dependent enzymes implicated in a variety of diseases. In the first chapter, Felczak and Pankiewicz reviewed a number of conformational and structural factors that might affect (improve) the affinity of various inhibitors to the NAD-binding domain. They discussed potential selectivity of NAD(P)-like molecules toward human IMPdehydrogenase (IMPDH) and other target enzymes, which is crucial for potential application of NAD analogues as therapeutic agents. Hedstrom at al. focused on bacterial IMPDHs as potential target for the development of new antibiotics. These enzymes share only 20-40 of amino acids sequences with the human enzyme. The identification of the structural features in IMPDHs from a wide variety of pathogenic bacteria is described as well as the discovery of an inhibitor against Helicobacter pylori. Sauve and co-workers reviewed biochemical activities of seven human sirtuin isoforms called SIRT1-7 and their roles in biology. These enzymes are involved in post-translational protein modifications, including NAD-dependent histone deacetylation. Strategies for how sirtuins can be targeted by small molecules are discussed. Chen described early sirtuin inhibitors that mimic NAD+ or substrate peptides as well as new structures identified by high-throughput and in silico screenings. His review outlines inhibitor chemotypes, and their biological evaluations, highlighting strategies to enhance inhibition, and selectivity among isoforms. Burgos reviewed the role of nicotinamide phosphoribosyltransferase (NAMPT), the enzyme which catalyzes the first step in the salvage pathway of NAD biosynthesis. The first NAMPT inhibitors entered clinical trials; however, it is clear that better understanding of the catalytic mechanism of NAMPT may permit the design of improved NAMPT inhibitors as potential drugs against cancer. Jayaram and co-workers focused on nicotinamide mononucleotide adenylyltransferease (NMNAT), an enzyme present in all organisms and involved in the biosynthesis of NAD from ATP and nicotinamide mononucleotide (NMN). The role of NMNAT in the regulation of NAD levels in the cell and consequently the enzyme effects on performance of NAD-utilizing enzymes are discussed. Cappellacci at al. described the design, chemistry, and potential therapeutic applications of inhibitors of the two last enzymes in NAD and NADP biosynthesis, i.e. NMNAT and NAD kinase. They concluded that the recognized role of NADKs and NMNATs in pathological conditions like cancer, and neuro-degenerative diseases makes these enzymes excellent targets for drug discovery. Also, bacterial NADK and NaMNAT are promising new targets for developing novel antibiotics. Finally, all chapters indicate enormous potential for innovative research in this field. NAD-based therapeutics are still in the early stage of development but the NAD-related field progresses faster than ever before.

Rehab of NAD(P)-Dependent Enzymes with NAD(P)-Based Inhibitors

Rehab of NAD(P)-Dependent Enzymes with NAD(P)-Based Inhibitors, 2011, 18(13) Pp. 1891-1908
K. Felczak and K. W. Pankiewicz

A large number of enzymes that use nicotinamide adenine dinucleotide NAD or its phosphorylated form NADP as a cofactor or substrate were found to play an important role in the growth and reproduction of living organisms. NAD(P)-dependent and NAD(P)- utilizing enzymes [NAD(P)-addicted?] have been extensively investigated and implicated in a wide variety of diseases. NAD, generally considered a key component involved in redox reactions, has been found to participate in a broad spectrum of cellular processes, including signal transduction, DNA repair, and post-translational protein modifications. The reduced form of NADP, i.e. NADPH, guards the cell against oxidative stress and it has been suggested that suppression of NADPH oxidase activity could result in anti-angiogenesis and anticancer effects. Consequently, small molecule NAD(P)-based inhibitors that selectively bind at the NAD(P)-binding domain of the targeted enzyme have been designed for novel treatment of medical disorders. The NAD(P)-binding domain is modular in nature; it can be divided into three sub-sites, the nicotinamide monophosphate (NMN) binding sub-site (N sub-site), the adenosine monophosphate (AMP) binding sub-site (A sub-site), and the pyrophosphate binding sub-site (P sub-site or P-groove). Each sub-site plays an important role in securing proper and tight binding; however, each has its own requirements. In this review we discuss a number of conformational and structural factors that might affect (improve) the affinity of various inhibitors to these sub-sites, as well as to the whole binding domain. We have focused on potential selectivity of NAD(P)-like molecules toward targeted enzymes and their potential application in biology and medicine.

The Antibiotic Potential of Prokaryotic IMP Dehydrogenase Inhibitors

The Antibiotic Potential of Prokaryotic IMP Dehydrogenase Inhibitors, 2011, 18(13) Pp. 1909-1918
L. Hedstrom, G. Liechti, J. B. Goldberg and D. R. Gollapalli

Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes the first committed step of guanosine 5'-monophosphate (GMP) biosynthesis, and thus regulates the guanine nucleotide pool, which in turn governs proliferation. Human IMPDHs are validated targets for immunosuppressive, antiviral and anticancer drugs, but as yet microbial IMPDHs have not been exploited in antimicrobial chemotherapy. Selective inhibitors of IMPDH from Cryptosporidium parvum have recently been discovered that display anti-parasitic activity in cell culture models of infection. X-ray crystal structure and mutagenesis experiments identified the structural features that determine inhibitor susceptibility. These features are found in IMPDHs from a wide variety of pathogenic bacteria, including select agents and multiply drug resistant strains. A second generation inhibitor displays antibacterial activity against Helicobacter pylori, demonstrating the antibiotic potential of IMPDH inhibitors.

Advances in Characterization of Human Sirtuin Isoforms: Chemistries, Targets and Therapeutic Applications

Advances in Characterization of Human Sirtuin Isoforms: Chemistries, Targets and Therapeutic Applications, 2011, 18(13) Pp. 1919-1935
Y. Cen, D. Y. Youn and A. A. Sauve

Since the discovery in 2000 that the yeast sirtuin called “Sir2” catalyzes NAD+ dependent histone deacetylation, a wave of research has focused on evaluating the biochemical and biological functions of sirtuins. Sirtuins are activated by low calorie diets in numerous organisms and are found throughout biology in species from archaea to humans. There are seven human sirtuin isoforms called SIRT1-SIRT7. The biochemical functions of SIRT1, SIRT2, SIRT3, SIRT5 and SIRT6 have been reported and NAD+ dependent deacetylase activities confirmed. In some instances the biological target substrates for each isoform have been identified, helping to connect distinct biological processes to sirtuin regulation. This knowledge has informed potential drug design strategies that target distinct sirtuin isoforms. This review presents current knowledge of biochemical activities of SIRT1-7 in humans and the biological consequences of these sirtuin activities. Regulatory principles that govern sirtuin deacetylation activity in cells are discussed as well as strategies for how sirtuins can be targeted by small molecules. Finally, this review updates research on pharmacologic sirtuin activation and allostery on sirtuins and considers new developments for detection and isolation of sirtuins in complex mixtures.

Medicinal Chemistry of Sirtuin Inhibitors

Medicinal Chemistry of Sirtuin Inhibitors, 2011, 18(13) Pp. 1936-1946
L. Chen

As members of Class III histone deacetylases (HDACs), sirtuins use stoichiometric nicotinamide adenine dinucleotide (NAD+) to remove the acetyl group from N-acetyl-lysines of histones or non-histone proteins. Sirtuins have been implicated in metabolic diseases, cancer, and neurodegenerative diseases, constituting a promising target for drug discovery. While the early sirtuin inhibitors mimicked NAD+ or substrate peptides, high-throughput and in silico screenings have identified a wide range of core structures, many of which have been subjected to medicinal chemistry efforts. This review outlines inhibitor chemotypes, and their chemical modifications and biological evaluations, highlighting strategies to enhance inhibitory activity and selectivity among isoforms.

NAMPT in Regulated NAD Biosynthesis and its Pivotal Role in Human Metabolism

NAMPT in Regulated NAD Biosynthesis and its Pivotal Role in Human Metabolism, 2011, 18(13) Pp. 1947-1961
E S. Burgos

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the first reversible step in NAD biosynthesis and nicotinamide (NAM) salvage. The enzyme is designed for efficient capture of nicotinamide by coupling of ATP hydrolysis to assist in extraordinary NAM binding affinity and formation of nicotinamide mononucleotide (NMN). NAMPT provides the mechanism to replenish the NAD pool in human metabolism. In addition to its role in redox biochemistry, NAD fuels the sirtuins (SIRTs) to regulate transcription factors involved in pathways linked to inflammation, diabetes and lifespan. NAMPT-mediated lifespan expansion has caused a focus on the catalytic mechanism, regulation and inhibition of NAMPT. Structural, mechanistic and inhibitor design all contribute to a developing but yet incomplete story of NAMPT function. Although the first generation of NAMPT inhibitors has entered clinical trials, disappointing outcomes suggest more powerful and specific inhibitors will be needed. Understanding the ATP-linked mechanism of NAMPT and the catalytic site machinery may permit the design of improved NAMPT inhibitors as more efficient drugs against cancer.

NMNAT Expression and its Relation to NAD Metabolism

NMNAT Expression and its Relation to NAD Metabolism, 2011, 18(13) Pp. 1962-1972
H. N. Jayaram, P. Kusumanchi and J. A. Yalowitz

Nicotinamide mononucleotide adenylyltransferease (NMNAT), a rate-limiting enzyme present in all organisms, reversibly catalyzes the important step in the biosynthesis of NAD from ATP and NMN. NAD and NADP are used reversibly in anabolic and catabolic reactions. NAD is necessary for cell survival in oxidative stress and DNA damage. Based on their localization, three different NMNAT's have been recognized, NMNAT-1 (homohexamer) in the nucleus (chromosome 1 p32-35), NMNAT-2 (homodimer) in the cytoplasm (chromosome 1q25) and NMNAT-3 (homotetramer) in the mitochondria. NMNAT also catalyzes the metabolic conversion of potent antitumor prodrugs like tiazofurin and benzamide riboside to their active forms which are analogs of NAD. NAD synthase- NMNAT acts as a chaperone to protect against neurodegeneration, injury-induced axonal degeneration and also correlates with DNA synthesis during cell cycle. Since its activity is rather low in tumor cells it can be exploited as a source for therapeutic targeting. Steps involved in NAD synthesis are being utilized as targets for chemoprevention, radiosensitization and therapy of wide range of diseases, such as cancer, multiple sclerosis, neurodegeneration and Huntington's disease.

NMN/NaMN Adenylyltransferase (NMNAT) and NAD Kinase (NADK) Inhibitors: Chemistry and Potential Therapeutic Applications

NMN/NaMN Adenylyltransferase (NMNAT) and NAD Kinase (NADK) Inhibitors: Chemistry and Potential Therapeutic Applications, 2011, 18(13) Pp. 1973-1992
R. Petrelli, K. Felczak and L. Cappellacci

Nicotinamide adenine dinucleotide (NAD+) has a crucial role in many cellular processes, both as a coenzyme for redox reactions and as a substrate to donate ADP-ribose units. Thus, enzymes involved in NAD+ metabolism are attractive targets for drug discovery against a variety of human diseases. Herein we focus on two of them: NMN/NaMN adenylyltransferase (NMNAT) and NAD kinase (NADK). NMNAT is a key enzyme in all organisms catalyzing coupling of ATP and NMN or NaMN yielding NAD or NaAD, respectively. NADKs are ubiquitous enzymes involved in the last step of the biosynthesis of NADP. They phosphorylate NAD to produce NADP using ATP (or inorganic polyphosphates) in the presence of Mg2+. No other pathway of NADP biosynthesis has been found in prokaryotic or eukaryotic cells. In this review we provide a comprehensive summary of NMNAT and NADK inhibitors highlighting their chemical modifications by different synthetic approaches, and structure-activity relationships depending on their potential therapeutic applications

Significant Breakthroughs in Search for Anti-Infectious Agents Derived from Erythromycin A

Significant Breakthroughs in Search for Anti-Infectious Agents Derived from Erythromycin A, 2011, 18(13) Pp. 1993-2015
Xiaodong Ma and Shutao Ma

As a well-established class, macrolide antibiotics continue to enjoy a remarkable interest within pharmaceutical industry. Several stunning breakthroughs in semi-synthetic study of erythromycin A (EMA) contribute to the important role played by the macrolide class in search for new anti-infectious agents. Earlier structural modifications of EMA to address the issue of acid instability resulted in the first breakthrough in search for anti-infectious agents derived from EMA. Clarithromycin (CAM) and azithromycin (AZM) are two representative antibacterials commercialized during this period. Afterwards, continued research on the modifications of EMA to combat bacterial resistance culminated in the second breakthrough in this field. Telithromycin and cethromycin are two innovative antibacterials discovered in this period for treating community-acquired pneumonia (CAP). Recently, further structural modifications of EMA generate promising antibacterials endlessly, which will hopefully arouse another breakthrough in the near future. In this review, we will give an account of these breakthroughs and discuss the future directions of semi-synthetic research on EMA. In particular, the design and synthesis of some distinguished or promising antibacterials derived from EMA will be highlighted.

Endoplasmic Reticulum Stress Inhibition Enhances Liver Tolerance to Ischemia/Reperfusion

Endoplasmic Reticulum Stress Inhibition Enhances Liver Tolerance to Ischemia/Reperfusion, 2011, 18(13) Pp. 2016-2024
C. Peralta and C. Brenner

In many physiopathological conditions, the cell controls its proper dysfunction via activation of the unfolded protein response to restore efficient protein synthesis and folding in the endoplasmic reticulum. However, whether the aim of unfolded protein response is to promote the cell survival, it can also lead to induction of cell death and then affect the cell fate. Recently, endoplasmic reticulum stress appeared to be critical for acute as well as chronic diseases including neurodegeneration, cardiac disease, cancer, obesity, type 2 diabetes, and ischemia/reperfusion injury. Therefore, inhibition of the endoplasmic reticulum stress could constitute a promising therapeutic strategy to limit cellular damage in pathologies such as hepatic ischemia/reperfusion.

Cyclin Dependent Kinase 1 Inhibitors: A Review of Recent Progress

Cyclin Dependent Kinase 1 Inhibitors: A Review of Recent Progress, 2011, 18(13) Pp. 2025-2043
Q. Wang, L. Su, N. Liu, L. Zhang, W. Xu and H. Fang

Cyclin dependent kinases (CDKs) are a family of proteins involved in the regulation of cell cycle progression and attractive targets in oncology. The regulation of CDKs activities is achieved by their association with cyclin partners and kinases, phosphatases and specific inhibitors. Different CDKs complexes exert their functions at different phases. CDK1 is a master modulator in the initiation and transition process through mitosis of the cell cycle. Previous studies have shown that loss of CDK1 activity or the aberrant expression of CDK1 involved in G2 phase arrest and many tumor types, thereby validating CDK1 as a therapeutic target. Therefore, a surge of interest has been devoted to searching for potent CDK1 inhibitors as effective chemotherapeutic agents. Herein we focus, in this review, mainly on the studies about the structure, functions and different structure classes of potent CDK1 inhibitors.

Editorial [Hot Topic:Epigenetic Mechanisms and Therapeutic Strategies (Guest Editors: Victoria Samanidou and Leda Kovatsi)]

Editorial [Hot Topic:Epigenetic Mechanisms and Therapeutic Strategies (Guest Editors: Victoria Samanidou and Leda Kovatsi)], 2011, 18(12) Pp. 1732-1732
Victoria Samanidou and Leda Kovatsi

Epigenetics is defined as heritable changes in gene expression which do not alter the DNA sequence. This is achieved through changes to chromatin structure: genes are inactivated when chromatin is condensed and expressed when chromatin is extended. These dynamic chromatin states are controlled by reversible epigenetic patterns of DNA methylation and histone modification. There is now increasing evidence that environmental events can directly modify the epigenetic state of the genome. Since most human diseases are related, in some way, to alterations in gene function, disruption of the balance of epigenetic networks can cause several major pathologies such as cancer, syndromes involving chromosomal instability, mental retardation and neurodegenerative diseases, imprinting disorders, a variety of cardiovascular diseases and a great number of other human life-threatening situations. Limited amount of research has also implicated epigenetics in drug toxicity and addiction. The possibility of reversing epigenetic marks may provide new pharmacological targets for emerging therapeutic interventions. Such epigenetic drugs would be novel, possibly possessing higher therapeutic potential and fewer adverse effects in comparison to current, conventional treatments. In this special issue titled “Epigenetic mechanisms and therapeutic strategies” five review manuscripts present and discuss both the epigenetic mechanisms implicated in the pathogenesis of various disorders and diseases as well as the currently available therapeutic strategies for controlling or reversing epigenetic lesions. In the first manuscript Liakopoulos et al. provide an overview of the role of epigenetic mechanisms in the pathogenesis of renal diseases. Demars et al. in the second review discuss epigenetic and genetic mechanisms of abnormal 11p15 genomic imprinting in Silver-Russell and Beckwith-Wiedemann syndromes. A comprehensive review by Daniilidou et al. summarizes the recent findings on synaptic dysfunction and cognitive decline caused by common epigenetic modifications. The authors also discuss potential treatment strategies targeting on the epigenetic machinery. Georgiou and Kouidou discuss the currently available epigenetic therapies for the treatment of hematological malignancies. Last but not least, the review by Kovatsi et al. discusses the advances in the field of epigenetics towards the understanding of the mechanisms underlying toxicity and addiction for ethanol, cocaine, amphetamines and heroin. As guest editors of this special issue, we would like to express our appreciation to all the contributors for their imperative work, as well as to the referees for their help towards publishing review articles of high quality. We believe that the aim of this special thematic issue has been fulfilled and we hope that the readers of the journal find it interesting and helpful for their own field of scientific interest and expertise.

Editorial [Hot Topic:Epigenetic Mechanisms and Therapeutic Strategies (Guest Editors: Victoria Samanidou and Leda Kovatsi)]

Epigenetic Mechanisms and Kidney Diseases

Epigenetic Mechanisms and Kidney Diseases, 2011, 18(12) Pp. 1733-1739
V. Liakopoulos, P. I. Georgianos, T. Eleftheriadis and P. A. Sarafidis

In recent years, molecular research has brought to light a series of mechanisms involved in the regulation of gene function without altering the DNA sequence. These mechanisms are described with the term “epigenetics” and include modifications in the structure of the human genome, leading to heritable and potentially reversible changes in gene expression. There is now increasing evidence suggesting that several characteristic features of chronic kidney disease such as hyperhomocysteinemia, subclinical inflammation, increased oxidative stress and others may affect the human epigenome. In addition, animal studies have suggested a possible link between nutrition and environmental exposure during the periconceptional period and epigenetic changes in the expression of major genes implicated in kidney organogenesis; these changes result in a diminished number of nephrons in the developing kidney, which predisposes to an increased risk for hypertension and chronic kidney disease in future life. The understanding of the role of epigenetic phenomena in the pathogenesis of chronic kidney disease opens new avenues for future therapeutic strategies, through the development of pharmaceutical agents that target directly with the changes in the human epigenome. Such epigenetic drugs are already in clinical use for the treatment of cancer as well as under investigation for the use in other diseases. This review will summarize the existing data on the link between epigenetic mechanisms and chronic uremic milieu, as well as the promising results of ongoing research in the field of epigenetic drugs that could represent additional options in our therapeutic armamentarium for patients with chronic kidney disease.

Epigenetic and Genetic Mechanisms of Abnormal 11p15 Genomic Imprinting in Silver-Russell and Beckwith-Wiedemann Syndromes

Epigenetic and Genetic Mechanisms of Abnormal 11p15 Genomic Imprinting in Silver-Russell and Beckwith-Wiedemann Syndromes, 2011, 18(12) Pp. 1740-1750
J. Demars, Y. Le Bouc, A. El-Osta and C. Gicquel

Fetal growth is a complex process depending on the genetics of the fetus, the availability of nutrients to the fetus, maternal nutrition and various growth factors and hormones of maternal, fetal and placental origin. The IGF system, and more particularly IGF2, is one of the most important endocrine and paracrine growth systems regulating fetal and placental growth (reviewed in [1]). The IGF2 gene is regulated by genomic imprinting and is expressed only from the paternally-inherited allele in most tissues during fetal development and after birth. Imprinted genes are tightly regulated and are therefore particularly susceptible to changes, including environmental and nutritional changes. Dysregulation of a cluster of imprinted genes, including the IGF2 gene within the 11p15 region, results in two fetal growth disorders (Silver-Russell and Beckwith-Wiedemann syndromes) with opposite growth phenotypes. Those two syndromes are model imprinting disorders to decipher the regulation of genomic imprinting.

Epigenetic Mechanisms in Alzheimer's Disease

Epigenetic Mechanisms in Alzheimer's Disease, 2011, 18(12) Pp. 1751-1756
M. Daniilidou, M. Koutroumani and M. Tsolaki

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders affecting elderly people (over 65 years old). Only a small percentage (less than 5%) of the disease is consistent with the Mendelian form of inheritance. The rest, named as Late Onset Alzheimer's Disease (more than 95%), is characterized as a complex multi-factorial disorder, missing familial traits. Although some genes have been implicated in the pathogenesis and the risk of developing sporadic AD, they only account for the minority of LOAD cases. Thus, over the past few years emerging data suggest a potential role of epigenetic mechanisms and chromatin remodeling on neurodegenerative processes leading to dementia. Alterations on the epigenomic machinery cause aberrant DNA methylation and histone acetylation. Therefore, these changes trigger alterations on the transcrpiptional level of genes involved in the pathogenesis of AD, such as APP. In this review we summarize recent advances on synaptic dysfunction and cognitive decline caused by common epigenetic modifications. We also discuss potential treatment strategies targeting on the epigenetic machinery.

Epigenetically - Targeted Therapies for the Treatment of Hematological Malignancies

Epigenetically - Targeted Therapies for the Treatment of Hematological Malignancies, 2011, 18(12) Pp. 1757-1764
E. Georgiou and S. Kouidou

Epigenetic modifications, which are heritable changes in gene expression not involving DNA sequence alterations, are important early events in the multi step process of tumorigenesis. Among them, DNA methylation and histone acetylation are the most extensively studied. Although they are, by definition, somatically heritable, epigenetic modifications of DNA and histones are also reversible. This characteristic difference from genetic alterations makes them interesting targets for therapeutic intervention. The huge amount of knowledge gathered in the field of epigenetics the last decade, was followed by the development of novel therapies: old drugs finding new identity and new targets and an increasing list of novel compounds for the treatment of malignant diseases. Hematological malignancies offer a broad spectrum of diseases where epigenetic therapies are shown to be active, providing encouraging results. Some of the more recent reports on this field of therapeutic interventions are reviewed below.

Drugs of Abuse: Epigenetic Mechanisms in Toxicity and Addiction

Drugs of Abuse: Epigenetic Mechanisms in Toxicity and Addiction, 2011, 18(12) Pp. 1765-1774
L. Kovatsi, D. Fragou, V. Samanidou, S. Njau and S. Kouidou

The abuse of substances such as ethanol, cocaine, amphetamines and heroin is associated with toxic effects on almost every system of the organism. Furthermore, the transition from occasional-recreational use to chronic abuse and addiction is a serious psychiatric disorder with only few chances for effective and definitive treatment since most individuals relapse, even after long periods of abstinence. It is therefore of utmost importance to elucidate the mechanisms by which these substances exert their toxicity and mediate addiction, in order to develop new, efficient therapeutic strategies with a long-term outcome, which are currently lacking. We already know that in a great number of these mechanisms, altered gene function is involved. But, with the new field of epigenetics, there is increasing evidence that changes in the epigenome are responsible for the altered gene function. The advances in the field of epigenetics towards elucidation of the mechanisms underlying toxicity and addiction for ethanol, cocaine, amphetamines and heroin are currently presented and discussed in this review.

Neuroinflammation and Neuroprotection: An Update on (Future) Neurotrophin-Related Strategies in Multiple Sclerosis Treatment

Neuroinflammation and Neuroprotection: An Update on (Future) Neurotrophin-Related Strategies in Multiple Sclerosis Treatment, 2011, 18(12) Pp. 1775-1784
L. De Santi, G. Polimeni, S. Cuzzocrea, E. Esposito, E. Sessa, P. Annunziata and P. Bramanti

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS), characterized by inflammation, demyelination and axonal loss underlying progressive clinical disability. The chronic inflammatory tissue damage involving myelin and axons is driven by autoreactive T cells and represents a key mechanism in the immunopathogenesis of MS. Over the last few years, evidence from MS and experimental models of neuroinflammation has suggested that autoimmune responses could exert neuroprotective effects through the release of neurotrophins by autoreactive T cells. Specifically, the role of the Brain-derived neurotrophic factor (BDNF) in facilitating brain tissue repair in experimental traumatic injury has been well recognized. Support for this hypothesis comes from recent studies showing that glatiramer acetate, a currently approved treatment for MS, promotes the expansion of T cell clones crossing the blood-brain barrier and releasing BDNF in situ. A small subset of autoreactive T cells expresses the high-affinity full-length receptor for BDNF (TrkB-TK) in the periphery. In MS patients, T cells show reduced susceptibility to activation-induced apoptosis, a crucial mechanism eliminating autoreactive T clones and contributing to peripheral immunologic tolerance. These findings suggest the existence of a dual effect exerted by BDNF, which not only provides neuroprotection in the CNS but also promotes the survival of autoreactive T cells through an autocrine/paracrine loop. The aim of this review is to discuss the neuroprotective effects of currently approved immunomodulatory treatments for MS and their role in regulating neurotrophin production. We will also describe novel therapeutic strategies arising from new insights on “neuroprotective autoimmunity”.

It is All About Proteases: From Drug Delivery to In Vivo Imaging and Photomedicine

It is All About Proteases: From Drug Delivery to In Vivo Imaging and Photomedicine, 2011, 18(12) Pp. 1785-1805
D. Gabriel, M. F. Zuluaga, H. van den Bergh, R. Gurny and N. Lange

Clinical studies provide overwhelming evidence for the importance of proteolytic imbalance and the upregulation of diverse protease classes in diseases such as cancer and arthritis. While the complex nature of proteolytic networks has hampered the development of protease inhibitors for these indications, aberrant enzyme activity could be successfully exploited for the development of proteasesensitive drug delivery systems and fluorescent in vivo imaging agents. More recently, these concepts have also been translated into photomedical applications to develop dual modality prodrugs for the simultaneous treatment and imaging of disease. After an introductory overview of proteases and their role in cancer, we present and discuss different strategies to exploit upregulated protease activity for the development of drug delivery systems, fluorescent in vivo reporter probes, and photosensitizer-prodrugs with respect to their potential and limitations. The main approaches used for targeting proteases in all three areas can be roughly divided into peptide-based and macromolecular strategies. Both involve the use of a short, peptide-based protease substrate, which is either directly tagged to the therapeutic agent or dye/quencher pair, or alternatively, serves as a linker between the polymeric carrier and a functional unit. In the latter case, the pharmacokinetic properties of peptide-based protease-sensitive prodrugs and imaging probes can be further ameliorated by the passive targeting capacity of macromolecular drug delivery systems for neoplastic and inflammatory lesions.

Cardiovascular Complications in Diabetes: Lessons from Animal Models

Cardiovascular Complications in Diabetes: Lessons from Animal Models, 2011, 18(12) Pp. 1806-1819
M. A. Potenza, C. Nacci, S. Gagliardi and M. Montagnani

Micro- and macro-vascular complications are the leading causes of morbidity and mortality in type 1 and type 2 diabetic patients. Despite the vast clinical experience linking diabetic metabolic abnormalities to cardiovascular lesions, the molecular basis of individual susceptibility to diabetic cardiovascular injury is still largely unknown. Significant advances in this area may come from studies on suitable animal models. Although no animal model can accurately reproduce the human disease, experimental studies in animals have the great advantage to eliminate factors such as ethnicity, economic and geographic variables, drug interactions, diet, gender and age differences that importantly limit clinical studies. Indeed, appropriate animal models have provided important information on genetic and environmental risks of diabetes, and helped to dissect molecular mechanisms underlying the development, progression and therapeutic control of this disease. Unfortunately, none of the diabetic models presently available fully mimics the human syndrome. Therefore, the current knowledge on the pathogenesis of cardiovascular complications relies on the evaluation of distinct phenotypes from various diabetic models. In addition to strains prone to diabetes, this disease can be induced by surgical, pharmacological or genetic manipulation in several animal species. Rodents are the most used, although some studies are still performed in larger animals as rabbits, cats, pigs or monkeys. Far from being exhaustive, this work should serve as a general overview of the most relevant clues provided by major species and models for the overall comprehension of cardiovascular complications in type 1 and type 2 diabetes.

NK-1 Receptor Antagonists: A New Paradigm in Pharmacological Therapy

NK-1 Receptor Antagonists: A New Paradigm in Pharmacological Therapy, 2011, 18(12) Pp. 1820-1831
M. Munoz and R. Covenas

The neuropeptide substance P (SP) shows a widespread distribution in both the central and peripheral nervous systems and it is known that after binding to the neurokinin-1 (NK-1) receptors, SP regulates many biological functions in the central nervous system such as emotional behaviour, stress, depression, anxiety, emesis, migraine, alcohol addiction and neurodegeneration. SP has been also implicated in pain, inflammation, hepatotoxicity and in virus proliferation, and it plays an important role in cancer (e.g., tumour cell proliferation, angiogenesis, and the migration of tumour cells for invasion and metastasis). By contrast, it is known that after binding to NK-1 receptors, NK-1 receptor antagonists specifically inhibit the above-mentioned biological functions mediated by SP. Thus, these antagonists exert an anxyolitic, antidepressant, antiemetic, antimigraine, antialcohol addiction or neuroprotector effect in the central nervous system, and they play a role in analgesic, antiinflammatory, hepatoprotector processes and in antivirus proliferation. Regarding cancer, NK-1 receptor antagonists exert an antitumour action (inducing tumour cell death by apoptosis), and induce antiangiogenesis and inhibit the migration of tumour cells. It is also known that NK-1 receptors have a widespread distribution and that they are overexpressed in tumour cells. Thus, NK-1 receptor antagonists are molecularly targeted agents. In general, current drugs have a single therapeutic effect, although less commonly they may exert several. However, the data reported above indicate that NK-1 receptor antagonists are promising drugs, exerting many therapeutic effects (the action of such antagonists is dose-dependent and, depending on the concentration, has more positive effects). In this review, we update the multiple therapeutic effects exerted by NK-1 receptor antagonists.

Oxidation Chemistry of Catecholamines and Neuronal Degeneration: An Update

Oxidation Chemistry of Catecholamines and Neuronal Degeneration: An Update, 2011, 18(12) Pp. 1832-1845
A. Napolitano, P. Manini and M. d'Ischia

Aberrant oxidative pathways of catecholamine neurotransmitters, i.e. dopamine and norepinephrine, are an important biochemical correlate of catecholaminergic neuron loss in some disabling neurodegenerative diseases of the elderly, notably Parkinson's disease. In an oxidative stress setting, under conditions of elevated lipid peroxidation, iron accumulation, impaired mitochondrial functioning and antioxidant depletion, catecholamines are oxidatively converted to the corresponding o-quinones, which may initiate a cascade of spontaneous reactions, including intramolecular cyclization, aminoethyl side chain fission and interaction with molecular targets. The overall outcome of the competing pathways may vary depending on contingent factors and the biochemical environment, and may include formation of nitrated derivatives, neuromelanin deposition, generation of chain fission products, conjugation with L-cysteine leading eventually to cytotoxic responses and altered cellular function. In addition, catecholamines may interact with products of lipid peroxidation and other species derived from oxidative breakdown of biomolecules, notably glyoxal and other aldehydes, leading e.g. to tetrahydroisoquinolines via Pictet-Spengler chemistry. After a brief introductory remark on oxidative stress biochemistry, the bulk of this review will deal with an overview of the basic chemical pathways of catecholamine oxidation, with special emphasis on the analogies and differences between the central neurotransmitters dopamine and norepinephrine. This chemistry will form the basis for a concise discussion of the latest advances in the mechanisms of catecholamine-associated neurotoxicity in neuronal degeneration.

Role of Lycopene in the Control of ROS-Mediated Cell Growth: Implications in Cancer Prevention

Role of Lycopene in the Control of ROS-Mediated Cell Growth: Implications in Cancer Prevention, 2011, 18(12) Pp. 1846-1860
P. Palozza, N. Parrone, R. Simone and A. Catalano

Dietary intakes of tomatoes and tomato products containing lycopene have been shown to be associated with decreased risk of chronic diseases, such as cancer. Although several mechanisms, including modulation of gap junction communication and enhancement of immune system, are thought to be implicated in its beneficial activities, evidence is accumulating to suggest that lycopene may act as a modulator of intracellular reactive oxygen species (ROS) and, therefore, control ROS-mediated cell growth. According with this, at high concentration, ROS have been reported to be hazardous for living organisms, whereas at moderate concentrations, they play an important role as regulatory mediators in signaling processes regulating cell growth. In this review, we report the available evidence on a role of lycopene as a redox agent in cell proliferation, differentiation and apoptosis. In particular, we focused our attention on lycopene prevention of cell oxidative damage and its influence in cell growth as well as on lycopene modulation of redox-sensitive molecular targets in cell signalling: growth factors and growth factor receptors, antioxidant response elements, MAPKs, transcription factors, such as NF-κB and AP-1, and cytokine expression. Moreover, we speculate on the possible influence that lycopene may have as a redox agent in cancer.

Claudin as a Target for Drug Development

Claudin as a Target for Drug Development, 2011, 18(12) Pp. 1861-1865
A. Takahashi, M. Kondoh, H. Suzuki and K. Yagi

Tight junctions (TJs) play pivotal roles in the fence and barrier functions of epithelial and endothelial cell sheets. Since the 1980s, the modulation of the TJ barrier has been utilized as a method for drug absorption. Over the last decade, the structural and functional biochemical components of TJs, such as occludin and claudin, have been determined, providing new insights into TJ-based pharmaceutical therapy. For example, the modulation of the claudin barrier enhances the jejunal absorption of drugs, and claudin expression is deregulated in cancer cells. Claudin is a co-receptor for the hepatitis C virus. Moreover, claudin is modulated during inflammatory conditions. These findings indicate that claudins are promising drug targets. In this review, we discuss the seeds of claudin-based drug development, which may provide potential pharmaceutical breakthroughs in the future.

Discovery of Small Molecules that Target Autophagy for Cancer Treatment

Discovery of Small Molecules that Target Autophagy for Cancer Treatment, 2011, 18(12) Pp. 1866-1873
L. Wu and B. Yan

Autophagy is a self-renewal process in cells by recycling redundant materials through lysosomal machinery. The basal level of autophagy in eukaryotic cells plays a “housekeeping” role by degrading redundant cellular materials and providing nutrients and energy. However acute and sustained autophagy may cause autophagic cell death. These two features of autophagy are consistent with its complex roles in both oncogenesis and cancer development. Many small molecule autophagy regulators are developed to turn autophagy on/off for therapeutic purpose. The roles of chemotherapeutic agents in regulating autophagy and facilitating cancer treatment can be classified into three categories: direct autophagy enhancers, indirect autophagy enhancers and autophagy inhibitors. The representative autophagy regulators and their roles in cancer treatment were reviewed.

Targeting FK506 Binding Proteins to Fight Malarial and Bacterial Infections:Current Advances and Future Perspectives

Targeting FK506 Binding Proteins to Fight Malarial and Bacterial Infections:Current Advances and Future Perspectives, 2011, 18(12) Pp. 1874-1889
N. Bharatham, M. W. Chang and H. S. Yoon

There is an urgent need for the design and development of new and selective drugs for the treatment of malaria and bacterial infections as these pathogens are developing resistance to presently available therapies. Malaria is a life threatening disease in many countries and responsible for almost one million deaths annually. In particular, drug-resistant malarial parasites are hindering effective control of malaria and prompting to find novel druggable targets and develop compounds with mechanism of action different from the conventional drugs. In this quest, efforts were made to determine three-dimensional structures of Plasmodium falciparum and Plasmodium vivax FK506 binding proteins which bind the macrolides (FK506 and rapamycin) and also demonstrate peptidylprolyl cis-trans isomerase activity in a similar manner as human FKBP12. Previous studies revealed that the immunosuppressive drug FK506 exhibits potential anti-malarial activity by binding FK506 binding domains (FKBD). This review focuses on three different types of FK506 binding proteins/domains in pathogens, their structural characteristics and biological roles. Binding ability of these proteins with the macrolides has opened new possibilities to develop selective inhibitors for these novel targets to combat the life threatening infections.

Editorial [Hot Topic: Targeted Cancer Therapies: Current Status and Future Directions (Guest Editors: Ioannis Starakis)]

Editorial [Hot Topic: Targeted Cancer Therapies: Current Status and Future Directions (Guest Editors: Ioannis Starakis)], 2011, 18(11) Pp. 1573-1574
Ioannis Starakis

During the last three decades, the advances in medical technology have elucidated many of the aspects of genetic and epigenetic pathways that commence the evolution of neoplasia. Standard therapeutic interventions include local control (surgery and/or radiotherapy) along with a combination of chemotherapeutic regimens for a systemic approach. Nevertheless, the appearance of genetically determined resistance to chemotherapeutic agents leads to treatment failures. Targeted tumor therapies consist of molecularly targeted substances that hamper the development and dissemination of malignant cells by interfering with the molecules implicated in cancer expansion and spreading. Targeted treatments, by focusing on specific molecular and cellular modifications of cancer cells, may be more successful than standard chemotherapy and, more importantly, less harmful to normal cells. There have already been some successful attempts of specialized targeting of malignant cells such as the antihormonal manipulation of testosterone and estrogen receptors in prostate and breast cancer, respectively. Our aim is to comprehensively review the current status and future directions of targeted cancer treatments focusing on colorectal cancer, the development of histone deacetylase inhibitors, the implication of endo-cannabinoid system in cancer therapies, the benefits from targeted treatment in lung adenocarcinoma patients, the incorporation of these agents in advanced gastric carcinoma, the emerging therapeutic targeted interventions in tumor-induced bone disease, the effect of targeted therapy in advanced renal cell carcinoma, and, finally, the resistance pathways to epidermal growth factor receptor tyrosine kinase inhibitors, in sufferers from non-small cell lung carcinoma. For decades before the year 2000, leucovorin (LV)-modulated 5-fluorouracil (5-FU) was the only active agent against colorectal cancer, but since then oxaliplatin and irinotecan and also three humanized monoclonal antibodies have been added in our armamentarium against this disease. These antibodies are targeting the vascular endothelial growth factor (bevacizumab) and the epidermal growth factor receptor (panitumumab and cetuximab). The purpose of adjuvant chemotherapy in colon cancer patients after a potentially therapeutic surgical resection is to eliminate micro-metastases, diminish recurrence and also augment cure rates. Adjuvant chemotherapy seems to be more beneficial in stage III (node-positive) disease, while advantage in stage II disease remains ambiguous and most authorities agree that bevacizumab and cetuximab are not recommended in this setting. On the other hand, in patients with non-operable, metastatic colorectal cancer the addition of bevacizumab to an assortment of first-line regimens have showed that improves outcomes. Nonetheless, this favourable response is accompanied by serious adverse events such as thromboembolic incidents, bleeding diathesis, bowel perforation, nephritic syndrome and hypertension. The second-line use of bevacizumab with another chemotherapeutic combination in patients who have failed to respond to the first-line bevacizumab containing regimens is still not established due to lack of sufficient evidence and more randomized clinical trials are needed. It could only be regarded as an option in a special patient group with K-ras mutations, because in those patients the administration of anti- epidermal growth factor receptor (EGFR) regimens is contraindicated. The combination of the anti-EGFR agent, cetuximab with irinotecan is valuable for patients with wild type K-ras tumors who do not respond to irinotecan and also as monotherapy for those who can not tolerate an irinotecan-based combination. Panitumumab has been used as monotherapy for patients with metastatic wild-type K-ras colorectal cancer, when all other agents have failed. The precise role of panitumumab in combination with chemotherapy, particularly for first-line therapy of metastatic colorectal cancer has to be further investigated. There is also accumulative evidence that in patients with wild type K-ras tumors, the combination of first and second line panitumumab with irinotecan or oxaliplatin regimens is more effective than chemotherapy alone but toxicity with severe diarrhoea and electrolytic disturbances was prominent. Further clinical trials comparing cetuximab versus panitumumab, but also each drug versus a bevacizumabcontaining combination are imperative. A deviant histone deacetylases activity has been recognized in several tumor types, rendering them an attractive potential therapeutic target.........

The Endocannabinoid System in the Cancer Therapy: An Overview

The Endocannabinoid System in the Cancer Therapy: An Overview, 2011, 18(11) Pp. 1575-1583
C. Grimaldi and A. Capasso

The endocannabinoid system comprises the cannabinoid receptors type 1 (CB1) and type 2 (CB2), their endogenous ligands (endocannabinoids), and the proteins responsible for their biosynthesis and degradation. This ubiquitous signalling system, that has attracted a great deal of scientist interest in the past 15 years, regulates several physiological and pathological functions. In mammals, among other functions, the endocannabinoid is involved in nervous, cardiovascular, metabolic, reproductive and immune functions. Finally, yet importantly, endocannabinoids are known to exert important antiproliferative actions in a great number of tumor cells including breast, brain, skin, thyroid, prostate and colorectal. The following review describes our current knowledge on the effects of two of the most studied endocannabinoids (AEA and 2-AG) on various types of tumor and summarizes the possible mechanism of observed antitumor effects.

Pathophysiology and Pharmacological Targeting of Tumor-Induced Bone Disease: Current Status and Emerging Therapeutic Interventions

Pathophysiology and Pharmacological Targeting of Tumor-Induced Bone Disease: Current Status and Emerging Therapeutic Interventions, 2011, 18(11) Pp. 1584-1598
V.T. Labropoulou, A.D. Theocharis, A. Symeonidis, S.S. Skandalis, N.K. Karamanos and H.P. Kalofonos

Bone disease is a common complication of metastatic solid tumors but also of primary hematological malignancies such as multiple myeloma. Our understanding of the molecular mechanisms underlying the development of bone disease by solid tumors and multiple myeloma has been significantly improved. A complex inter-dependence exists between bone disease and malignant cell growth, creating a vicious cycle of extensive bone destruction and tumor progression. Although myeloma and solid tumors share a number of common molecular pathogenetic mechanisms, they involve distinct pathophysiological pathways, resulting in osteoclastic bone resorption and inhibition of bone formation. In this review, we analyze the molecular mechanisms, involved in tumor-induced bone disease and discuss the current therapeutic approaches and the most recent clinical developments of emerging targeted therapies.

Targeted Therapy in Colorectal Cancer: Current Status and Future Challenges

Targeted Therapy in Colorectal Cancer: Current Status and Future Challenges, 2011, 18(11) Pp. 1599-1612
A.K. Koutras, I. Starakis, U. Kyriakopoulou, P. Katsaounis, A. Nikolakopoulos and H.P. Kalofonos

Treatment of metastatic colorectal cancer (mCRC) has progressed significantly over the last years, particularly with the introduction of targeted therapies. Two groups of agents targeting either the epidermal growth factor receptor (EGFR) or the vascular endothelial growth factor (VEGF) have been integrated into clinical practice. Currently available agents with established role include the anti-EGFR monoclonal antibodies (mAbs) cetuximab / panitumumab and the anti-VEGF mAb bevacizumab. This review presents an update on the clinical studies evaluating the role of anti-EGFR and anti-VEGF agents in mCRC. Moreover, we provide current data regarding the mechanism of action and pathways mediating resistance to these agents. In addition, we present recent data with respect to biomarkers and we discuss future therapeutic strategies.

Mechanisms of Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients with Advanced Non-Small-Cell Lung Cancer: Clinical and Molecular Considerations

Mechanisms of Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients with Advanced Non-Small-Cell Lung Cancer: Clinical and Molecular Considerations, 2011, 18(11) Pp. 1613-1628
A. Pallis, E. Briasoulis, H. Linardou, C. Papadimitriou, D. Bafaloukos, P. Kosmidis and S. Murray

Non-Small-Cell Lung Cancer (NSCLC) with somatic mutations of the epidermal growth factor receptor (EGFR) is anticipated to respond to small-molecule tyrosine kinase inhibitors (TKIs) of the EGFR tyrosine kinase. There are, however, patients with EGFR mutated tumors who do not demonstrate tumor response. The most widely accepted mechanism of ‘de novo’ (inherent) resistance to these TKIs involves mutations of the KRAS gene. KRAS is a downstream mediator of EGFR-induced cell signaling, such mutations appear to be mutually exclusive from EGFR mutations in lung cancer. The first molecular modifier of resistance identified in patients who developed resistance (termed ‘acquired resistance’) to TK inhibition was a new acquired somatic EGFR mutation (T790M). Today there is an ever-growing series of molecular events that have recently come to the forefront to explain other instances of TKI resistance not attributable to T790M or KRAS. These include a number of molecules that interact with EGFR or form part of its downstream signaling pathway such as HER-2, IGFR-1, MET and B-RAF. Considering that the majority of studies carried out to date with respect to the identification of resistant clones have not used highly sensitive techniques (e.g. allelic discrimination to identify somatic mutations), coupled with the relatively low number of studies examining multiple molecular markers and the accepted molecular heterogeneity of NSCLC raise question as to the existence of ‘acquired’ versus ‘de-novo’ resistance. By examining the current knowledge base with respect to mechanisms of resistance to EGFR TKIs in NSCLC, we explore whether ‘acquired’ resistance is ‘de-novo’ resistance in disguise, and discuss the promises and limitations of molecular stratification with respect to strategies incorporating TKIs in the treatment of NSCLC.

Incorporation of Targeted Agents in the Management of Patients with Advanced Gastric Cancer

Incorporation of Targeted Agents in the Management of Patients with Advanced Gastric Cancer, 2011, 18(11) Pp. 1629-1639
G. Pentheroudakis and A. Stoyianni

Despite declining incidence in developed countries, gastric cancer is still the second cause of cancer death worldwide, while proximal gastric cancer is increasing in incidence. Cytotoxic combinations of platinum salts, fluoropyrimidines with or without taxanes or anthracyclines improved response rates but failed to improve the median survival of patients with advanced gastric cancer beyond the 12-month benchmark. Novel rationally designed therapies targeting molecular aberrations which are tumour-specific and pivotal for tumour survival, are urgently needed in order to improve patient outcome. Angiogenic mediators, transmembrane receptors, signal transduction molecules, transcription factors, epigenetic regulators and other biomolecules are among potential targets being modulated by monoclonal antibodies or small molecules in current phase I, II and III clinical trials. To date, only the addition of trastuzumab, an anti-HER2 monoclonal antibody combined with chemotherapy has yielded a clinically meaningful survival improvement in patients with advanced gastric cancer overexpressing HER2.

Targeted Therapies and other Agents as First-Line Maintenance and Beyond: Particular Benefit in Pulmonary Adenocarcinoma Patients

Targeted Therapies and other Agents as First-Line Maintenance and Beyond: Particular Benefit in Pulmonary Adenocarcinoma Patients, 2011, 18(11) Pp. 1640-1650
F. Petrelli, K. Borgonovo, M. Cabiddu, M. Ghilardi and S. Barni

As of today, advanced non-small cell lung cancer is still an incurable disease. However, recent researches on the biology of adenocarcinoma have led to considerable progress in the treatment of this subgroup of patients. The administration of bevacizumab and pemetrexed as first-line therapy, erlotinib in the maintenance phase and erlotinib again combined with vandetanib as second-line therapy, gives patients with lung adenocarcinoma new hope. In particular, in metastatic adenocarcinoma with an EML4-ALK fusion oncogene, crizotinib (a selective, ATP-competitive, small molecule, orally bioavailable inhibitor of the ALK and MET/HGF receptor tyrosine kinases), led to a response rate of 64%, which is similar to the results achieved in chronic myeloid leukemia and GIST with imatinib. Overall, the application of all available active therapies during the natural history of adenocarcinoma may lead to a survival benefit that was unimaginable only a few years ago. This article reviews the main studies on molecular targeted therapies in various lines of treatment of advanced lung adenocarcinoma.

Targeted-Therapy in Advanced Renal Cell Carcinoma

Targeted-Therapy in Advanced Renal Cell Carcinoma, 2011, 18(11) Pp. 1651-1657
M.T. Pirrotta, P. Bernardeschi and G. Fiorentini

Surgery has been the mainstay of renal cell carcinoma (RCC) treatment for resectable tumours. In stages I-III disease, nephrectomy is the standard of care and may be curative. Historically, patients presenting with stage IV disease may achieve improved survival with debulking nephrectomy, which is commonly performed prior to systemic therapy. The response rate of immunotherapy is low, with a smaller percentage exhibiting complete remission upon treatment. Therefore, new therapeutic approaches against metastatic RCC are necessary. Recently, molecular mechanisms responsible for the proliferation of RCC have been identified, and molecular targeted therapy has developed. Clear cell RCC commonly features mutation or inactivation of the von Hippel- Lindau (VHL) gene and resultant over-expression of vascular endothelial growth factor (VEGF). The first drug to validate VEGF as a target in the treatment of clear cell RCC was the monoclonal antibody bevacizumab. Sunitinib is now a standard first-line therapy for advanced disease and sorafenib is among the second-line treatment options. Mammalian target of rapamycin (mTOR) is a second validated therapeutic target as the mTOR inhibitor temsirolimus has been shown to prolong survival in first-line treatment of poor prognosis RCC of all histologies. Everolimus is an oral mTOR inhibitor and has been shown to prolong progression-free survival (PFS) when used in second-line treatment. This review describes recent advances in molecular targeted therapy for metastatic RCC, focusing on chemical structure and mechanism of action of VEGFR and mTOR inhibitors.

Developing Histone Deacetylase Inhibitors as Anti-Cancer Therapeutics

Developing Histone Deacetylase Inhibitors as Anti-Cancer Therapeutics, 2011, 18(11) Pp. 1658-1671
B. Venugopal and T.R.J. Evans

Post translational modification of histones and non-histone proteins by acetylation play a key role in tumourigenesis. Histone deacetylases (HDACs) are enzymes involved in remodelling of chromatin by deacetylating the lysine residues and play a pivotal role in epigenetic regulation of gene expression. An aberrant activity of HDACs has been documented in several types of cancers and HDACs have emerged as an attractive therapeutic target. HDAC inhibitors (HDACi) are a structurally diverse group of anti-cancer agents which have a potential role in regulation of gene expression and induction of cell death, cell cycle arrest, and differentiation by altering the acetylation status of histone and non-histone proteins. HDACi have pleiotropic effects on malignant cells and have demonstrated potent anti-cancer activity in pre-clinical studies. A number of clinical trials of HDACi as a monotherapy and/or in combination with conventional and novel chemotherapeutic drugs in solid and haematologic tumours have been published with variable efficacy.

Cinnamic Acid Derivatives as Anticancer Agents-A Review

Cinnamic Acid Derivatives as Anticancer Agents-A Review, 2011, 18(11) Pp. 1672-1703
P. De, M. Baltas and F. Bedos-Belval

Cinnamic acid and its phenolic analogues are natural substances. Chemically, in cinnamic acids the 3-phenyl acrylic acid functionality offers three main reactive sites; substitution at the phenyl ring, addition at the α,β-unsaturation and the reactions of the carboxylic acid functionality. Owing to these chemical aspects cinnamic acid derivatives received much attention in medicinal research as traditional as well as recent synthetic antitumor agents. We observed that in spite of their rich medicinal tradition, cinnamic acid derivatives and their anticancer potentials remained underutilized for several decades since the first published clinical use in 1905. In last two decades, there has been huge attention towards various cinnamoyl derivatives and their antitumor efficacy. This review provides a comprehensive and unprecedented literature compilation concerning the synthesis and biological evaluation of various cinnamoyl acids, esters, amides, hydrazides and related derivatives in anticancer research. We envisage that our effort in this review contributes a much needed and timely addition to the literature of medicinal research.

Recent Advances in Studies on Hydroxamates as Matrix Metalloproteinase Inhibitors: A Review

Recent Advances in Studies on Hydroxamates as Matrix Metalloproteinase Inhibitors: A Review, 2011, 18(11) Pp. 1704-1722
R.K. Yadav, S.P. Gupta, P.K. Sharma and V.M. Patil

Matrix metalloproteinases (MMPs) are a large family of calcium-dependent zinc- containing endopeptidases, which are responsible for the tissue remodeling and degradation of the extracellular matrix (ECM), including collagens, elastins, gelatin, matrix glycoproteins, and proteoglycan. The inappropriate expression of these MMPs constitutes part of the pathogenic mechanism in several diseases, therefore they are subject to inhibition. They can be inhibited by endogenous proteinase inhibitors such as α2-macroglobulin or by the family of tissue inhibitors of metalloproteinases (TIMPs), which are glycoproteins of molecular weight 21-30 kDa, consisting of 184- 194 amino acid residues. Recently, many different classes of synthetic inhibitors have been developed in which the hydroxamic acidbased class of compounds (hydroxamates) have been most widely studied, as their hydroxamic acid group (CONHOH) enables them to act as a bidentate ligand with the zinc ion present in MMPs, leading to much stronger interaction with the receptor as compared to any other class of inhibitors. The present review describes in detail the recent development on this class of MMP inihibitors. Compounds like 12,17e, f, g and h, 45j, 45k, 50f, 62a, 63a, and 63b have been reported to be highly promising for further development.

Iron Regulation in Tuberculosis Research: Promise and Challenges

Iron Regulation in Tuberculosis Research: Promise and Challenges, 2011, 18(11) Pp. 1723-1731
A.K. Sharma, R. Naithani, V. Kumar and S.S. Sandhu

Tuberculosis is a major global health challenge and is far from being controlled. Development of resistance to currently available drugs due to the successful adaptation of the pathogen has been a major contributing factor for its control failure. Presently, there is an immense interest in identification of pathways, unique to the intracellular environment that could be utilized for the development of new and better drugs. In this sequence, targeting essential functions of Mycobacterium tuberculosis has emerged as a reliable strategy for containing the spread of the disease by this organism. The fact that iron has been known to be the key player required for its survival and ability to spread infection, the organism must carefully balance iron acquisition with iron uptake for its infectivity. Conversely, this iron homeostatic process could be disrupted to interfere with the survival and replication of this bacterium in host. Urgency to develop such an approach has been further strengthened with the worldwide recrudescence of tuberculosis especially in the developing nations of the world. In the current review, we have focused on the recent developments in targeting the essential functions of mycobacterium especially interfering in its iron homeostatic process. The relevance of iron for mycobacterial virulence, the intracellular survival and the immense potential of targeting iron-sulfur (Fe-S) cluster containing proteins in tuberculosis drug discovery has been discussed.

Editorial [Hot Topic: Non-Invasive Assessment of Asthmatic Inflammation: From Bench to Bedside (Guest Editors: S. Loukides, K. Kostikas and P. Bakakos)]

Editorial [Hot Topic: Non-Invasive Assessment of Asthmatic Inflammation: From Bench to Bedside (Guest Editors: S. Loukides, K. Kostikas and P. Bakakos)], 2011, 18(10) Pp. 1413-1414
Stelios Loukides, Konstantinos Kostikas and Petros Bakakos

Asthma is now recognized as a heterogeneous disease, based on clinical parameters, the type of inflammation, the response to treatment, the rate of exacerbations and, finally, the underlying control and/or severity. Attempts to apply the above diverse characteristics to the clinical presentation of the disease have led to the identification of different phenotypes, with significant overlapping. The field of non invasive techniques has been rapidly developed since the time that the fraction of exhaled nitric oxide (FeNO) was recognized as an easily measured mediator in the exhaled air [1]. At approximately the same time, induced sputum was recognized as a valuable technique for the identification of the inflammatory cellular population as well as for the evaluation of different mediators in sputum supernatants [2]. Exhaled breath condensate (EBC), a totally non invasive technique, gave us the opportunity to sample the airways in an even more easily applicable approach, but the several methodological pitfalls of this method prevent it from being an accurate procedure for the evaluation of airways inflammation [3]. The attempt to connect the whole asthma entity and its numerous phenotypes using those minimally invasive techniques, i.e. FeNO, induced sputum and EBC, involves two major steps: First, these techniques must become more widely accepted and applied and, second, we need data from large multicenter studies that will identify the distinct inflammatory characteristics of specific phenotypes. Every single biomarker obtained by non invasive techniques must fulfill some requirements, in order to be applicable in every day clinical practice: it must be measurable in the field, be measurable in the specific disease, have a standardized methodology, have normal values that clearly discriminate normality from disease, present reproducibility and stability within measurements, be associated with an established inflammatory process and, finally, be applicable as a tool for guided treatment strategy. According to these requirements, it is quite difficult or even impossible for a single biomarker obtained from non invasive techniques to fulfill them. The majority of the numerous studies involving non invasive techniques for the assessment of airways inflammation evaluated the discriminative power of biomarkers in respect to the presence or absence of a specific disease. This approach has certain value, but does not add useful information for clinical practice in an inflammatory disease that presents significant day-to-day variability such as asthma. A more useful approach would be to evaluate a specific biomarker using statistical tools dedicated to test the diagnostic performance of a biomarker. For example, using receiver operating characteristics (ROC) analysis we can define specific cut-off values that may characterize the potential utility of a biomarker as a predictive tool for survival or disease progression or even as a tool for the prediction of other significant outcomes related to treatment response. There is additional need for the validation of such cut-off points in prospective trials involving decisionmaking. The current literature presents only limited data in that direction at the moment. The most promising data to-date are those published for induced sputum, that have used a specific cut-off value for eosinophils as predictors of severe exacerbations in respect to treatment intervention with inhaled steroids [4]. Similar data exist for FeNO in predicting multiple outcomes in asthma, both clinical and/or inflammatory [5]. The majority of the later studies have focused on sputum cellular population, and particularly on eosinophils. In contrast to those two widely evaluated biomarkers, the literature on EBC still does not include any data for the support of the aforementioned requirements. EBC pH is nowadays considered a promising parameter, since its values may discriminate between asthmatics and normal subjects [6] and present an association with eosinophilic inflammation [7], but the absence of robust longitudinal data still limits its application in clinical practice. Recently published data in a prospective study showed that EBC pH can be used to monitor asthma exacerbations, however with no associations with alterations in lung function or FeNO [8]. In this hot topic issue, the three most widespread techniques of non invasive or minimally invasive assessment of airways inflammation are described in details, all the way from the point of technical considerations to the implementation in clinical practice. It is widely accepted that all these techniques have provided clinicians and researchers with tools for the understanding of the underlying pathophysiology of the disease. But is this the main target? Definitely not. What we really need from non invasive techniques is to be implemented in clinical practice and provide useful information for the diagnostic approach, the identification of specific phenotypes, the evaluation of asthma control and the facilitation of decision-making. FeNO represents the only exhaled asthma biomarker that has reached clinical practice today. Despite some methodological issues, FeNO represents a good surrogate biomarker of eosinophilic airways inflammation, can serve as an aid to the diagnosis of asthma, may identify loss or restoration of asthma control as well as certain clinically relevant phenotypes (including an “at risk” phenotype in severe asthma), may predict steroid response and exacerbations, and may provide a possible aid for treatment guidance, especially in patients with difficult asthma [1]. Which is the contribution of EBC in the above requirements? Although promising, EBC is currently used only as a research tool, due to the lack of appropriate standardization and the absence of reference values [9]. Some of the biomarkers obtained by EBC can identify certain phenotypes, but with significant overlapping between measurements. Last but not least, sputum induction may share with FeNO some clinically useful applications mainly related to the detection of non-adherence to corticosteroid therapy, the assessment of the adequacy of inhaled corticosteroid therapy, the long-term management of asthma and the adjustment of oral corticosteroid dose in refractory asthma. Specifically, induced sputum may be used to study the dose-response effect of inhaled corticosteroids and may be useful to establish the relative potency of different corticosteroid formulations and delivery devices. Finally, prospective studies have shown that it is better than clinical assessment in reducing the rate of exacerbations [2], especially the eosinophilic ones [10]. What do we expect from the biomarkers obtained by non invasive methods in asthma? Based on the heterogeneity of the disease, the need for identification of the different disease phenotypes within the range of these syndromes is crucial for the proper management of the individual patient. Based on current knowledge, it is not likely that a single biomarker will suffice for the identification of the underlying pathophysiology and/or the clinically useful phenotyping of asthma. What is definitely needed is the proper combination of biomarkers, even from different techniques, in order to achieve their maximal effectiveness. Clinical assessment and physiologic parameters, such as spirometry, provide highly useful information, but they can not provide objective information in relation to the inflammatory process. The quest for a non invasive inflammometer has been a target for both clinicians and researchers in the past twenty years. Considering that the term inflammation is highly heterogeneous, we should be definitely seeking ways to combine the inflammatory characteristics with clinical features in order to characterize particular phenotypes. This concept may help physicians provide individualized treatment for each patient in the future......

Induced Sputum in Asthma: From Bench to Bedside

Induced Sputum in Asthma: From Bench to Bedside, 2011, 18(10) Pp. 1415-1422
P. Bakakos, F. Schleich, M. Alchanatis and R. Louis

During recent years there has been a growing interest in using non-invasive biomarkers to understand and monitor the airway inflammation in subjects with respiratory tract disorders and mainly asthma and chronic obstructive pulmonary disease (COPD). Sputum induction is generally a well-tolerated and safe procedure and a European Respiratory Society Task Force has published a comprehensive review on sputum methodology. Induced sputum cell count and, to a lesser extent, mediator measurements have been particularly well validated. In asthma, the sputum and the cell culture supernatant can be used for the measurement of a variety of soluble mediators, including eosinophil-derived proteins, nitric oxide (NO) derivatives, cytokines and remodelling-associated proteins. Sputum eosinophilia ( > 3%) is a classic feature of asthma although half of the patients seems to be non eosinophilic. Measuring the percentage of sputum eosinophils has proved to be useful in the clinical arena in helping to predict short term response to inhaled corticosteroids (ICS) and tailor the dose of ICS in the severe patients but there is scope for the application of other induced sputum markers potentially useful in clinical practice. The widespread application of induced sputum in asthma across the spectrum of disease severity has given insight into the relationship between airway function and airway inflammation, proposed new disease phenotypes and defined which of these phenotypes respond to current therapy, and perhaps most importantly provided an additional tool to guide the clinical management of asthmatic patients. To date sputum induction is the only non-invasive measure of airway inflammation that has a clearly proven role in asthma management.

Exhaled Nitric Oxide in Asthma in Adults: The End is the Beginning?

Exhaled Nitric Oxide in Asthma in Adults: The End is the Beginning?, 2011, 18(10) Pp. 1423-1431
K. Kostikas, M. Minas, A. I. Papaioannou, S. Papiris and R. A. Dweik

Approximately 20 years after the initial report of the measurement of exhaled nitric oxide (NO) in the exhaled air of humans, numerous publications have evaluated the possible applications of the fraction of exhaled NO (FeNO) in patients with asthma. The aim of the present review is to evaluate the technical issues and confounding factors related to FeNO measurements, as well as the role of FeNO in the diagnosis of asthma, the evaluation of asthmatic patients and the guidance of treatment. Several other issues, including the pursuit for “normal” and best personal values, the prediction of clinically relevant asthma outcomes and the identification of asthma phenotypes and future directions are discussed. FeNO represents the only exhaled biomarker that has reached clinical practice even in primary care settings and this review provides a critical view of the possible applications of this biomarker, both for the basic researcher and the clinician.

Exhaled Breath Condensate in Asthma: From Bench to Bedside

Exhaled Breath Condensate in Asthma: From Bench to Bedside, 2011, 18(10) Pp. 1432-1443
S. Loukides, K. Kontogianni, G. Hillas and I. Horvath

The need for non-invasive assessment of airway inflammation is imperative, since inflammatory airway diseases, such as asthma and COPD, are characterized by variation in their clinical presentation throughout their course. Exhaled breath condensate (EBC) collection represents a rather appealing method that can be used to conveniently and noninvasively collect a wide range of volatile and non-volatile molecules from the respiratory tract, without affecting airway function or inflammation. Although promising, EBC is currently used only as a research tool, due to the lack of appropriate standardization and the absence of reference values. A large number of mediators of inflammation, oxidative and nitrosative stress, including adenosine, ammonia, hydrogen peroxide, isoprostanes, leukotrienes, prostanoids, nitrogen oxides, peptides and cytokines, have been studied in EBC. This review focuses mainly on the presentation of the above biomarkers in asthma as well as on the effect of various factors on their concentrations. Concentrations of such mediators have been shown to be related to the underlying asthma and its severity and to be modulated by therapeutic interventions. Despite the encouraging positive results up-to-date, the introduction of EBC in everyday clinical practice requires the work-out of some methodological pitfalls, the standardization of EBC collection, and finally the identification of a reliable biomarker which is reproducible, has normal values and provides information for the underlying inflammatory process and the response to treatment. So far none of the parameters studied in EBC fulfils the aforementioned requirements.

The Importance of Alkynyl Chain Presence for the Activity of Adenine Nucleosides/Nucleotides on Purinergic Receptors

The Importance of Alkynyl Chain Presence for the Activity of Adenine Nucleosides/Nucleotides on Purinergic Receptors, 2011, 18(10) Pp. 1444-1463
D. Dal Ben, M. Buccioni, C. Lambertucci, G. Marucci, R. Volpini and G. Cristalli

The first demonstrations in the early seventies that adenosine had marked effects in the cerebral cortex, which were independent of its role in intermediary metabolism and could be antagonised by methylxanthines, were followed by the observations that other purine derivatives, notably ATP, may also play a critical role in cell function. In 1978 Burnstock first introduced the terms Pl for the nucleoside receptors and P2 for the nucleotide receptors, based on the most fundamental divisions of purine receptors between those for nucleosides such as adenosine and those for nucleotides such as ATP. At present, the P1 (adenosine) receptor family presents 4 subtypes, while the P2 (ATP, ADP and UTP) receptor family has been divided into P2X ionotropic receptors and P2Y metabotropic G proteincoupled receptors (GPCRs). While knowledge on the purinergic receptor pharmacology was increasing, the development of potent and selective ligands for these receptors has been a target of medicinal chemistry research for several decades. In particular, synthesis of 2- substituted adenosines was carried out in many laboratories starting from seventies aimed at finding adenosine derivatives more resistant than the parent nucleoside to rapid uptake into cells, to deamination by adenosine deaminase, and to phosphorylation by adenosine kinase. In the present review the synthesis of alkynyl derivatives of adenine, adenosine, N-alkylcarboxamidoadenosine, and adenine nucleotides, which have been tested on purinergic receptors, will be summarized. Furthermore, the contribution of chemistry, molecular modelling, and pharmacology to the development of structure-activity relationships in this class of purinergic receptor ligands will be outlined.

Hybrid Molecules Incorporating Natural Products: Applications in Cancer Therapy, Neurodegenerative Disorders and Beyond

Hybrid Molecules Incorporating Natural Products: Applications in Cancer Therapy, Neurodegenerative Disorders and Beyond, 2011, 18(10) Pp. 1464-1475
M. Decker

In this article the design of hybrid molecules that covalently connect two distinct drug entities in one molecule, at least one part being a biologically active natural product will be discussed. In the quest for novel drug entities, the hybrid approach is a promising path to drug molecules that can effectively target multifactorial diseases including neurodegenerative disorders like Alzheimer's and Parkinson's diseases (AD and PD). The hybrid approach can also be used to optimize certain biological properties like affinity and selectivity, but also to gain novel biological activities distinct from the ones of the components. Due to the high potential of natural products to exhibit pronounced biological activities, natural products have been one of the major sources of components in hybrid molecules. This review will cover their applications in developing drugs for neurodegenerative disorders, in the diverse field of anti-cancer agents (which represents the major application for natural products in medicinal chemistry), but also in miscellaneous areas of bioactive compounds including antioxidants, antimalarial drugs and estrogen-related hybrids to reach various therapeutic aims. The unique tasks of hybrid molecule design will be addressed, such as describing suitable ways to chemically connect the drug components, how to use the approach to enhance biological activity with respect to both activity and selectivity and potential drawbacks of the hybrid approach. It will be shown that hybrids can be more than the sum of their components, but in many cases should be considered as pharmacological entities in their own respect.

The Role of Cytokines in Atopic Asthma

The Role of Cytokines in Atopic Asthma, 2011, 18(10) Pp. 1476-1487
M. Finiasz, C. Otero, L. Bezrodnik and S. Fink

Atopic asthma results from airway inflammation triggered by an environmental allergen. Symptoms include wheezing, dyspnea and cough, airway narrowing and/or hyperresponsiveness to several inhaled stimuli. Inflammation develops in a two-phase fashion. The first phase after exposure to the allergen consists of degranulation and release of both histamine and other stored preformed inflammatory mediators as well as newly synthesized ones, including cytokines, all of which increase mucus secretion and smooth muscle contraction. The second phase occurs later and lasts longer; it is due to different molecules: several cytokines and chemokines, arachidonic acid derivatives, enzymes such as metalloproteinases and cell adhesion molecules. Cytokines are key players in the chronic inflammation in asthma patients, but details on their role and interactions still remain undetermined. Recent evidence suggests that allergic asthma is a multifaceted condition actively controlled by effector as well as regulatory T cells (Tregs). T helper (Th) 2 cells and Th17 cells increase airway inflammation, while Tregs are anti- inflammatory. Cytokines are involved in the development and activation of all T cell subpopulations. They are also involved directly or indirectly in most approaches to asthma treatment. Several cytokines have been tested as therapeutic targets and some of the currently used therapies like corticosteroids, beta agonists and allergen immunotherapy affect cytokine production. The increased knowledge on cytokine interplay and lymphocyte subsets should generate new therapeutic strategies in the near future.

Quinoline as a Privileged Scaffold in Cancer Drug Discovery

Quinoline as a Privileged Scaffold in Cancer Drug Discovery, 2011, 18(10) Pp. 1488-1508
V. R. Solomon and H. Lee

Quinoline (1-azanaphthalene) is a heterocyclic aromatic nitrogen compound characterized by a double-ring structure that contains a benzene ring fused to pyridine at two adjacent carbon atoms. Quinoline compounds are widely used as “parental” compounds to synthesize molecules with medical benefits, especially with anti-malarial and anti-microbial activities. Certain quinoline-based compounds also show effective anticancer activity. This broad spectrum of biological and biochemical activities has been further facilitated by the synthetic versatility of quinoline, which allows the generation of a large number of structurally diverse derivatives. This includes numerous analogues derived from substitution of the quinoline ring system, and derivatization of quinoline ring structure. Quinoline and its analogs have recently been examined for their modes of function in the inhibition of tyrosine kinases, proteasome, tubulin polymerization and DNA repair. In this review, we have summarized our knowledge on quinoline compounds with respect to their anticancer activities, mechanisms of action, structure-activity relationship (SAR), and selective and specific activity against various cancer drug targets. In particular, we focus our review on in vitro and in vivo anticancer activities of quinoline and its analogs in the context of cancer drug development and refinement.

Exploring Old Drugs for the Treatment of Hematological Malignancies

Exploring Old Drugs for the Treatment of Hematological Malignancies, 2011, 18(10) Pp. 1509-1514
F. Gan, B. Cao, D. Wu, Z. Chen, T. Hou and X. Mao

Drug discovery is costly and time-consuming, but it will become easier and simpler if a drug could be developed from an old one with well-documented investigations associated with pharmacology, pharmacokinetics, toxicology and clinical safety. In terms of hematological malignancies, several successful drugs have been discovered and developed from old ones such as arsenic trioxide for acute promyelocytic leukemia and thalidomide for multiple myeloma. In this review, we discussed the latest advancement in exploring old drugs for the treatment of hematological malignancies.

Oxysterol Derivatives of Cholesterol in Neurodegenerative Disorders

Oxysterol Derivatives of Cholesterol in Neurodegenerative Disorders, 2011, 18(10) Pp. 1515-1525
T. M. Jeitner, I. Voloshyna and A. B. Reiss

Cholesterol is essential to the functions of the brain, which contains approximately 20% of the body's stores of this sterol. Most brain cholesterol is found in compacted myelin. The operation of the blood brain barrier (BBB) precludes the uptake of cholesterol from the periphery and consequently this sterol is produced de novo in the brain. In contrast, oxysterols a class of hydroxylated cholesterol catabolites traverse the BBB readily and facilitate the elimination of cholesterol from the brain. Oxysterols not only act as a transport form of cholesterol, but serve as endogenous regulators of gene expression in lipid metabolism and behave as ligands to nuclear receptors. Two of the more important brain-derived oxysterols are 24S-hydroxycholesterol and 27-hydroxycholesterol. Aberrant cholesterol metabolism has been implicated in a number of neurological disorders. Since oxysterols are thought to reflect the cerebral cholesterol turnover there has been great interest in the diagnostic and prognostic value of these metabolites in neurodegenerative diseases of the brain. The following article provides an overview of the involvement of oxysterols in Alzheimer's disease, multiple sclerosis and spastic paraplegias.

Pharmacophore Design of p38α MAP Kinase Inhibitors with Either 2,4,5-Trisubstituted or 1,2,4,5-Tetrasubstituted Imidazole Scaffold

Pharmacophore Design of p38α MAP Kinase Inhibitors with Either 2,4,5-Trisubstituted or 1,2,4,5-Tetrasubstituted Imidazole Scaffold, 2011, 18(10) Pp. 1526-1539
T. Scior, D. M. Domeyer, K. Cuanalo-Contreras and S. A. Laufer

Synthetic compounds with a tri- and tetra-substituted imidazole scaffold are known as selective inhibitors of the p38 mitogenactivated protein (MAP) kinase responsible for proinflammatory cytokine release. The scope is to review the literature describing their design, synthesis and activity studies. To date a great plethora of crystal structures of p38 in complex with small organic ligands have been published. Cocrystallized ligand information is of particular interest to our review study, i.e. ATP itself, the reference inhibitor SB203580 with its aryl-pyridinyl-imidazoles and related imidazole and pyrimidine-based derivatives. The selective inhibitors bind to the pocket of adenosine 5'-triphoshate (ATP) replacing the latter. The hydrophobic region II, however, is not occupied by the natural binder ATP, but accommodates the pyridine substituents preserving the 4-fluorophenyl ring occupation in pocket I as a prerequisite to gain higher binding selectivity and potency than the reference compound SB203580 (4-[5-(4-fluoro-phenyl)-2-(4-methanesulfinyl-phenyl)-3himidazol- 4-yl]-pyridine). Experimental and computed work is reviewed which evidence that the 2 position of the pyrimidine ring is amenable to the introduction of a side chain and the replacement of pyridine in SB203580 by a pyrimidine ring improves both inhibitory activity and selectivity for p38 over other kinases. All ligands with a pyridyl C2 side chain occupy the hydrophobic pocket II and in some cases a double hydrogen bond is reported between methionine 109 and glycine 110 of the hinge region, following an observed backbone shift. The substituted pyridine ring binds stronger than the two other side chains on the imidazole scaffold.

Enlarging the NSAIDs Family: Ether, Ester and Acid Derivatives of the 1,5-Diarylpyrrole Scaffold as Novel Anti-Inflammatory and Analgesic Agents

Enlarging the NSAIDs Family: Ether, Ester and Acid Derivatives of the 1,5-Diarylpyrrole Scaffold as Novel Anti-Inflammatory and Analgesic Agents, 2011, 18(10) Pp. 1540-1554
M. Biava, G. C. Porretta, G. Poce, C. Battilocchio, M. Botta, F. Manetti, M. Rovini, A. Cappelli, L. Sautebin, A. Rossi, C. Pergola, C. Ghelardini, N. Galeotti, F. Makovec, A. Giordani, P. Anzellotti, S. Tacconelli, P. Patrignani and M. Anzini

The development of the coxib family has represented a stimulating approach in the treatment of inflammatory disorders, such as arthritis, and for the management of acute pains, in relation to the well-known traditional Non-Steroidal Anti-inflammatory Drugs (t- NSAIDs). Prompted by the pursuit for new cyclooxygenase-2 (COX-2) inhibitors, endowed with fine tuned selectivity and high potency, in the past years we have identified novel classes of ether, ester and acid molecules characterized by the 1,5-diarylpyrrole scaffold as potentially powerful anti-inflammatory molecules (12-66). All compounds proved to exert an in vitro inhibition profile as good as that shown by reference compounds. Compounds bearing a p-methylsulfonylphenyl substituent at C5 displayed the best issues. In particular, ester derivatives proved to perform the best in vitro profile in terms of selectivity and activity toward COX-2. The cell-based assay data showed that an increase of hindrance at the C3 side chain of compounds could translate to activity enhancement. The human whole blood (HWB) test let to highlight that submitted compounds displayed 5-10 fold higher selectivity for COX-2 vs COX-1 which should translate clinically to an acceptable gastrointestinal safety and mitigate the cardiovascular effects highlighted by highly selective COX-2 inhibitors. Finally, to assess in vivo anti-inflammatory and analgesic activity three different tests (rat paw pressure, rat paw oedema and abdominal constriction) were performed. Results showed good in vivo anti-inflammatory and analgesic activities. The issues gained with these classes of compounds represent, nowadays, a potent stimulus for a further enlargement of the NSAIDs family. In this review we describe the results obtained by our research group on this topic.

Falcipains, Plasmodium falciparum Cysteine Proteases as Key Drug Targets Against Malaria

Falcipains, Plasmodium falciparum Cysteine Proteases as Key Drug Targets Against Malaria, 2011, 18(10) Pp. 1555-1572
C. Teixeira, J. R.B. Gomes and P. Gomes

There is a high demand for new drugs against malaria, which takes millions of lives annually. The abuse of classical antimalarials from the late 1940's to the early 1980's has bred resistant parasites, which led to the use of more potent drugs that ended up by refueling the resistance cycle. An example is chloroquine, once highly effective but now virtually useless against malaria. Structure-based rational drug design relies on high-resolution target structures to allow for screening of selective ligands/inhibitors. For the past two decades, and especially after the unveiling of the Plasmodium falciparum genome in 2002, enzymes of this lethal malaria parasite species have been increasingly attracting the attention of Medicinal Chemists worldwide as promising drug targets. There is particular emphasis on proteases having key roles on the degradation of host's hemoglobin within the food vacuole of blood-stage parasites, as these depend on such process for their survival. Among such enzymes, Plasmepsins (aspartic proteases) and, especially, Falcipains (cysteine proteases) are highly promising antimalarial drug targets. The present review will focus on the computational approaches made so far towards the unraveling of the structure, function and inhibition of Falcipains that, by virtue of their quite specific features, are excellent targets for highly selective inhibitors.

Editorial [Hot Topic:Protein targets for development of drugs against Mycobacterium tuberculosis (Guest Editor: Walter Filgueira de Azevedo)]

Editorial [Hot Topic:Protein targets for development of drugs against Mycobacterium tuberculosis (Guest Editor: Walter Filgueira de Azevedo)], 2011, 18(9) Pp. 1255-1257
Walter Filgueira de Azevedo

The bacterium Mycobacterium tuberculosis remains a major challenge to public health systems worldwide, especially affecting developing countries in Asia, Africa, Latin America and Eastern Europe. Tuberculosis (TB) is one the most common bacterial diseases of humans, and World Health Organization estimates that nearly thirty percent of the world's population is infected with M. tuberculosis in a latent form and, as a result, at risk of developing active TB [1]. Furthermore, the appearance of multidrug-resistant (MDR) and extensively drug-resistant (XDR, resistant to first- and second-line anti-TB drugs) strains of M. tuberculosis has worsened the situation. . This scenario makes clear the need for development of a new generation of successful drugs against TB. The development of a new drug is result of combination of biological activity and drug-like properties. These qualities can be evaluated by computational approaches in the initial stages of drug discovery and development. Being structure-based virtual screen (SBVS) the major methodology applied for this end. SBVS is a methodology that requires structural information about protein targets, and can be applied to test libraries of small-molecule compounds against important targets for drug design, including targets identified in the Mycobacterium tuberculosis [2]. The use of combination of different drugs is of pivotal importance to stop the appearance of multiple drug resistant (MDR) organisms by spontaneous genetic mutations, which can lead to an ineffective treatment. Therefore new proteins should be targeted for drug development. Several enzymes of the purine and pyrimidine salvage pathways [3,4], shikimate pathway [5], and mycolic acid biosynthetic pathway [6] have been validated as anti-TB targets. The present volume of Current Medicinal Chemistry brings reviews focused on protein targets identified in Mycobacterium tuberculosis. There are reviews about protein-drug interactions and structural basis for inhibition of protein targets identified in the Mycobacterium tuberculosis genome. Among them the enzymes of the shikimate pathway, which represent potential protein targets for developing antibacterial agents, and anti-parasite drugs, because these enzymes are of pivotal importance for bacteria and protozoans, but they are absent from humans [5]. The shikimate pathway is a connection between the metabolism of carbohydrates and the biosynthesis of aromatic compounds through seven metabolic steps. In these pathway phosphoenolpyruvate (PEP) and erythrose 4-phosphate are converted to chorismic acid [7,8]. Due to importance of this pathway, several structural studies focused on these enzymes were carried our [9-19]. This structural information opened the possibility for structure-based virtual screens, which may be able to identity new anti-tubercular drugs [20]. This volume presents two reviews with information about structural studies of shikimate kinase (EC 2.7.1.71) and chorismate synthase (EC 4.2.3.5)...... In addition, a review by Obiol-Pardo and collaborators describes the mechanism of action and inhibitors of the seven enzymes of the methylerythritol phosphate (MEP) pathway for isoprenoid biosynthesis, with special attention to the reported studies in M. tuberculosis. Enzymes of this pathway are also potential targets for antitubercular drugs. Three other metabolic pathways are reviewed here: purine salvage pathway (by Ducati and collaborators), pyrimidine salvage pathway (by Villela and collaborators) and mycolic acid biosynthetic pathway (by Singh and collaborators). It is also discussed here recent development of structure-based virtual screening methodologies, including a review on modern computational approaches to molecular docking simulations. Molecular docking is a computer simulation methodology to predict the conformations of a receptor-ligand complex [21-28]. It is possible to visualize that this simulation is analogous to the key-and-lock problem, where the lock is the receptor and the key the ligand. The goal in this kind of simulation is to adjust the position of the key in the lock. In a computer simulation it is generated many possible positions for the key in the lock, which are called poses. Docking simulations employ one or more of the following methodologies: Monte Carlo (MC) [29], fast shape matching (SM) [30], incremental construction (IC) [31, 32], distance geometry (DG) [33], simulated annealing (SA) [34, 35] and tabu search (TS) [36]. All these computational methodologies have been recently reviewed [37]. Although intense research has been performed on the application of the above mentioned algorithms to the problem of molecular docking simulations, recent results strongly indicate that the most successful approaches are those based on BIAs [27, 38], such as evolutionary programming (EP) [39, 40] and genetic algorithms (GA) [41-43]. These approaches and their application to development of antiTB drugs are discussed here. Structural aspects such as intermolecular hydrogen bonds, contact area and electrostatic interactions can be analyzed from threedimensional structures of complexes involving protein-targets and ligand [44]. Nevertheless, the precise analysis of protein-drug interactions from these structures is inadequate since crystal structures are average structures obtained from the molecules packed in the crystal lattice. It is hard to identify directly from crystallographic structure the flexible parts of the molecule. These limitations can be overcome by application of molecular dynamics simulations. Three-dimensional structures obtained experimentally or by homology modeling can be submitted to this simulation, where dynamical features of the complexes can be analyzed. These methods are also described in the present volume. Several recent applications of SBVS successful identified new drugs, which serve as incentives for development of new methodologies and also for extending the application to a wide range of protein targets and diseases [45-69]. In conclusion, one of the most defying challenges in the post-genomic era is the understanding of dynamics and structural features of the protein-drug interaction. Information obtained from structural studies of protein targets together with molecular docking and dynamics simulations will pave the way for discovery and development of a new generation of drugs. Finally, I would like to express gratitude to the authors for their significant contribution to this special issue, which hopefully will be of significance to researchers working in the development of a new generation of antiTB drugs.

Purine Salvage Pathway in Mycobacterium tuberculosis

Purine Salvage Pathway in Mycobacterium tuberculosis, 2011, 18(9) Pp. 1258-1275
R. G. Ducati, A. Breda, L. A. Basso and D. S. Santos

Millions of deaths worldwide are caused by the aetiological agent of tuberculosis, Mycobacterium tuberculosis. The increasing prevalence of this disease, the emergence of drug-resistant strains, and the devastating effect of human immunodeficiency virus coinfection have led to an urgent need for the development of new and more efficient antimycobacterial drugs. The modern approach to the development of new chemical compounds against complex diseases, especially the neglected endemic ones, such as tuberculosis, is based on the use of defined molecular targets. Among the advantages, this approach allows (i) the search and identification of lead compounds with defined molecular mechanisms against a specific target (e.g. enzymes from defined pathways), (ii) the analysis of a great number of compounds with a favorable cost/benefit ratio, and (iii) the development of compounds with selective toxicity. The present review describes the enzymes of the purine salvage pathway in M. tuberculosis as attractive targets for the development of new antimycobacterial agents. Enzyme kinetics and structural data have been included to provide a thorough knowledge on which to base the search for compounds with biological activity. We have focused on the mycobacterial homologues of this pathway as potential targets for the development of new antitubercular agents.

Analysis of Molecular Targets of Mycobacterium tuberculosis by Analytical Ultracentrifugation

Analysis of Molecular Targets of Mycobacterium tuberculosis by Analytical Ultracentrifugation, 2011, 18(9) Pp. 1276-1285
J. C. Borges and C. H.I. Ramos

The interest in analytical ultracentrifugation (AUC) to analyze protein structural parameters and interactions has increased in the past decades as a result of several developments on new generation instrumentation and data analysis tools. In this article, we review AUC principles and applications to study proteins, emphasizing molecular targets of Mycobacterium tuberculosis.

Pyrimidine Salvage Pathway in Mycobacterium tuberculosis

Pyrimidine Salvage Pathway in Mycobacterium tuberculosis, 2011, 18(9) Pp. 1286-1298
A. D. Villela, Z. A. Sanchez-Quitian, R. G. Ducati, D. S. Santos and L. A. Basso

The causative agent of tuberculosis (TB), Mycobacterium tuberculosis, infects one-third of the world population. TB remains the leading cause of mortality due to a single bacterial pathogen. The worldwide increase in incidence of M. tuberculosis has been attributed to the high proliferation rates of multi and extensively drug-resistant strains, and to co-infection with the human immunodeficiency virus. There is thus a continuous requirement for studies on mycobacterial metabolism to identify promising targets for the development of new agents to combat TB. Singular characteristics of this pathogen, such as functional and structural features of enzymes involved in fundamental metabolic pathways, can be evaluated to identify possible targets for drug development. Enzymes involved in the pyrimidine salvage pathway might be attractive targets for rational drug design against TB, since this pathway is vital for all bacterial cells, and is composed of enzymes considerably different from those present in humans. Moreover, the enzymes of the pyrimidine salvage pathway might have an important role in the mycobacterial latent state, since M. tuberculosis has to recycle bases and/or nucleosides to survive in the hostile environment imposed by the host. The present review describes the enzymes of M. tuberculosis pyrimidine salvage pathway as attractive targets for the development of new antimycobacterial agents. Enzyme functional and structural data have been included to provide a broader knowledge on which to base the search for compounds with selective biological activity.

Shikimate Kinase (EC 2.7.1.71) from Mycobacterium tuberculosis: Kinetics and Structural Dynamics of a Potential Molecular Target for Drug Development

Shikimate Kinase (EC 2.7.1.71) from Mycobacterium tuberculosis: Kinetics and Structural Dynamics of a Potential Molecular Target for Drug Development, 2011, 18(9) Pp. 1299-1310
D. M. Saidemberg, A. W. Passarelli, A. V. Rodrigues, L. A. Basso, D. S. Santos and M. S. Palma

The enzymes of the shikimate pathway represent potential molecular targets for the development of non-toxic antimicrobial agents and anti-parasite drugs. One of the most promising of these enzymes is shikimate kinase (EC 2.7.1.71), which is responsible for the fifth step in the shikimate pathway. This enzyme phosphorylates shikimic acid to yield shikimate-3-phosphate, using ATP as a substrate. In this work, the conformational dynamics of the shikimate kinase from Mycobacterium tuberculosis was investigated in its apostate in solution. For this study, the enzyme was subjected to a gradient of temperatures from 15 C to 45 C in the presence or absence of deuterium oxide, and the amide H/D exchange was monitored using ESI-mass spectrometry. We observed: i) the phosphate binding domain in the apo-enzyme is fairly rigid and largely protected from solvent access, even at relatively high temperatures; ii) the shikimate binding domain is highly flexible, as indicated by the tendency of the apo-enzyme to exhibit large conformational changes to permit LID closure after the shikimate binding; iii) the nucleotide binding domain is initially conformationally rigid, which seems to favour the initial orientation of ADP/ATP, but becomes highly flexible at temperatures above 30C, which may permit domain rotation; iv) part of the LID domain, including the phosphate binding site, is partially rigid, while another part is highly flexible and accessible to the solvent.

Understanding the Structure, Activity and Inhibition of Chorismate Synthase from Mycobacterium tuberculosis

Understanding the Structure, Activity and Inhibition of Chorismate Synthase from Mycobacterium tuberculosis, 2011, 18(9) Pp. 1311-1317
H. A. Arcuri and M. S. Palma

Tuberculosis is considered a worldwide health problem mainly due to co-infection with HIV and proliferation of multi-drugresistant strains. The enzymes of the shikimate pathway are potential targets for the development of new therapies because they are essential for bacteria, but absent from mammals. The last step in this pathway is performed by chorismate synthase (CS), which catalyzes the conversion of 5-enolpyruvylshikimate-3-phosphate (EPSP) to chorismate. The aim of this article is to review the available information on chorismate synthase from Mycobacterium tuberculosis.

The β-Ketoacyl-ACP Synthase from Mycobacterium tuberculosis as Potential Drug Targets

The β-Ketoacyl-ACP Synthase from Mycobacterium tuberculosis as Potential Drug Targets, 2011, 18(9) Pp. 1318-1324
V. Singh, I. Mani, D. K. Chaudhary and P. Somvanshi

The continuous preventive measures and control of tuberculosis are often hampered by re-emergence of multi-drug-resistant (MDR) strains of Mycobacterium tuberculosis. A novel drug approach is desperately needed to combat the global threat posed by MDR strains. In spite of current advancement in biological techniques viz. microarray and proteomics data for tuberculosis, no such potent drug has been developed in the past decades yet. Therefore, mycolic acid is an essential constituent which is involved in the formation of cell wall of Mycobacterium species. The biosynthesis of mycolic acid is involved in two fatty acid synthase systems, the multifunctional polypeptide fatty acid synthase I (FASI) which performs de novo fatty acid synthesis and dissociate FASII system. FASII system consists of monofunctional enzymes and acyl carrier protein (ACP), elongating FASI products to long chain mycolic acid precursor. In this review, the β-ketoacyl-ACP synthases (fadH, kasA and kasB) are distinct and play a vital role in mycolic acid synthesis, cell wall synthesis, biofilm formation and also pathogenesis. On the basis of substantial observation we suggest that these enzymes may be used as promising and attractive targets for novel anti-TB drugs designing and discovery.

The Methylerythritol Phosphate (MEP) Pathway for Isoprenoid Biosynthesis as a Target for the Development of New Drugs Against Tuberculosis

The Methylerythritol Phosphate (MEP) Pathway for Isoprenoid Biosynthesis as a Target for the Development of New Drugs Against Tuberculosis, 2011, 18(9) Pp. 1325-1338
C. Obiol-Pardo, J. Rubio-Martinez and S. Imperial

Tuberculosis remains a major infectious disease to humans. It accounts for approximately 8-9 million new cases worldwide and an estimated 1.6 million deaths annually. Effective treatments for tuberculosis consist of a combination of several drugs administered over long periods of time. Since Mycobacterium tuberculosis often acquires multiple drug resistant mechanisms, development of new drugs with innovative actions is urgently required. The 2C-methyl-D-erythritol 4-phosphate (MEP) pathway, in charge of the essential biosynthesis of isoprenoids, represents a promising and selective target for developing new drugs against tuberculosis. To date, only fosmidomycin, a molecule that targets the second enzyme of the MEP pathway, has reached clinical trials but recent advances elucidating the structure and kinetics of the MEP enzymes are likely to change this scenario. This review describes the structure, mechanism of action and inhibitors of the seven enzymes of the MEP pathway, with special attention to the reported studies in M. tuberculosis.

Bio-Inspired Algorithms Applied to Molecular Docking Simulations

Bio-Inspired Algorithms Applied to Molecular Docking Simulations, 2011, 18(9) Pp. 1339-1352
G. Heberle and W. F. de Azevedo

Nature as a source of inspiration has been shown to have a great beneficial impact on the development of new computational methodologies. In this scenario, analyses of the interactions between a protein target and a ligand can be simulated by biologically inspired algorithms (BIAs). These algorithms mimic biological systems to create new paradigms for computation, such as neural networks, evolutionary computing, and swarm intelligence. This review provides a description of the main concepts behind BIAs applied to molecular docking simulations. Special attention is devoted to evolutionary algorithms, guided-directed evolutionary algorithms, and Lamarckian genetic algorithms. Recent applications of these methodologies to protein targets identified in the Mycobacterium tuberculosis genome are described.

Molecular Dynamics Simulations of Protein Targets Identified in Mycobacterium tuberculosis

Molecular Dynamics Simulations of Protein Targets Identified in Mycobacterium tuberculosis, 2011, 18(9) Pp. 1353-1366
W. F. de Azevedo

Application of molecular dynamics simulation technique has become a conventional computational methodology to calculate significant processes at the molecular level. This computational methodology is particularly useful for analyzing the dynamics of proteinligand systems. Several uses of molecular dynamics simulation makes possible evaluation of important structural features found at interface between a ligand and a protein, such as intermolecular hydrogen bonds, contact area and binding energy. Considering structurebased virtual screening, molecular dynamics simulations play a pivotal role in understanding the features that are important for ligandbinding affinity. This information could be employed to select higher-affinity ligands obtained in screening processes. Many protein targets such as enoyl-[acyl-carrier-protein] reductase (InhA), purine nucleoside phosphorylase (PNP), and shikimate kinase have been submitted to these simulations and will be analyzed here. All command files used in this review are available for download at http://azevedolab.net/md_75.html.

Tumor Physiology and Charge Dynamics of Anticancer Drugs: Implications for Camptothecin-based Drug Development

Tumor Physiology and Charge Dynamics of Anticancer Drugs: Implications for Camptothecin-based Drug Development, 2011, 18(9) Pp. 1367-1372
D. J. Adams and L. R. Morgan

Charge is an important characteristic of drug molecules, since ionization sites determine the pKa at a particular pH. The pKa in turn can affect many parameters, including solubility, dissolution rate, reaction kinetics, formulation, cell permeability, tissue distribution, renal elimination, metabolism, protein binding and receptor interactions. The impact of charge dynamics is amplified in human solid tumors that exhibit the glycolytic phenotype and associated acidic extracellular microenvironment. This phenotype is driven by hypoxia and creates a pH gradient in tumors that favors uptake of weak acids and exclusion of weak bases. Established anticancer drugs exhibit a range of pKa's and thus variable ability to exploit the tumor pH gradient. The camptothecins are a prime example as they represent a diverse class of approved anticancer drugs and drug candidates whose charge distribution varies with pH. An in silico method was used to predict charge distribution of camptothecins at physiological versus acidic pH in both the lactone and carboxylate forms. A significant amount of uncharged carboxylate was predicted at acidic pH that could enter tumor cells and accumulate in mitochondria to inhibit mitochondrial topoisomerase I. A model is presented to describe the charge dynamics of a new camptothecin analog and the impact on nuclear and mitochondrial mechanism(s) of action. This example illustrates the importance of integrating tumor physiology and charge dynamics into anticancer drug development.

The Delivery of Biologically Active (Therapeutic) Peptides and Proteins into Cells

The Delivery of Biologically Active (Therapeutic) Peptides and Proteins into Cells, 2011, 18(9) Pp. 1373-1379
M. Grdisa

Biologically active peptides and proteins have a great potential to act as targeted drug therapies in the treatment of a variety of diseases, including cancer. However, their use in vivo is limited by their low stability and cell permeability. Thus, it is necessary to develop efficient and safe peptide/protein delivery systems that can overcome these problems and increase a therapy's bioavailability. The search for promising vectors has led to the use of compounds called cell-penetrating peptides or protein transduction domains. The cellpenetrating peptides, as effective transporter, are utilized to enhance uptake of various biologically active peptide/protein cargos upon fusion or attachment to its sequences. Cell-penetrating peptides have been the subject of investigation of many researchers, however this review only focuses on the arginine-rich and amphipathic carriers and their potential therapeutic use.

Schizophrenia: A Systematic Review of the Disease State, Current Therapeutics and their Molecular Mechanisms of Action

Schizophrenia: A Systematic Review of the Disease State, Current Therapeutics and their Molecular Mechanisms of Action, 2011, 18(9) Pp. 1380-1404
J. K. Shin, D. T. Malone, I. T. Crosby and B. Capuano

The treatment of schizophrenia, one of the most debilitating mental illnesses, began by the serendipitous discovery of chlorpromazine. Since then, researchers have endeavored to find the cause of the illness but it remains unresolved. As a result, literature on the etiology of schizophrenia is littered with hypotheses and theories that are constantly reviewed, modified and rejected. Two hypotheses, however, have withstood the test of time and serve as the basis for the drug treatment, namely the dopamine and serotonin hypotheses. This review introduces the disease state, summarizes in detail the two leading hypotheses on schizophrenia, presents drugs that are currently available for treatment, and discusses some of the promising drug candidates based on their pre and early clinical trial results.

Regulation of Gene Expression by Retinoids

Regulation of Gene Expression by Retinoids, 2011, 18(9) Pp. 1405-1412
P. M. Amann, S. B. Eichmuller, J. Schmidt and A. V. Bazhin

Vitamin A serves as substrate for the biosynthesis of several derivates (retinoids) which are important for cell growth and cell differentiation as well as for vision. Retinoic acid is the major physiologically active form of vitamin A regulating the expression of different genes. At present, hundreds of genes are known to be regulated by retinoic acid. This regulation is very complex and is, in turn, regulated on many levels. To date, two families of retinoid nuclear receptors have been identified: retinoic acid receptors and retinoid X receptors, which are members of the steroid hormone receptor superfamily of ligand-activated transcription factors. In order to regulate gene expression, all-trans retinal needs to be oxidized to retinoic acid. All-trans retinal, in turn, can be produced during oxidation of alltrans retinol or in a retinol-independent metabolic pathway through cleavage of β-carotene with all-trans retinal as an intermediate metabolite. Recently it has been shown that not only retinoic acid is an active form of vitamin A, but also that all-trans retinal can play an important role in gene regulation. In this review we comprehensively summarize recent literature on regulation of gene expression by retinoids, biochemistry of retinoid receptors, and molecular mechanisms of retinoid-mediated effects on gene regulation.

Resveratrol, a Phytochemical Inducer of Multiple Cell Death Pathways: Apoptosis, Autophagy and Mitotic Catastrophe

Resveratrol, a Phytochemical Inducer of Multiple Cell Death Pathways: Apoptosis, Autophagy and Mitotic Catastrophe, 2011, 18(8) Pp. 1100-1121
D. Delmas, E. Solary and N. Latruffe

Cancers are the largest cause of mortality and morbidity in industrialized countries. In the field of the medicinal chemistry of natural products, numerous studies have reported interesting properties of trans-resveratrol as a chemopreventing agent against cancers, inflammation, and viral infection. Tumor growth inhibition has been linked to the ability of resveratrol to arrest cell cycle progression and to trigger cell death. This review focuses on the pathways that mediate resveratrol-induced cell death. Resveratrol impacts on the mitochondrial functions (respiratory chain, oncoproteins, gene expression, etc), in which p53 protein can be involved and its acetylated or phosphorylated forms. This polyphenol also affects death receptor distribution in ceramide-enriched membrane platforms which serve to trap and cluster receptor molecules, and facilitates the formation of a death-inducing signaling complex in the cell. To induce apoptosis, resveratrol also activates the ceramide / sphingomyelin pathway, which promotes ceramide generation and the downstream activation of kinase cascades. Resveratrol can activate alternative pathways to cell death such as those leading to autophagy, senescence or mitotic catastrophe. Furthermore, numerous attempts have been made using resveratrol analogs to improve the molecule's ability to block cell proliferation and induce cell death. Moreover, structural modification of natural phenolics is expected to produce analogs that may be useful tools to study the structure-activity relationships. Lastly, in various cancer types, resveratrol behaves as a chemosensitizer that lowers the threshold of cell death induction by classical anticancer agents and counteracts tumor cell chemoresistance.

In Silico Methods to Assist Drug Developers in Acetylcholinesterase Inhibitor Design

In Silico Methods to Assist Drug Developers in Acetylcholinesterase Inhibitor Design, 2011, 18(8) Pp. 1122-1136
J. A. Bermudez-Lugo, M. C. Rosales-Hernandez, O. Deeb, J. Trujillo-Ferrara and J. Correa-Basurto

Alzheimer's disease (AD) is a neurodegenerative disease characterized by a low acetylcholine (ACh) concentration in the hippocampus and cortex. ACh is a neurotransmitter hydrolyzed by acetylcholinesterase (AChE). Therefore, it is not surprising that AChE inhibitors (AChEIs) have shown better results in the treatment of AD than any other strategy. To improve the effects of AD, many researchers have focused on designing and testing new AChEIs. One of the principal strategies has been the use of computational methods (structural bioinformatics or in silico methods). In this review, we summarize the in silico methods used to enhance the understanding of AChE, particularly at the binding site, to design new AChEIs. Several computational methods have been used, such as docking approaches, molecular dynamics studies, quantum mechanical studies, electronic properties, hindrance effects, partition coefficients (Log P) and molecular electrostatic potentials surfaces, among other physicochemical methods that exhibit quantitative structure-activity relationships.

Phenolic Compounds from Plants as Nitric Oxide Production Inhibitors

Phenolic Compounds from Plants as Nitric Oxide Production Inhibitors, 2011, 18(8) Pp. 1137-1145
F. Conforti and F. Menichini

Nitric oxide (NO) is a diatomic free radical produced from L-arginine by constitutive and inducible nitric oxide synthase (cNOS and iNOS) in numerous mammalian cells and tissues. Nitric oxide (NO), superoxide (O2-) and their reaction product peroxynitrite (ONOO-) may be generated in excess during the host response against viral and antibacterial infections and contribute to some pathogenesis by promoting oxidative stress, tissue injury and, even, cancer. Oxidative damage, caused by action of free radicals, may initiate and promote the progression of a number of chronic diseases, including cancer, cardiovascular diseases, Alzheimer's disease, diabetes and inflammation. The mechanism of inflammation injury is attributed, in part, to release of reactive oxygen species from activated neutrophils and macrophages. ROS propagate inflammation by stimulating release of mediators such as NO and cytokines. The interest of the research is motivated by the current need to find new substances of natural origin which have demonstrated effectiveness in the described fields of application and low degree of toxicity for humans. Natural products provide a vast pool of NO inhibitors that can possibly be developed into clinical products. This article reviews some plenolic secondary metabolites from plants with NO inhibitory properties and their structure-activity relationship studies that can be focused for drug development programs.

Lycopene and Cardiovascular Diseases: An Update

Lycopene and Cardiovascular Diseases: An Update, 2011, 18(8) Pp. 1146-1163
A. Mordente, B. Guantario, E. Meucci, A. Silvestrini, E. Lombardi, G. E. Martorana, B. Giardina and V. Bohm

Cardiovascular disease (CVD) is the leading cause of death in Western societies and accounts for up to a third of all deaths worldwide. In comparison to the Northern European or other Western countries, the Mediterranean area has lower rates of mortality from cardiovascular diseases and cancer, and this is attributed, at least in part, to the so-called Mediterranean diet, which is rich in plantderived bioactive phytochemicals. Identification of the active constituents of the Mediterranean diet is therefore crucial to the formulation of appropriate dietary guidelines. Lycopene is a natural carotenoid found in tomato, an essential component of the Mediterranean diet, which, although belonging to the carotenoid family, does not have pro-vitamin A activity but many other biochemical functions as an antioxidant scavenger, hypolipaemic agent, inhibitor of pro-inflammatory and pro-thrombotic factors, thus potentially of benefit in CVD. In particular, the review intends to conduct a systematic analysis of the literature (epidemiological studies and interventional trials) in order to critically evaluate the association between lycopene (or tomato products) supplementation and cardiovascular diseases and/or cardiovascular disease risk factors progression, and to prepare provision of evidence-based guidelines for patients and clinicians. Several reports have appeared in support of the role of lycopene in the prevention of CVD, mostly based on epidemiological studies showing a dose-response relationship between lycopene and CVD. A less clear and more complex picture emerges from the interventional trials, where several works have reported conflicting results. Although many aspects of lycopene in vivo metabolism, functions and clinical indications remain to be clarified, supplementation of low doses of lycopene has been already suggested as a preventive measure for contrasting and ameliorating many aspects of CVD.

Novel Trends in the Treatment of Cardiovascular Disorders: Site- and Event- Selective Adenosinergic Drugs

Novel Trends in the Treatment of Cardiovascular Disorders: Site- and Event- Selective Adenosinergic Drugs, 2011, 18(8) Pp. 1164-1187
A. J. Szentmiklosi, A. Cseppento, G. Harmati and P. P. Nanasi

This review focuses on the potential role of site- and event-selective adenosinergic drugs in the treatment of cardiovascular diseases. Adenosine is released from the myocardium and vessels in response to various forms of stress and acts on four receptor subtypes (A1, A2A, A2B and A3). Adenosine is an important endogenous substance with important homeostatic activity in the regulation of cardiac function and circulation. Adenosine receptors are also involved in the modulation of various cellular events playing crucial role in physiological and pathological processes of the cardiovascular system. These actions are associated to activation of distinct adenosine receptor subtypes, therefore drugs targeting specific adenosine receptors might be promising therapeutic tools in treatment of several disorders including various forms of cardiac arrhythmia, myocardial ischemia-reperfusion injury, angina pectoris, chronic heart failure, etc. Recently, in addition to subtype-specific adenosine receptor agonists and antagonists, a number of substances that enhance adenosine receptor activation locally at the site where the release of endogenous adenosine is the most intensive have been developed. Thus global actions of adenosine receptor agonists and antagonists, as well as desensitization or down-regulation following chronic administration of these orthosteric compounds can possibly be avoided. We discuss the chemical, pharmacological and clinical features of these compounds: (1) inhibitors of membrane adenosine transporters (NBTI, dipyridamole), (2) inhibitors of adenosine deaminase (coformycin, EHNA), (3) inhibitors of adenosine kinase (tubercidin, aristeromycin), (4) inhibitors of AMP deaminase (GP3269), (5) activators of 5'- nucleotidase (methotrexate), (6) adenosine regulators (acadesine) and (7) allosteric adenosine receptor modulators (PD81723, LUF6000). The development of this type of substances might offer a novel therapeutic approach for treating cardiovascular diseases in the near future.

Structure-Based Approach for the Discovery of Novel Selective Estrogen Receptor Modulators

Structure-Based Approach for the Discovery of Novel Selective Estrogen Receptor Modulators, 2011, 18(8) Pp. 1188-1194
C. Rosano, E. Stec-Martyna, R. Lappano and M. Maggiolini

In the last twenty years the efforts to design and optimize new drugs have been based on the three dimensional structure of the selected target proteins. In this regard, useful information has been achieved mainly by protein crystallography, which has recently turned from a low into a high-throughput process thanks to the improvement in robot technologies, automation procedure and the use of synchrotron radiation facilities [1-3]. This review examines the impact of Structure Based Drug Design (SBDD) on the discovery of ligands as the selective estrogen receptor modulators (SERMs) of the Estrogen Receptor (ER)α, which is involved in the regulation of several physiological and pathological processes.

Neuroprotective Actions of Flavonoids

Neuroprotective Actions of Flavonoids, 2011, 18(8) Pp. 1195-1212
C. Gutierrez-Merino, C. Lopez-Sanchez, R. Lagoa, A. K. Samhan-Arias, C. Bueno and V. Garcia-Martinez

The experimental evidences accumulated during last years point out a relevant role of oxidative stress in neurodegeneration. As anti-cellular oxidative stress agents flavonoids can act either as direct chemical antioxidants, the classic view of flavonoids as antioxidants, or as modulators of enzymes and metabolic and signaling pathways leading to an overshot of reactive oxygen species (ROS) formation, a more recently emerging concept. Flavonoids, a large family of natural antioxidants, undergo a significant hepatic metabolism leading to flavonoid-derived metabolites that are also bioactive as antioxidant agents. The development of more efficient flavonoid's based anti-oxidative stress therapies should also take into account their bioavailability in the brain using alternate administration protocols, and also that the major ROS triggering the cellular oxidative stress are not the same for all neurodegenerative insults and diseases. On these grounds, we have reviewed the reports on neuroprotection by different classes of flavonoids on cellular cultures and model animals. In addition, as they are now becoming valuable pharmacological drugs, due to their low toxicity, the reported adverse effects of flavonoids in model experimental animals and humans are briefly discussed.

Is Androstadienone a Putative Human Pheromone?

Is Androstadienone a Putative Human Pheromone?, 2011, 18(8) Pp. 1213-1219
D. Marazziti, P. Torri, S. Baroni, M. Catena Dell'Osso, G. Consoli and V. Boncinelli

On the basis of different evidences, androstadienone, a steroid compound produced in the armpit, has been proposed as a human pheromone, although its physiological levels appear too low to induce a response under experimental conditions. For this reason, the majority of researchers in this area puts into question the “legitimacy” of androstadienone, and prefers to consider the axillary extracts in its entirety, like a sort of “medicinal tea”, the components of which still remain to be identified, but that taken together may induce a response, or function as a carrier of other active substances. Another option is that androstadienone acts with varying degrees of potency and, at lower concentrations, according to the context and to specific behavioral situations. The aim of this paper is to review all relevant data regarding androstadienone, in order to ascertain whether it may be considered a physiological pheromone and, as such, a possible target of future modulators of some human behaviors.

Lactoferrin: A Biologically Active Molecule for Bone Regeneration

Lactoferrin: A Biologically Active Molecule for Bone Regeneration, 2011, 18(8) Pp. 1220-1229
A. A. Amini and L. S. Nair

Lactoferrin, a member of the “Siderophilin” family, is an iron binding glycoprotein. Lactoferrin is produced by various exocrine glands in our body and is abundantly present in milk and colostrums. The uniqueness of lactoferrin as a skeletal regenerative molecule lies in its ability to favorably modulate the responses of the various cell types involved in musculoskeletal regeneration. Lactoferrin exhibits pleiotropic functions and recent studies indicate that lactoferrin promotes the proliferation and differentiation of osteoblast cells and inhibits osteoclast-mediated bone resorption. Human lactoferrin is also known to promote neovascularization. This review aims to summarize the most recent studies on lactoferrin focusing on its anabolic effect to bone tissue and the ability to modulate immune responses with specific focus on osteoimmunology.

Adalimumab in Crohn's Disease: Tips and Tricks After 5 Years of Clinical Experience

Adalimumab in Crohn's Disease: Tips and Tricks After 5 Years of Clinical Experience, 2011, 18(8) Pp. 1230-1238
G. Fiorino, H. Szabo, W. Fries, A. Malesci, L. Peyrin-Biroulet and S. Danese

Introduction: Three anti TNF-α agents have currently been approved for the treatment of moderate-to-severe or complicated Crohn's disease (CD): infliximab, certolizumab and adalimumab. Infliximab is effective in CD, but for reasons linked to its chimeric structure, response to treatment may be lost overtime and as a result, it can sometimes be unable to provide long term durable treatment of CD. Adalimumab, a fully human anti TNF-α antibody, demonstrates similar treatment efficacy as infliximab and certolizumab, and can easily be self-administered at home. Aim and Methods: A literature search in the Cochrane, MEDLINE, PUBMED, Ovid MEDLINER and EMBASE databases has been performed on the efficacy, safety and the impact adalimumab has on the quality of life and natural history of CD. Abstracts presented at the DDW, UEGW and ECCO Congresses have also been reviewed as well as references from review articles, meta-analysis studies and published RCTs. Results: Adalimumab induced remission of CD in 64% of patients, and maintained remission in more than 80% of initial responders. Adalimumab did not significantly increase the risk of adverse events compared with conventional medication up to 3 years of follow-up. Adalimumab reduces more than 50% the risk for hospitalisation and surgery due to CD. It is also effective for fistula closure, for the healing of the mucosa, and improving quality of life. Conclusion: Adalimumab is effective in the induction and maintenance of clinical remission in CD and is generally well tolerated. It has been proved to have a positive impact by improving quality of life of patients, and reducing the need for hospitalisation and surgery due to CD. According to the European Crohn's and Colitis Organisation (ECCO), infliximab or adalimumab can be used for the treatment of fistulizing CD.

Promising Targets for Anti-Hepatitis C Virus Agents

Promising Targets for Anti-Hepatitis C Virus Agents, 2011, 18(8) Pp. 1239-1244
T. Yoshida, M. Kondoh and K. Yagi

Hepatitis C virus (HCV) infection is a serious global health problem, with 3-4 million new cases reported each year. Chronic HCV infection places 170 million people at risk of developing liver cirrhosis and hepatocellular carcinoma. However, difficulties in preparing HCV particles in vitro have delayed development of effective anti-HCV therapies. In 2005, Wakita et al. developed an in vitro method to prepare HCV particles, thereby enabling researchers to better understand the mechanism of HCV infection. Other recent advances include development of a virus-free system for evaluating HCV replication and the identification of HCV receptors, such as claudin-1 and occludin, that may serve as targets for anti-HCV drugs. In this review, we discuss recent findings in HCV infection research, including discovery of new potential targets for anti-HCV therapy.

Chemopreventive Properties and Molecular Mechanisms of the Bioactive Compounds in Hibiscus Sabdariffa Linne

Chemopreventive Properties and Molecular Mechanisms of the Bioactive Compounds in Hibiscus Sabdariffa Linne, 2011, 18(8) Pp. 1245-1254
Hui-Hsuan Lin, Jing-Hsien Chen and Chau-Jong Wang

Hibiscus sabdariffa Linne is a traditional Chinese rose tea and has been effectively used in folk medicines for treatment of hypertension, inflammatory conditions. H. sabdariffa aqueous extracts (HSE) were prepared from the dried flowers of H. sabdariffa L., which are rich in phenolic acids, flavonoids and anthocyanins. In this review, we discuss the chemopreventive properties and possible mechanisms of various H. sabdariffa extracts. It has been demonstrated that HSE, H. sabdariffa polyphenol-rich extracts (HPE), H. sabdariffa anthocyanins (HAs), and H. sabdariffa protocatechuic acid (PCA) exert many biologic effects. PCA and HAs protected against oxidative damage induced by tert-butyl droperoxide (t-BHP) in rat primary hepatocytes. In rabbits fed cholesterol and human experimental studies, these studies imply HSE could be pursued as atherosclerosis chemopreventive agents as they inhibit LDL oxidation, foam cell formation, as well as smooth muscle cell migration and proliferation. The extracts also offer hepatoprotection by influencing the levels of lipid peroxidation products and liver marker enzymes in experimental hyperammonemia. PCA has also been shown to inhibit the carcinogenic action of various chemicals in different tissues of the rat. HAs and HPE were demonstrated to cause cancer cell apoptosis, especially in leukemia and gastric cancer. More recent studies investigated the protective effect of HSE and HPE in streptozotocin induced diabetic nephropathy. From all these studies, it is clear that various H. sabdariffa extracts exhibit activities against atherosclerosis, liver disease, cancer, diabetes and other metabolic syndromes. These results indicate that naturally occurring agents such as the bioactive compounds in H. sabdariffa could be developed as potent chemopreventive agents and natural healthy foods.

Novel Substituted Quinazolines for Potent EGFR Tyrosine Kinase Inhibitors

Novel Substituted Quinazolines for Potent EGFR Tyrosine Kinase Inhibitors, 2011, 18(7) Pp. 943-963
O. Cruz-Lopez, A. Conejo-Garcia, M. C. Nunez, M. Kimatrai, M. E. Garcia-Rubino, F. Morales, V. Gomez-Perez and J. M. Campos

The type I receptor tyrosine kinases (RTKs) are involved in various aspects of cell growth, survival, and differentiation. Among the known RTKs, the epidermal growth factor receptor (EGFR) and ErbB-2 (HER-2) are two widely studied proteins that are prototypic members of the ErbB family which also includes ErbB-3 (Her-3) and ErbB-4 (Her-4). Overexpression of ErbB-2 and EGFR has been associated with aggressive disease and poor patient prognosis in a range of human tumour types (e.g. breast, lung, ovarian, prostate, and squamous carcinoma of head and neck). Disruption of signal transduction of these kinases has been shown to have an antiproliferative effect. Various approaches have been developed to target the ErbB signalling pathways including monoclonal antibodies (trastuzumab/ Herceptin™ and cetuximab/Erbitux™ ) directed against the receptor, and synthetic tyrosine kinase inhibitors (gefitinib/Iressa™ and erlotinib/Tarceva™). Since many tumours overexpress ErbB receptors, simultaneous targeting of multiple ErbB receptors therefore becomes a promising approach to cancer treatment. Lapatinib (Tykerb™), a potent dual EGFR/ErbB-2 inhibitor, was approved for the treatment of ErbB-2-positive breast cancer. Despite years of intensive research on EGFR inhibitors, there is a surprising dearth of chemically distinct small inhibitors with a high degree of selectivity. There is also a need for new scaffolds due to the recent finding of EGFR mutations which render the kinase resistant to gefinitib and erlotinib. The structures under study will be quinazolines with different substituents. The structure-activity relationships and biological evaluation of compounds published during the last four years will be reviewed herein.

Progress in the Development of Bestatin Analogues as Aminopeptidases Inhibitors

Progress in the Development of Bestatin Analogues as Aminopeptidases Inhibitors, 2011, 18(7) Pp. 964-976
L. Chen, Y. Teng and W. Xu

Aminopeptidases play essential roles in protein maturation, activation, and stability as well as in the degradation and regulation of hormonal and nonhormonal peptides that can serve as important enzyme targets for drug design. This review will focus on an effective inhibitor of aminopeptidases, bestatin, including work to find better inhibitors in the past three decades that has sought to optimize bestatin and prospective developments in bestatin optimization in the future.

New Hope for the Treatment of Osteoarthritis Through Selective Inhibition of MMP-13

New Hope for the Treatment of Osteoarthritis Through Selective Inhibition of MMP-13, 2011, 18(7) Pp. 977-1001
N.-G. Li, Z.-H. Shi, Y.-P. Tang, Z.-J. Wang, S.-L. Song, L.-H. Qian, D.-W. Qian and J.-A. Duan

Osteoarthritis (OA) is the leading cause of joint pain and disability in middle-aged and elderly patients, and is characterized by progressive loss of articular cartilage that eventually leads to a complex process involving degradation of various components of the cartilage matrix, chief among them are the cartilage-specific type II collagen (CII) and aggrecan. While the loss of aggrecan is thought to be an early and reversible process, degradation of CII is considered to be irreversible and a key step in the loss of structural and functional integrity of cartilage. Among the various matrix metalloproteinases (MMPs), MMP-13 is specifically expressed in the cartilage of human OA patients and is not present in normal adult cartilage. It is the major collagenase in OA cartilage and has the highest activity against CII. However, the clinical utility of broad-spectrum MMP inhibitors developed for treatment of OA has been restricted by dose- and duration- dependent musculoskeletal side effects in humans. Consequently, selectively inhibiting the MMP-13 would seem to be an attractive therapeutic objective. This review mainly focuses on selective MMP-13 inhibitors development in terms of OA since the late 90s, in terms of synthetic compounds of low molecular mass incorporating specific zinc-binding groups, non-zinc-binding groups. In addition, dual inhibitors of MMP-13 and aggrecanase are also reviewed. Special emphasis is placed on logistic concerns for lead compound search as well as the structure activity relationship (SAR) in this field. Through these methods, new hope is emerging for the treatment of OA through selective inhibition of MMP-13.

Glycans in Magnetic Resonance Imaging: Determinants of Relaxivity to Smart Agents, and Potential Applications in Biomedicine

Glycans in Magnetic Resonance Imaging: Determinants of Relaxivity to Smart Agents, and Potential Applications in Biomedicine, 2011, 18(7) Pp. 1002-1018
Laura Cipolla, Maria Gregori and Po-Wah So

Carbohydrate chemistry and glycobiology have become a “hot” subject. These extensive, complex structures serve essential roles in cell surface phenomena, but we are only beginning to understand what some of these functions are; any advances in the development of synthetic and/or analytical tools for glycobiology are extremely useful for our understanding of the roles of carbohydrates in biology, and as biomarkers of physiological/pathological states. This review provides an outlook of the potential of carbohydrate chemistry/ biology in magnetic resonance imaging (MRI), a major important and prominent technique in diagnostic clinical medicine and biomedical research. During the last 30 years, MRI has developed from an intriguing research project to an essential diagnostic method in the clinic. Although MRI contrast in endogenous tissues provides excellent sensitivity for detecting subtle changes in anatomy and function, MRI still has poor specificity for attributing image contrast to specific biological processes. To overcome this limitation, MRI methods are being developed that induce changes in MR image contrast in response to molecular compositions and functions that serve as early biomarkers of pathologies. Carbohydrates with their intriguing chemistry, not only can provide structures for novel MRI probes for imaging specific biological processes, but can themselves provide novel targets/biomarkers. For example, the glycan structure can simply provide a molecular scaffold for modulating the physicochemical properties of the imaging contrast agent, or can be used for the design of novel MR agents with the ability to disclose relevant physiological or pathological cellular events.

Evaluation of Post-Surgical Cognitive Function and Protein Fingerprints in the Cerebro-Spinal Fluid Utilizing Surface-Enhanced Laser Desorption/Ionization Time-of-Flight Mass-Spectrometry (SELDI-TOF MS) After Coronary Artery Bypass Grafting: Review of Proteomic Analytic Tools and Introducing a New Syndrome

Evaluation of Post-Surgical Cognitive Function and Protein Fingerprints in the Cerebro-Spinal Fluid Utilizing Surface-Enhanced Laser Desorption/Ionization Time-of-Flight Mass-Spectrometry (SELDI-TOF MS) After Coronary Artery Bypass Grafting: Review of Proteomic Analytic Tools and Introducing a New Syndrome, 2011, 18(7) Pp. 1019-1037
H. J. Reis, L. Wang, T. Verano-Braga, A. M.C. Pimenta, J. Kalman, G. Bogats, B. Babik, L. B. Vieira, A. L. Teixeira, M. A. Mukhamedyarov, A. L. Zefirov, A. P. Kiyasov, A. A. Rizvanov, K. Matin, M. Palotas, M. M. Guimaraes, C. N. Ferreira, M. E. Yalvac, Z. Janka and A. Palotas

Cognitive dysfunction following surgery is a common complication, which increases the incidence of other co-morbid conditions, hospital and health-care costs. The reported rate of the occurrence of post-operative cognitive decline varies with different studies, depending on population profile, type of surgery, definition of cognitive disorder and detection methods, design of study, etc. It remains unclear whether these psychiatric signs and symptoms are direct results of the effects of surgery or general anesthesia. Nonetheless they are more frequent after cardiac surgery and are likely to be multi-factorial, but the patho-mechanisms are not yet fully characterized. This communication provides a synopsis of proteomics tools and delineates novel SELDI-TOF results to evaluate biomarkers in this regard. Presented for the first time is a classification of the clinically relevant forms of post-operative cognitive decline with the advent of a novel subclass.

Non-Genotoxic p53-Activators and their Significance as Antitumor Therapy of Future

Non-Genotoxic p53-Activators and their Significance as Antitumor Therapy of Future, 2011, 18(7) Pp. 1038-1049
S. K. Nayak, P. S. Panesar and H. Kumar

The tumor suppressor protein p53 mediates critical cellular functions including regulation of cell cycle, apoptosis, DNA repair, and senescence. This protein has been found to be inactivated or functionally down-regulated in several malignancies such as Li- Fraumeni syndrom, hepatocellular carcinoma, breast cancer, cervical cancer, and acute myeloid leukemia. Thus, p53 represents an attractive target for therapeutic design and development of new anticancer agents. The most clinically used cytotoxic agents target stabilization of wt-p53 through DNA damage and are associated with several unwanted and life threatening side effects. There are a number of recently developed approaches that hold promise for non-genotoxic reactivation of p53. Earlier, we have reported various inhibitors of p53 and their importance to prevent unwanted death of normal cells in a variety of diseases [1]. To extend p53 protein as new target for anticancer agents, in this review we discussed the mechanisms of p53 inactivation. Subsequently, we described some of recently developed non-genotoxic activators of p53 and their significance in various neoplastic disorders. Additionally, we summarized advantages of nongenotoxic p53-activating agents over conventional anticancer therapy and challenges in future of p53 based therapy.

The Medicinal Potential of Influenza Virus Surface Proteins: Hemagglutinin and Neuraminidase

The Medicinal Potential of Influenza Virus Surface Proteins: Hemagglutinin and Neuraminidase, 2011, 18(7) Pp. 1050-1066
Y. Xie, J. Gong, M. Li, H. Fang and W. Xu

Nowadays, influenza virus is still a big threat to human. Hemagglutinin (HA) and neuraminidase (NA) are the two viral surface proteins, which play important roles in the life cycle of influenza virus. Current influenza vaccines and anti-influenza drugs work mainly by interfering with the functions of the two proteins. In this review, we will display some recent studies about the two proteins. As to HA, this review covers a lot including its fusion function, receptor specificity, antigenic shift hypothesis, novel antibodies and various inhibitors in order to deeply discuss this protein. As to NA, this review mainly focuses on studies about the newly identified 150-cavity of group-1 NAs and shows some untypical NA inhibitors aiming to provide a broader range of lead compounds for anti-influenza drug design.

Current Trends in the Application of Nanoparticles in Drug Delivery

Current Trends in the Application of Nanoparticles in Drug Delivery, 2011, 18(7) Pp. 1067-1078
Y. Malam, E. J. Lim and A. M. Seifalian

The discovery of new biologically active compounds that can be exploited therapeutically to treat disease has stalled, with fewer new drugs entering the market every year. The spotlight has now turned onto nanoparticles (NPs) as a versatile and multifaceted platform for the delivery of drugs. NPs offer better pharmacokinetic properties, controlled and sustained release, and targeting of specific cells, tissues or organs. All these features can improve the efficacy of existing drugs. The use of NPs can dramatically impact the treatment of many diseases. Many potential therapeutics that exist for alleviating brain diseases such as epilepsy, Alzheimer's disease and tumours are not feasible due to a lack of means to deliver drugs across the blood brain barrier. NPs offer an alternative solution, since they can be modified to cross the blood brain barrier. Additionally, NPs can also play a part in alternative methods of non-parental administration of drugs e.g. pulmonary and transdermally. Through active targeting and the enhanced permeation and retention effect, NPs reduce the systemic toxicity of chemotherapeutic drugs by ensuring delivery only to the site of the tumour, thus enhancing cancer treatment. We critically review the literature to provide a summary of current synthesis methodologies and applications of NPs in drug delivery.

In Vitro Models for the Study of Non-Alcoholic Fatty Liver Disease

In Vitro Models for the Study of Non-Alcoholic Fatty Liver Disease, 2011, 18(7) Pp. 1079-1084
N. C. Chavez-Tapia, N. Rosso and C. Tiribelli

Non-alcoholic fatty liver disease is regarded as the hepatic manifestation of metabolic syndrome and is an important and common cause of chronic liver disease with a potential to develop end-stage liver disease. While important advances in the pathophysiology have been achieved using genetically modified and diet-induced animal models, in-vitro models have been only recently proposed. These models include primary culture and immortalized cell lines. Here we critically review the characteristics of the in vitro models described, the advantages and limitations of the in vitro approach, and the results derived.

Cannabinoids: Occurrence and Medicinal Chemistry

Cannabinoids: Occurrence and Medicinal Chemistry, 2011, 18(7) Pp. 1085-1099
G. Appendino, G. Chianese and O. Taglialatela-Scafati

With an inventory of several hundreds secondary metabolites identified, Cannabis sativa L. (hemp) is one of the phytochemically best characterized plant species. The biomedical relevance of hemp undoubtedly underlies the wealth of data on its constituents and their biological activities, and cannabinoids, a class of unique meroterpenoids derived from the alkylation of an olivetollike alkyl resorcinol with a monoterpene unit, are the most typical constituents of Cannabis. In addition to the well-known psychotropic properties of Δ9-THC, cannabinoids have been reported to show potential in various fields of medicine, with the capacity to address unmet needs like the relief of chemotherapy-derived nausea and anorexia, and symptomatic mitigation of multiple sclerosis. Many of the potential therapeutic uses of cannabinoids are related to the interaction with (at least) two cannabinoid G-protein coupled receptors (CB1 and CB2). However, a number of activities, like the antibacterial or the antitumor properties are non totally dependent or fully independent from the interaction with these proteins. These pharmacological activities are particularly interesting since, in principle, they could be easily dissociated by the unwanted psychotropic effects. This review aims at giving readers a survey of the more recent advances in both phytochemistry of C. sativa, the medicinal chemistry of cannabinoids, and their distribution in plants, highlighting the impact that research in these hot fields could have for modern medicinal chemistry and pharmacology.

Anticancer Active Illudins: Recent Developments of a Potent Alkylating Compound Class

Anticancer Active Illudins: Recent Developments of a Potent Alkylating Compound Class, 2011, 18(6) Pp. 790-807
R. Schobert, S. Knauer, S. Seibt and B. Biersack

An overview of anticancer active spirocyclopropanes of the illudin class is provided. After a short introduction on the history and general chemistry of illudins M and S, new discoveries concerning their mode of action and metabolism are reported as well as new synthetic endeavors towards derivatives with improved selectivity for and efficacy against cancer cells. In addition, common and recently tapped biological sources and isolation procedures for known and new illudins are discussed. Pertinent literature is covered up to 2010.

Natural Products as Anti-Invasive and Anti-Metastatic Agents

Natural Products as Anti-Invasive and Anti-Metastatic Agents, 2011, 18(6) Pp. 808-829
Y.-L. Jiang and Z.-P. Liu

Invasion and metastasis, the hallmark of malignant tumor, is the main reason for the clinical death of most cancer patients. Tumor invasion and metastasis are complex, multi-step biochemical processes, which involve cell detachment, invasion, migration, intravasation and circulation, implantation, angiogenesis and proliferation. Therefore, how to prevent tumor metastasis has been the biggest challenge in cancer chemotherapy. In recent years, many natural products have been found to have anti-invasive and anti-metastatic activities. In this paper, these natural compounds are classified as polyphenols, terpenoids, alkaloids, steroids and saponins, saccharides, macrolides, amides and others, their anti-invasive and anti-metastatic activities as well as their biological targets are reviewed.

New Targets for Antibacterial Design: Kdo Biosynthesis and LPS Machinery Transport to the Cell Surface

New Targets for Antibacterial Design: Kdo Biosynthesis and LPS Machinery Transport to the Cell Surface, 2011, 18(6) Pp. 830-852
L. Cipolla, A. Polissi, C. Airoldi, L. Gabrielli, S. Merlo and F. Nicotra

Lipopolysaccharide (LPS), which constitutes the lipid portion of the outer leaflet of Gram-negative bacteria, is essential for growth. It is also responsible for the variety of biological effects associated with Gram-negative sepsis. Recent advances have elucidated the exact chemical structure of this highly complex macromolecule and much of the enzymology involved in its biosynthesis. Enzymes involved in LPS biogenesis are optimal targets for the development of novel therapeutics since they are sufficiently conserved among diverse, clinically-relevant bacteria and no analogue counterpart is present in humans. During the last thirty years a number of inhibitors of LPS biosynthesis have been developed: some of these compounds have antibacterial properties, while others show excellent in vitro activity and are undergoing further investigation. The main focus of this review will be the biology of LPS in bacteria summarizing the knowledge about structure and enzymatic catalysis, as well as chemical efforts towards the synthesis of inhibitors of the key enzymes involved in the biosynthesis of Kdo, toward the minimal conserve structure Kdo2-LipA. In addition, very recent advances in deciphering the molecular mechanisms of LPS transport to the cell surface, as a new target to develop novel antibacterials, will be reported. Future directions and perspectives will also be outlined.

Road Towards New Antimalarials Overview of the Strategies and their Chemical Progress

Road Towards New Antimalarials Overview of the Strategies and their Chemical Progress, 2011, 18(6) Pp. 853-871
Tao Wu, Advait S. Nagle and Arnab K. Chatterjee

Malaria is a major health and economic threat to about 40% of the world's population. The absence of effective vaccines and widespread resistance to many of the current antimalarials make this disease an urgent target for the scientific community. As a developing world disease, most of the efforts towards new drugs have been from academic and government supported projects. This has recently changed with the emergence of new funding mechanisms and public-private partnerships (PPP). The purpose of this review is to highlight the different approaches used to discover new antimalarial agents, including target-based approaches, derivatization of known antimalarial pharmacophores, drug repositioning from non-malaria indication and cell-based screening. Specific examples are provided to illustrate the pros and cons in the context of how to best address the ever-increasing drug resistance and how to cost-effectively identify new antimalarials. More attention is given to relatively mature programs that have gone through extensive SAR study, pharmacology and/or toxicity studies in the last ten years.

Pleiotropic Effects of Cardioactive Glycosides

Pleiotropic Effects of Cardioactive Glycosides, 2011, 18(6) Pp. 872-885
C. Riganti, I. Campia, J. Kopecka, E. Gazzano, S. Doublier, E. Aldieri, A. Bosia and D. Ghigo

Cardioactive glycosides, like digoxin, ouabain and related compounds, are drugs that inhibit Na+/K+-ATPase and have a strong inotropic effect on heart: they cause the Na+/Ca2+ exchanger to extrude Na+ in exchange with Ca2+ and therefore increase the [Ca2+]i concentration. For this reason, some of these drugs are currently used in the treatment of congestive heart failure and cardiac arrhythmias. Recently it has been discovered that cardiac glycosides exert pleiotropic effects on many aspects of cell metabolism. Na+/K+-ATPase is not the exclusive target, as they affect the cell response to hypoxia, modulate several signaling pathways involved in cell death and proliferation, regulate the transcription of different genes and modify the pharmacokinetics of other drugs, by altering the expression and activity of drug-metabolizing enzymes. Some of these effects are related to the steroid structure of glycosides, a property which also makes them fine modulators of the synthesis of cholesterol and steroid hormones. Moreover, new endogenously synthesized glycosides have been discovered in the last years: these molecules are involved in the balance of salt and in the control of blood pressure. This review will focus on the recent studies which have demonstrated that exogenous and endogenous glycosides, besides playing a role as inotropic agents, are also important in the pathogenesis and therapy of different human diseases, such as stroke, diabetes, neurological diseases and cancer.

Comparison of Status Epilepticus Models Induced by Pilocarpine and Nerve Agents - A Systematic Review of the Underlying Aetiology and Adopted Therapeutic Approaches

Comparison of Status Epilepticus Models Induced by Pilocarpine and Nerve Agents - A Systematic Review of the Underlying Aetiology and Adopted Therapeutic Approaches, 2011, 18(6) Pp. 886-899
F. R. Tang, W. K. Loke and E. A. Ling

Among potential radiological, nuclear, biological and chemical weapons, cholinergic nerve agents from chemical weapons remain a realistic terrorist threat due to its combination of high lethality, demonstrated use and relative abundance of un-destroyed stockpiles in various militaries around the world. While current fielded antidotes are able to mitigate acute poisoning, effective neuroprotection in the field remains a challenge amongst subjects with established status epilepticus following nerve agent intoxication. Due to ethical, safety and surety issues, extensive preclinical and clinical research on cholinergic nerve agents is not possible. This may have been a contributory factor for the slow progress in uncovering new neuroprotectants for nerve agent casualties with established status epilepticus. To overcome this challenge, comparative research with surrogate chemicals that produce similar hypercholinergic toxicity but with less security concerns would be a useful approach forward. In this paper, we will systemically compare the mechanism of seizure generation, propagation and the subsequent clinical, hematologic, and metabolic, biochemical, neuroinflammatory changes and current therapeutic approaches reported in pilocarpine, soman, and sarin models of seizures. This review will be an important first step in closing this knowledge gap among different closely related models of seizures and neurotoxicity. Hopefully, it will spur further efforts in using surrogate cholinergic models by the wider scientific community to expedite the development of a new generation of antidotes that are better able to protect against delayed neurological effects inflicted by nerve agents.

Novel Aspects of Neuronal Differentiation In Vitro and Monitoring with Advanced Biosensor Tools

Novel Aspects of Neuronal Differentiation In Vitro and Monitoring with Advanced Biosensor Tools, 2011, 18(6) Pp. 900-908
T. Valero and S. Kintzios

Neuronal differentiation is a very complex and sophisticated cellular process that encompasses the development of mature neurons and their specialization. In this review we will focus on the novel and less well-known aspects of neuronal differentiation. Cell lines, to which some pro-differentiation drugs are added, have been widely used because of their convenience in terms of cost-efficiency, ease of use and reproducibility. After a brief overview of these systems, this review focuses on the new pharmacological aspects of differentiation related to mitochondrial changes and cellular redox homeostasis. A number of different parameters are commonly evaluated to assess neuronal differentiation. These include neurite length, differential gene expression, mitochondrial mass, free radical levels, enzyme induction and others. However, the classical techniques used to detect neuronal differentiation (such as immunochemistry, flow cytometry and gene expression analysis) are time-consuming or dependent on the subjective view of the researcher. On the other hand, emerging novel, miniaturized biosensor technologies have the potential to revolutionize the study of neuronal differentiation, by detecting neuron-derived electrical signals and differentiation markers, such as shape or attachment in a non-invasive and high throughput fashion. These state-of-the-art technologies are being extensively reviewed. Emphasis is given to progress, made in the field of integrated systems (including impedance sensing, microfluidics and associated nanotechnologies), neuronal differentiation in 3-D cultures and the identification of novel agents controlling neuronal cell fate.

Emerging Targets for the Treatment of Dyslipidemia

Emerging Targets for the Treatment of Dyslipidemia, 2011, 18(6) Pp. 909-922
A. Tavridou, G. Ragia and V. G. Manolopoulos

Dyslipidemia is one of the main risk factors leading to atherosclerotic cardiovascular disease (CVD). According to recent treatment guidelines, subjects at substantial risk of CVD should meet more aggressive targets for low-density lipoprotein(LDL)- cholesterol levels. Treatment with statins fails to protect a significant percentage of patients from cardiovascular events despite efficient cholesterol-lowering. Moreover, clinical and epidemiologic data highlight the need of therapies to reduce the residual cardiovascular risk associated with low high-density lipoprotein(HDL)-cholesterol and elevated triglyceride levels. There are several novel agents undergoing preclinical or clinical development for the treatment of dyslipidemia. Squalene synthase inhibitors, antisense oligonucleotides targeting the production of apolipoprotein(apo)B-100, inhibitors of proprotein convertase subtilisin/kexin type 9, microsomal triglyceride transfer protein inhibitors, peroxisome proliferator-activated receptor agonists, and thyroid hormone receptor agonists are some of the alternative approaches for lipid-lowering. Moreover, HDL-targeted therapies such as the cholesteryl ester transfer protein inhibitors, HDLderived proteins, and mimetic peptides/lipids can increase HDL-cholesterol levels or improve the antiatherosclerotic properties of HDL. In conclusion, the emergence of agents that act in monotherapy or in combination with available lipid-modifying drugs may allow more effective management of dyslipidemia and, consequently, reduce the burden of CVD.

How to Generate Reliable and Predictive CoMFA Models

How to Generate Reliable and Predictive CoMFA Models, 2011, 18(6) Pp. 923-930
Lei Zhang, Keng-Chang Tsai, Lupei Du, Hao Fang, Minyong Li and Wenfang Xu

Comparative Molecular Field Analysis (CoMFA) is a mainstream and down-to-earth 3D QSAR technique in the coverage of drug discovery and development. Even though CoMFA is remarkable for high predictive capacity, the intrinsic data-dependent characteristic still makes this methodology certainly be handicapped by noise. It's well known that the default settings in CoMFA can bring about predictive QSAR models, in the meanwhile optimized parameters was proven to provide more predictive results. Accordingly, so far numerous endeavors have been accomplished to ameliorate the CoMFA model's robustness and predictive accuracy by considering various factors, including molecular conformation and alignment, field descriptors and grid spacing. Herein, we would like to make a comprehensive survey of the conceivable descriptors and their contribution to the CoMFA model's predictive ability.

Emerging Role of Antioxidants in the Protection of Uveitis Complications

Emerging Role of Antioxidants in the Protection of Uveitis Complications, 2011, 18(6) Pp. 931-942
U. C.S. Yadav, N. M. Kalariya and K. V. Ramana

Current understanding of the role of oxidative stress in ocular inflammatory diseases indicates that antioxidant therapy may be important to optimize the treatment. Recently investigated antioxidant therapies for ocular inflammatory diseases include various vitamins, plant products and reactive oxygen species scavengers. Oxidative stress plays a causative role in both non-infectious and infectious uveitis complications, and novel strategies to diminish tissue damage and dysfunction with antioxidant therapy may ameliorate visual complications. Preclinical studies with experimental animals and cultured cells demonstrate significant anti-inflammatory effects of a number of promising antioxidant agents. Many of these antioxidants are under clinical trial for various inflammatory diseases other than uveitis such as cardiovascular, rheumatoid arthritis and cancer. Well planned interventional clinical studies in the filed of ocular inflammation will be necessary to sufficiently investigate the potential medical benefits of antioxidant therapies for uveitis. This review summarizes the recent investigations of novel antioxidant agents for ocular inflammation, with selected studies focused on uveitis.

Novel and Emerging Drugs for Acute Myeloid Leukemia: Pharmacology and Therapeutic Activity

Novel and Emerging Drugs for Acute Myeloid Leukemia: Pharmacology and Therapeutic Activity, 2011, 18(5) Pp. 638-666
T. Robak, A. Szmigielska-Kaplon, A. Pluta, O. Grzybowska-Izydorczyk, A. Wolska, M. Czemerska and A Wierzbowska

For the last twenty years, significant progress in Molecular and Cellular Biology has resulted in a better characterization and understanding of the biology and prognosis of acute myeloid leukemia (AML). These achievements have provided new opportunities for the development of innovative, more effective therapies. Novel agents potentially useful in the treatment of patients with AML include new formulations of established drugs, newer nucleoside analogs, molecular target drugs, monoclonal antibodies and other agents. Three newer nucleoside analogs, clofarabine, troxacitabine and sapacitabine have been recently investigated in patients with AML. Two methylation inhibitors, 5-azacyticline and decitabine are pyrimidine nucleoside analogs of cytidine which can be incorporated into RNA and/or DNA. Lower doses of these agents are active in AML and have been extensively investigated, especially in secondary AML and AML in elderly patients. Tipifarnib and lonafarnib are orally available farnesyltransferase inhibitors with in vitro and in vivo activity against AML. In recent years, FLT3 inhibitors, lestaurinib, tandutinib and PKC 412 have been developed and tested in AML. The preclinical observations and clinical studies indicate that FLT3 inhibitors are promising agents in the treatment of FLT3 mutated AML patients, especially when used in combinations with chemotherapy. Several newer MDR inhibitors, including valspodar (PSC-833) and zosuquidar trihydrochloride have been also tested for the treatment of relapsed AML. This article reviews the various classes of AML targets and drugs that are under early phase clinical evaluation, especially those that are likely to enter clinical practice in the near future.

Clinical Drugs Undergoing Polymorphic Metabolism by Human Cytochrome P450 2C9 and the Implication in Drug Development

Clinical Drugs Undergoing Polymorphic Metabolism by Human Cytochrome P450 2C9 and the Implication in Drug Development, 2011, 18(5) Pp. 667-713
S.-M. He, Z.-W. Zhou, X.-T. Li and S.-F. Zhou

CYP2C9 metabolizes more than 100 clinically used drugs including phenytoin, S-warfarin, tolbutamide, glipizide, diclofenac, and losartan with varying contributions. CYP2C9 is considered one of the most important CYPs, with substrate specificity typical of many new chemical entities (i.e. lipophilic bases). A large interindividual variation has been identified for the CYP2C9 activity and for the clinical response to the therapeutics metabolised by the enzyme. So far, at least 33 variants of CYP2C9 (*2 through to *34) have been identified. CYP2C9 is one of the clinically significant drug metabolising enzymes that demonstrates genetic variants with significant phenotype and clinical outcomes. This review updates our current knowledge on the polymorphic metabolism of drugs by CYP2C9 and discusses its implications in drug development. The authors have searched through computer-based literatures by full text search in Medline (via Pubmed), ScienceDirect, Genetics Abstracts (CSA), SCOPUS, Chemical Abstracts, Current Contents Connect (ISI), Cochrance Library, CINAHL (EBSCO), CrossRef Search and Embase (all from inception to October 31 2010). A comprehensive literature search has identified 32 drugs that are subject to CYP2C9-mediated polymorphic metabolism. Drugs that are subject to polymorphic metabolism with clinical significance include nine nonsteroidal anti-inflammatory agents, six sulfonylurea antidiabetic drugs and, most critically, three oral coumarin anticoagulants. Polymorphisms in CYP2C9 have the potential to affect the clearance and clinical response of CYP2C9 substrate drugs with low therapeutic indices such as warfarin, phenytoin, and certain antidiabetic drugs. Warfarin has served as a model drug of how pharmacogenetics can be employed to achieve maximum efficacy and minimum toxicity. Minimizing interindividual variability in drug exposure due to CYP2C9 polymorphisms is an important goal in drug development and discovery.

Pharmacological Interventions on Asymmetric Dimethylarginine, a Clinical Marker of Vascular Disease

Pharmacological Interventions on Asymmetric Dimethylarginine, a Clinical Marker of Vascular Disease, 2011, 18(5) Pp. 714-724
M. Marin and S. Manez

The aim of this paper is to review the latest data on the pharmacological modulation of asymmetric dimethylarginine in human disease. When the terminal nitrogens of the guanidine portion of an arginine become methylated through the action of N-methyl transferases, two chemically close, but physiologically different amino acids are synthesized: symmetric and asymmetric dimethylarginine. The vascular origin of asymmetric dimethylarginine and its inhibitory activity on endothelial nitric oxide synthase give it an important role in certain diseases in which microcirculation is compromised: hypertension, atherosclerosis, inflammatory bowel disease, and diabetes. This review discusses the role that asymmetric dimethylarginine plays in the development of vascular disease, and, wherever possible, evaluates its use in clinical diagnosis. The fact that a number of chemically unrelated drugs, such as angiotensin II antagonists, selective beta- 1 adrenergic antagonists, plant phenolics, statins, and farnesoid X receptor agonists have all been found to reduce dimethylarginine levels in plasma or tissue allows for an integrated study. Although it is difficult to determine exactly why these various agents all have the same effect on arginine metabolism, an explanation of their mechanisms of action is needed. We have thus analyzed the mechanisms involved and reviewed potential trends in the therapeutic use of these drugs.

Toward a Biochemical Diagnosis of NASH: Insights From Pathophysiology For Distinguishing Simple Steatosis From Steatohepatitis

Toward a Biochemical Diagnosis of NASH: Insights From Pathophysiology For Distinguishing Simple Steatosis From Steatohepatitis, 2011, 18(5) Pp. 725-732
Y. Yilmaz and E. Ulukaya

With the continuing epidemics of obesity and diabetes, nonalcoholic fatty liver disease (NAFLD) has received increased attention. Great efforts are being undertaken to improve the noninvasive diagnosis of NAFLD, with the ultimate goal of optimizing treatment options and clinical outcomes. Research suggests that blood-borne biochemical markers can be used to distinguish simple steatosis from nonalcoholic steatohepatitis (NASH), thus reducing the need of liver biopsy. Future developments in the field of diagnostic biochemistry within the spectrum of NAFLD can make this approach ideal for screening and monitoring purposes. In this review, we provide an overview of the different blood-borne markers which have been recently proposed for differentiating simple steatosis from NASH. We will also consider the practical and statistical issues that seem to be limiting the effective integration of biomarkers into clinical development.

New Lead Structures in Antifungal Drug Discovery

New Lead Structures in Antifungal Drug Discovery, 2011, 18(5) Pp. 733-766
Chunquan Sheng and Wannian Zhang

During the past two decades, the incidence of invasive fungal infections has been increasing dramatically. Clinical available antifungal agents have several drawbacks such as limited potency and spectrum, drug related toxicity, non-optimal pharmacokinetics, and severe resistance. There is an emergent need to develop new antifungal drugs with novel chemical structures and novel mechanism of action. This review will focus on the most significant achievements in the discovery of antifungal lead structures within last few years. In particular, we pay more attention on the structureactivity relationship of antifungal leads and provide perspectives for future antifungal drug discovery.

Chemistry and Pharmacology of Neglected Helminthic Diseases

Chemistry and Pharmacology of Neglected Helminthic Diseases, 2011, 18(5) Pp. 767-789
A. Mullner, A. Helfer, D. Kotlyar, J. Oswald and T. Efferth

Neglected helminthic diseases cause many social, economic and health care challenges in developing countries. The high number of patients suffering from these parasitic infections and the lack of sufficient treatment options represent severe problems. Research on new drugs and therapies to meet this urgent requirement has to be intensified. This review focuses on infections caused by four helminthic parasites, which have been declared as neglected diseases by the World Health Organization: namely drancunculiasis, lymphatic filariasis, onchoceriasis, and schistosomiasis. They show a considerable overlap in their world-wide prevalence and treatment strategies. Nevertheless, treatment is not without complications. The most efficient lymphatic filariasis drug, diethylcarbamazine, causes severe adverse effects in onchocerciasis patients and completely fails in the treatment of drancunculiasis. In this review, we discuss these incongruities at the molecular and cellular level. Furthermore, established or investigational drug combination regimens are highlighted. In the past years, progress has been made in the area of schistosomiasis and onchocerciasis. The molecular biology of underlying mechanisms, signalling pathways and related targets affected by drug therapy are discussed in detail. Finally, successful treatment strategies and remaining future challenges are summarized.

Aurora B: A New Prognostic Marker and Therapeutic Target in Cancer

Aurora B: A New Prognostic Marker and Therapeutic Target in Cancer, 2011, 18(4) Pp. 482-496
G. Portella, C. Passaro and P. Chieffi

Aurora B is a serine-threonine kinase belonging to the highly conserved Aurora family of mitotic kinases. Aurora B is a chromosomal passenger protein involved in chromosome segregation, spindle-checkpoint, and cytokinesis. Alteration of each of these steps could induce aneuploidy, one of main features, and driving force of cancer progression. The overexpression of Aurora B has been observed in several tumor types, and has been linked with a poor prognosis of cancer patients. In this review we will focus on the role of Aurora B in cancer development, its role as a prognostic marker, and the clinical outcome of recently developed Aurora(s) inhibitors.

The CXCL12/CXCR4 Axis as a Therapeutic Target in Cancer and HIV-1 Infection

The CXCL12/CXCR4 Axis as a Therapeutic Target in Cancer and HIV-1 Infection, 2011, 18(4) Pp. 497-512
L. Patrussi and C. T. Baldari

The seven-spanning transmembrane G-protein coupled receptor CXCR4, which specifically binds to the chemokine CXCL12, is expressed on many cell types, including various types of tumour cells. CXCR4 plays a crucial role in organ-specific metastasis, directing migration of malignant cells expressing this receptor toward microenvironments where the cognate ligand is secreted. CXCL12 has a direct growth and survival-promoting effect for various cancer cells and enhances moreover tumour angiogenesis by recruiting endothelial progenitor cells to tumours. Drugs which modulate the CXCL12/CXCR4 axis are therefore promising candidates in anti-cancer therapies. CXCR4 is also a coreceptor for human immunodeficiency virus type 1 (HIV-1) X4 virus and, as such, plays an important role in virus entry into target cells. Hence, antiviral agents that bind to CXCR4 are expected to inhibit HIV-1 entry. Here we review the structure, mechanism of action and biological activity of the main CXCR4 antagonists (peptide inhibitors, non-peptide antagonists, neutralizing antibodies, modified analogues of CXCL12) and agonists (CXCL12 peptide analogues) and discuss the CXCL12/CXCR4 axis as an important target in development of anti-tumoral and anti-HIV-1 therapies.

Endocrine Therapy of Breast Cancer

Endocrine Therapy of Breast Cancer, 2011, 18(4) Pp. 513-522
F. Lumachi, G. Luisetto, S. M.M. Basso, U. Basso, A. Brunello and V. Camozzi

Breast cancer remains one of the first leading causes of death in women, and currently endocrine treatment is of major therapeutic value in patients with estrogen-receptor positive tumors. Selective estrogen-receptor modulators (SERMs), such as tamoxifen and raloxifene, aromatase inhibitors, and GnRH agonists are the drugs of choice. Tamoxifen, a partial nonsteroidal estrogen agonist, is a type II competitive inhibitor of estradiol at its receptor, and the prototype of SERMs. Aromatase inhibitors significantly lower serum estradiol concentration in postmenopausal patients, having no detectable effects on adrenocortical steroids formation, while GnRH agonists suppress ovarian function, inducing a menopause- like condition in premenopausal women. Endocrine therapy has generally a relatively low morbidity, leading to a significant reduction of mortality for breast cancer. The aim of chemoprevention is to interfere early with the process of carcinogenesis, reducing the risk of cancer development. As preventive agents, raloxifene and tamoxifene are equivalent, while raloxifene has more potent antiresorptive effects in postmenopausal osteoporosis. Endocrine treatment is usually considered a standard choice for patients with estrogen-receptor positive cancers and non-life-threatening advanced disease, or for older patients unfit for aggressive chemotherapy regimens. Several therapeutic protocols used in patients with breast cancer are associated with bone loss, which may lead to an increased risk of fracture. Bisphosphonates are the drugs of choice to treat such a drug-induced bone disease. The aim of this review is to outline current understanding on endocrine therapy of breast cancer.

Developments of Combretastatin A-4 Derivatives as Anticancer Agents

Developments of Combretastatin A-4 Derivatives as Anticancer Agents, 2011, 18(4) Pp. 523-538
Y. Shan Shan, J. Zhang, Z. Liu, M. Wang and Y. Dong

Tubulin protein is one of several members of a small family of globular proteins. It offers a potential target for anticancer drug design and development. Combretastatin A-4 (CA-4) is a potent anticancer and antiangiogenesis natural substance isolated from Combretum caffrum. Modifications on the CA-4 structure have led to a great number of novel CA-4 derivatives as potent tubulin inhibitors and high cytotoxic anticancer agents is becoming an interesting field, leading to a breakthrough in the treatment of cancer. In this review, the recent developments of novel CA-4 derivatives via the modifications on the A- and B-ring and the double bond as anticancer agents are discussed.

Macrophage-Assisted Inflammation and Pharmacological Regulation of the Cholinergic Anti-Inflammatory Pathway

Macrophage-Assisted Inflammation and Pharmacological Regulation of the Cholinergic Anti-Inflammatory Pathway, 2011, 18(4) Pp. 539-551
M. Pohanka, S. Snopkova, K. Havlickova, P. Bostik, Z. Sinkorova, J. Fusek, K. Kuca and Jiri Pikula

Macrophages play an important role in the immune system. They also participate in multiple processes including angiogenesis and triggering of inflammation. The present study summarizes pieces of knowledge on the importance of macrophages in disease, especially the inflammation. Special attention is paid to the cholinergic anti-inflammatory pathway (CAP) associated with the nicotinic acetylcholine receptor (nAChR) and the parasympathetic nervous system. The current pharmacological effectiveness in suppressing the inflammation in general and the septic shock in particular, is limited. CAP was discovered recently and it seems to be a suitable target for the development of new drugs. Moreover, available drugs binding to either nAChR or acetylcholinesterase (AChE) are candidates for either an inhibition or enhancement of CAP. Though the current scientific databases do not include all necessary data on the association of CAP with body functions and the research is quite intensive, the objective of the present review is to introduce the current trends and to critically evaluate CAP and macrophage-associated pathways.

A Step Further Towards Multitarget Drugs for Alzheimer and Neuronal Vascular Diseases: Targeting the Cholinergic System, Amyloid-β Aggregation and Ca2++ Dyshomeostasis

A Step Further Towards Multitarget Drugs for Alzheimer and Neuronal Vascular Diseases: Targeting the Cholinergic System, Amyloid-β Aggregation and Ca2++ Dyshomeostasis, 2011, 18(4) Pp. 552-576
R. Leon and J. Marco-Contelles

Alzheimer's disease (AD) is the most common neurodegenerative disease, affecting mainly elderly people. The reasons why AD occurs are complex and multifactorial and several biochemical targets are thought to play a key role in its progress and development. This fact has led to the development of a multitarget-directed ligand strategy as a logical approach for designing a suitable therapy. Currently, most prescribed drugs for treating AD are acetylcholinesterase inhibitors (AChEI), although these inhibitors represent solely palliative treatment. This account will summarize our current therapeutic approach for the design of multitarget drugs primarily aimed at inhibiting AChE using the key features of tacrine, which was the first approved drug for AD treatment. Secondly, as calcium homeostasis is directly related to the cell death-survival equilibrium, suitable therapy might include an action that regulates calcium homeostasis by means of targeting voltage dependent calcium channels. It is, therefore, hoped that targeting calcium homeostasis will lead directly to the development of potential neuroprotective agents. Thus, 1,4-dihydropyridines, well-known voltage-dependent calcium channel (VDCC) ligands, will be incorporated into the new molecules as a second structural feature in order to bring about this action. As a result of this development, herein, we describe the synthetic and pharmacological profile of new [1,8]-naphthyridine analogues, which are hybrids of tacrine and 1,4-dihydropyridines. Some of our molecules have shown improved inhibitory action against cholinesterases, whilst maintaining their VDCC modulating activity, and have good characteristics as neuroprotective agents. Based on kinetic analysis of the AChE inhibition experiments, it has been shown that many of the compounds bind at the peripheral anionic site (PAS). Since the AChE PAS is linked to β-amyloid aggregation, this would give a third biological target for further preclinical development, making these molecules highly interesting targets in the search to obtain better treatments for AD.

Peptide Immunotherapies in Type 1 Diabetes: Lessons from Animal Models

Peptide Immunotherapies in Type 1 Diabetes: Lessons from Animal Models, 2011, 18(4) Pp. 577-586
A. Fierabracci

Insulin dependent diabetes mellitus (Type 1 diabetes, T1D) is a chronic autoimmune disorder characterized by the destruction of insulin-producing pancreatic beta cells by proinflammatory autoreactive T cells. In the past, several therapeutic approaches have been exploited by immunologists aiming to regulate the autoimmune response; this can occur by deleting lymphocyte subsets and/or re-establishing immune tolerance via activation of regulatory T cells. The use of broad immunosuppressive drugs was the first approach to be explored. Subsequently, antibody-based immunotherapies failed to discriminate between autoreactive versus non-autoimmune effectors. Antigen-based immunotherapy is a third approach developed to manipulate beta cell autoimmunity. This approach allows the selective targeting of disease-relevant T cells, while leaving the remainder of the immune system intact. Animal models have been successfully employed to prevent or treat T1D by injection of either the self proteins or peptides derived from them. Peptide immunotherapies have been mainly experimented in the NOD mouse spontaneous model of disease. In this review we therefore report the main approaches that rely on the use of peptides obtained from relevant autoantigens such as glutamic acid decarboxylase, isoform 65 (GAD65), insulin, proinsulin and islet-specific glucose 6 phosphatase catalytic subunit-related protein (IGRP). Protective peptides have proven to be effective in treating or delaying the diabetic process. We also highlight the main difficulties encountered in extrapolating data to guide clinical translational investigations in humans.

Soluble Epoxide Hydrolase Inhibitors and their Potential for Treatment of Multiple Pathologic Conditions

Soluble Epoxide Hydrolase Inhibitors and their Potential for Treatment of Multiple Pathologic Conditions, 2011, 18(4) Pp. 587-603
R. H. Ingraham, R. D. Gless and H. Y. Lo

Epoxyeicosanoids, including the epoxyeicosatrienoic acids, are signaling molecules which appear to help ameliorate the effects of a wide variety of pathological conditions. The enzyme soluble epoxide hydrolase (sEH) metabolizes these molecules by converting them to their corresponding vicinal diols. Inhibition of sEH either by knockout or chemical inhibitors increases epoxyeicosanoid levels in vivo and provides significant organ protection in models of brain, cardiac, and renal injury. sEH also appears to be involved in modulating inflammation, pain pathways, pulmonary function, hypertension, and diabetes. Potent sEH inhibitors have been developed in academic, pharmaceutical, and biotech laboratories and described in the patent and scientific literature. Most of the inhibitor scaffolds employ a urea or amide which functions as an active-site transition state mimic. Arete Therapeutics compound AR9281 successfully completed phase Ia and Ib studies. A phase IIa proof of concept trial for treatment of impaired glucose tolerance has been completed, but the results are not yet reported.

Vaccination and Antiviral Treatment of Neglected Diseases Caused by Flaviviral Infections

Vaccination and Antiviral Treatment of Neglected Diseases Caused by Flaviviral Infections, 2011, 18(4) Pp. 604-614
K. Schleich, C. Nurnberger, A. Sobanski and T. Efferth

Flaviviral infections have a re-emerging impact on the health situation in developing countries with several billion of people living at risk. In the present review, we focus on three members of the genus Flavivirus belonging to the Flaviviridae family. They are transmitted to humans by mosquito bites, namely those viruses leading to Dengue Fever, Yellow Fever and mosquito-borne Japanese encephalitis. All three virus groups have a spherical structure with a diameter of approximately 50 nm. Although sharing a similar genomic structure and intracellular life cycle, they show different clinical manifestations. Infections are incurable, as there is no antiviral treatment available for either of the three viruses. Thus, prevention and vaccination are the best defenses. The most promising vaccines are live attenuated vaccines (LAVs), such as the YF17D strain against Yellow Fever or the SA-14-14-2 strain against Japanese encephalitis. Additionally, recombinant vaccines for Japanese encephalitis are in development. Although Dengue Fever is the most prevalent arthropode- borne flaviviral infection and a lot of research to develop a vaccine against all four Dengue Fever serotypes was undertaken, no vaccine is available on the market yet. Promising tetravalent vaccine candidates are currently undergoing clinical phase trials, including LAVs, recombinant and chimeric candidates as well as non-replicating vaccine approaches. Additionally, encouraging anti-flaviviral approaches target non-structural proteins, virus-specific proteases essential for cellular maturation of viral particles. Peptide inhibitors against the highly conserved NS2B and NS3 proteases are attractive as pan-flaviviral drug candidates.

Microwave-Assisted Synthesis of Medicinally Relevant Indoles

Microwave-Assisted Synthesis of Medicinally Relevant Indoles, 2011, 18(4) Pp. 615-637
S. A. Patil, R. Patil and D. D. Miller

Indoles represent an important structural class in medicinal chemistry with broad spectrum of biological activities. The synthesis of indoles, therefore, has attracted enormous attention from synthetic chemists. Microwave methods for the preparation of indole analogs have been developed to speed up the synthesis, therefore, microwave assisted organic synthesis (MAOS) in controlled conditions is an invaluable technique for medicinal chemistry. In this review, indole forming classical reactions such as Fischer, Madelung, Bischler-Mohlau, Batcho-Leimgruber, Hemetsberger Knittel, Graebe-Ullmann, Diels-Alder and Wittig type reactions using microwave radiation has been summarized. In addition, metal mediated cyclizations along with solid phase synthesis of indoles have been discussed.

Quassinoids: From Traditional Drugs to New Cancer Therapeutics

Quassinoids: From Traditional Drugs to New Cancer Therapeutics, 2011, 18(3) Pp. 316-328
G. Fiaschetti, M. A. Grotzer, T. Shalaby, D. Castelletti and A. Arcaro

Quassinoids are a group of compounds extracted from plants of the Simaroubaceae family, which have been used for many years in folk medicine. These molecules gained notoriety after the initial discovery of the anti-leukemic activity of one member, bruceantin, in 1975. Currently over 150 quassinoids have been isolated and classified based on their chemical structures and biological properties investigated in vitro and in vivo. Many molecules display a wide range of inhibitory effects, including anti-inflammatory, anti-viral, anti-malarial and anti-proliferative effects on various tumor cell types. Although often the exact mechanism of action of the single agents remains unclear, some agents have been shown to affect protein synthesis in general, or specifically HIF-1α and MYC, membrane polarization and the apoptotic machinery. Considering that future research into chemical modifications is likely to generate more active and less toxic derivatives of natural quassinoids, this family represents a powerful source of promising small molecules targeting key prosurvival signaling pathways relevant for diverse pathologies. Here, we review available knowledge of functionality and possible applications of quassinoids and quassinoid derivatives, spanning traditional use to the potential impact on modern medicine as cancer therapeutics.

Drug Transporters in Chemotherapy Induced Peripheral Neurotoxicity:Current Knowledge and Clinical Implications

Drug Transporters in Chemotherapy Induced Peripheral Neurotoxicity:Current Knowledge and Clinical Implications, 2011, 18(3) Pp. 329-341
C. Ceresa and G. Cavaletti

Several antineoplastic drugs induce severe and dose-limiting peripheral neurotoxicity that can significatly affect the quality of life of cancer patients and cause chronic discomfort. Despite extensive investigation, the fine mechanisms of this side-effect remain unclear. It has recently been suggested that several classes of drug transporters are involved in the genesis of chemotherapyinduced peripheral neurotoxicity. Furthermore, the differential distribution and activity of these transporters could also explain the higher sensitivity of the peripheral rather than central nervous system tissues to the toxic action of the anticancer agents. These observations may have important therapeutic implications. In fact, the characterization of the proteins that mediate significant transport of clinically relevant drugs in the nervous system, and the understanding of their changes in the different pathological conditions are important in order to elucidate pathogenetic mechanisms and to identify new potential therapeutic targets so as to limit the severity of chemotherapy-induced peripheral neurotoxicity. This review will be focused on the most recent research progress on the role of drug transporters in chemotherapy-induced peripheral neurotoxicity, and we will discuss the possibility of targeting these transporters as a new and interesting potential strategy for the treatment of the neurotoxic side-effects of antineoplastic drugs.

Novel, Selective CDK9 Inhibitors for the Treatment of HIV Infection

Novel, Selective CDK9 Inhibitors for the Treatment of HIV Infection, 2011, 18(3) Pp. 342-358
G. Nemeth, Z. Varga, Z. Greff, G. Bencze, A. Sipos, C. Szantai-Kis, F. Baska, A. Gyuris, K. Kelemenics, Z. Szathmary, J. Minarovits, G. Keri and L. Orfi

Cyclin Dependent Kinases (CDKs) are important regulators of cell cycle and gene expression. Since an up-todate review about the pharmacological inhibitors of CDK family (CDK1-10) is not available; therefore in the present paper we briefly summarize the most relevant inhibitors and point out the low number of selective inhibitors. Among CDKs, CDK9 is a validated pathological target in HIV infection, inflammation and cardiac hypertrophy; however selective CDK9 inhibitors are still not available. We present a selective inhibitor family of CDK9 based on the 4-phenylamino-6- phenylpyrimidine nucleus. We show a convenient synthetic method to prepare a useful intermediate and its derivatisation resulting in novel compounds. The CDK9 inhibitory activity of the derivatives was measured in specific kinase assay and the CDK inhibitory profile of the best ones (IC50 > 100nM) was determined. The most selective compounds had high selectivity over CDK1, 2, 3, 5, 6, 7 and showed at least one order of magnitude higher inhibitory activity over CDK4 inhibition. The most selective molecules were examined in cytotoxicity assays and their ability to inhibit HIV-1 replication was determined in cellular assays.

Recent Advances in DAPYs and Related Analogues as HIV-1 NNRTIs

Recent Advances in DAPYs and Related Analogues as HIV-1 NNRTIs, 2011, 18(3) Pp. 359-376
Xuwang Chen, Peng Zhan, Dongyue Li, Erik De Clercq and Xinyong Liu

HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) nowadays represent most promising anti- AIDS drugs that specifically inhibit HIV-1 reverse transcriptase (RT). They have a unique antiviral potency, high specificity and low cytotoxicity. However, to a great extent, the efficacy of HIV-1 NNRTIs is compounded by rapid emergence of drug resistant virus strains, which calls for continuous efforts to develop novel HIV-1 NNRTIs. Diarylpyrimidine (DAPY) derivatives, one family of NNRTIs with superior activity profiles against wild-type HIV-1 and mutant strains, have attracted considerable attention over the past few years. Among the potent lead DAPY compounds, etravirine was approved by FDA in January 2008, and its analogue rilpivirine (TMC278) has advanced to phase III clinical trials. The successful development of DAPYs results from a multidisciplinary approach involving traditional medicinal chemistry, structural biology, crystallography and computational chemistry. Recently, a number of novel characteristics of DAPYs including conformational flexibility, positional adaptability, key hydrogen bonds and specifically targeting conserved residues of RT, have been identified, providing valuable avenues for further optimization and development of new DAPY analogues as promising anti-HIV drug candidates. In this review, we first present a brief historical account of the medicinal chemistry of the DAPY NNRTIs, then focus on the extensive structural modifications, SAR studies, and binding mode analysis based on crystallographic and molecular modeling. Other structural related NNRTI scaffolds will also be reviewed.

Voltage-Gated Sodium Channels: Mutations, Channelopathies and Targets

Voltage-Gated Sodium Channels: Mutations, Channelopathies and Targets, 2011, 18(3) Pp. 377-397
G. S.B. Andavan and R. Lemmens-Gruber

Voltage-gated sodium channels produce fast depolarization, which is responsible for the rising phase of the action potential in neurons, muscles and heart. These channels are very large membrane proteins and are encoded by ten genes in mammals. Sodium channels are a crucial component of excitable tissues; hence, they are a target for various neurotoxins that are produced by plants and animals for defence and protection, such as tetrodotoxin, scorpion toxins and batrachotoxin. Several mutations in various sodium channel subtypes cause multiple inherited diseases known as channelopathies. When these mutated sodium channel subtypes are expressed in various tissues, channelopathies in brain, skeletal muscle and cardiac muscle develop as well as neuropathic pain. In this review, we discuss aspects of voltage-gated sodium channel genes with an emphasis on cardiac muscle sodium channels. In addition, we report novel mutations that underlie a spectrum of diseases, such as Brugada, long QT syndrome and inherited conduction disorders. Furthermore, this review explains commonalities and differences among the channel subtypes, the channelopathies caused by the sodium channel gene mutation and the specificity of toxins and blockers of the channel subtypes.

Intestinal Epithelial Barrier Dysfunction in Disease and Possible Therapeutical Interventions

Intestinal Epithelial Barrier Dysfunction in Disease and Possible Therapeutical Interventions, 2011, 18(3) Pp. 398-426
R.-M. Catalioto, C. A. Maggi and S. Giuliani

The intestinal epithelial monolayer constitutes a physical and functional barrier between the organism and the external environment. It regulates nutrients absorption, water and ion fluxes, and represents the first defensive barrier against toxins and enteric pathogens. Epithelial cells are linked together at the apical junctional complex by tight junctions that reduce the extracellular space and the passage of charge entities while forming a physical barrier to lipophilic molecules. Cultured intestinal epithelial cells have been extensively used to study intestinal absorption of newly synthesized drugs and the regulation of tight junctions structure and function. In vitro mild irritants, proinflammatory cytokines, toxins and pathogens, and adverse environmental conditions open tight junctions and increase paracellular permeability, an effect often accompanied by immune activation of the enterocytes. Conversely, inhibition of proinflammatory cytokines, exposure to growth factors and probiotics, among others, exert a protective effect. Impaired barrier function results from activation of signalling pathways that lead to alteration of junctional proteins expression and/or distribution. In vivo, intestinal barrier dysfunction is associated with various intestinal and non-intestinal disorders including inflammatory bowel disease, celiac disease, and diarrhoeal infection. This review will describe the current knowledge of the mechanisms regulating tight junctions and intestinal permeability, how these findings have lead to a better understanding of barrier alteration in human intestinal disorders, and what the emerging therapies to treat these pathologies are.

The Role of the Cytochrome P450 Polymorphisms in Clopidogrel Efficacy and Clinical Utility

The Role of the Cytochrome P450 Polymorphisms in Clopidogrel Efficacy and Clinical Utility, 2011, 18(3) Pp. 427-438
D. Tousoulis, G. Siasos, M. Zaromytidou, N. Papageorgiou, E. Stefanadi, E. Oikonomou and C. Stefanadis

Clopidogrel, an antiplatelet agent, prevents platelet aggregation by inhibiting the adenosine disphosphate (ADP) P2Y12 receptor, which is located on the platelet surface. Although dual antiplatelet therapy appears to be efficient, a considerable number of patients continue to experience adverse cardiovascular events, such as stent thrombosis. The percentage of low response to antiplatelet therapy varies from 4% to 30% of patients depending on the cut-off values. In addition, several factors such as poor absorption, drug-to-drug interactions, inadequate dosing, elevated body mass index, insulin resistance and the nature of acute coronary syndromes have been implicated in low clopidogrel response. Recently, studies have focused on the role of genetic polymorphisms encoding enzymes that participate in clopidogrel hepatic metabolism or receptors involved in intestinal absorption and ADP induced platelet aggregation, which may affect the percentage of platelet inhibition after clopidogrel administration. The management of clopidogrel resistance remains a controversial issue and additional studies are required to evaluate the safety and efficacy of increased loading of clopidogrel or replacement with other new antiplatelet agents such as prasugrel.

Structural and Functional Properties of Human Multidrug Resistance Protein 1 (MRP1/ABCC1)

Structural and Functional Properties of Human Multidrug Resistance Protein 1 (MRP1/ABCC1), 2011, 18(3) Pp. 439-481
S.-M. He, R. Li, J. R. Kanwar and S.-F. Zhou

Multidrug ABC transporters such as P-glycoprotein (P-gp/MDR1/ABCB1) and multidrug resistance protein 1 (MRP1/ABCC1) play an important role in the extrusion of drugs from the cell and their overexpression can be a cause of failure of anticancer and antimicrobial chemotherapy. Recently, the mouse P-gp/Abcb1a structure has been determined and this has significantly enhanced our understanding of the structure-activity relationship (SAR) of mammalian ABC transporters. This paper highlights our current knowledge on the structural and functional properties and the SAR of human MRP1/ABCC1. Although the crystal structure of MRP1/ABCC1 has yet to be resolved, the current topological model of MRP1/ABCC1 contains two transmembrane domains (TMD1 and TMD2) each followed by a nucleotide binding domain (NBD) plus a third NH2-terminal TMD0. MRP1/ABCC1 is expressed in the liver, kidney, intestine, brain and other tissues. MRP1/ABCC1 transports a structurally diverse array of important endogenous substances (e.g. leukotrienes and estrogen conjugates) and xenobiotics and their metabolites, including various conjugates, anticancer drugs, heavy metals, organic anions and lipids. Cells that highly express MRP1/ABCC1 confer resistance to a variety of natural product anticancer drugs such as vinca alkaloids (e.g. vincristine), anthracyclines (e.g. etoposide) and epipodophyllotoxins (e.g. doxorubicin and mitoxantrone). MRP1/ABCC1 is associated with tumor resistance which is often caused by an increased efflux and decreased intracellular accumulation of natural product anticancer drugs and other anticancer agents. However, most compounds that efficiently reverse P-gp/ABCB1-mediated multidrug resistance have only low affinity for MRP1/ABCC1 and there are only a few effective and relatively specific MRP1/ABCC1 inhibitors available. A number of site-directed mutagenesis studies, biophysical and photolabeling studies, SAR and QSAR, molecular docking and homology modeling studies have documented the role of multiple residues in determining the substrate specificity and inhibitor selectivity of MRP1/ABCC1. Most of these residues are located in the TMs of TMD1 and TMD2, in particular TMs 4, 6, 7, 8, 10, 11, 14, 16, and 17, or in close proximity to the membrane/cytosol interface of MRP1/ABCC1. The exact transporting mechanism of MRP1/ABCC1 is unclear. MRP1/ABCC1 and other multidrug transporters are front-line mediators of drug resistance in cancers and represent important therapeutic targets in future chemotherapy. The crystal structure of human MRP1/ABCC1 is expected to be resolved in the near future and this will provide an insight into the SAR of MRP1/ABCC1 and allow for rational design of anticancer drugs and potent and selective MRP1/ABCC1 inhibitors.

Development of RET Kinase Inhibitors for Targeted Cancer Therapy

Development of RET Kinase Inhibitors for Targeted Cancer Therapy, 2011, 18(2) Pp. 162-175
L. Mologni

RET (Rearranged during Transfection) is a transmembrane tyrosine kinase expressed in central and peripheral nervous system and neural crest-derived cells and acts as a co-receptor of GDNF family neurotrophic factor in complex with GRFα family proteins. RET protein comprises an extracellular portion with four cadherine-like domains and a cysteine- rich region important for intermolecular interactions; a hydrophobic transmembrane domain; an intracellular part comprising the juxtamembrane domain with regulatory function and the catalytic domain that phosphorylates the tyrosine residues of substrates. RET is involved in the development of enteric nervous system and renal organogenesis during embryonic life. Mutations of RET are associated to a subset of colorectal cancer and are commonly found in hereditary and sporadic thyroid cancer. Activating point mutations in the cystein-rich or the kinase domain of RET cause multiple endocrine neoplasia type 2 (MEN2), a group of familial cancer syndromes characterized by medullary thyroid carcinoma, pheochromocytoma, parathyroid hyperplasia and ganglioneuromatosis of the gastroenteric mucosa. Rearranged forms of RET (termed RET/PTC) are detected in the majority of papillary thyroid carcinomas (PTC). At present, the therapeutic treatment available for these pathologies is the total or partial surgical removal of thyroid, associated with radio-iodine therapy or chemotherapy: despite widespread use of multimodality treatment, survival rates have not improved much in the past few decades, which suggests that new treatment options should be explored. Several small-molecule inhibitors of RET kinase activity have been described in the last decade, some of which are currently undergoing clinical evaluation. Here, I review the large preclinical effort to the development of specific RET inhibitors, including medicinal chemistry analyses that may help refine potency and selectivity of future RET-targeted inhibitors.

Diagnostic and Therapeutic Use of Membrane Proteins in Cancer Cells

Diagnostic and Therapeutic Use of Membrane Proteins in Cancer Cells, 2011, 18(2) Pp. 176-190
D. Grimm, J. Bauer, J. Pietsch, M. Infanger, J. Eucker, C. Eilles and J. Schoenberger

As proteomics technologies develop, increasing number of membrane-associated proteins specific for cancer cells are being discovered. These proteins are of great interest, particularly because they are rich in targets for antibodies. Amongst them candidate biomarkers for early tumor diagnosis, prognosis and treatment have been detected. The suitability of several membrane-associated proteins as targets for drugs or antibodies has already been tested in preclinical and clinical studies. The results were encouraging in some cases, but not in all. They demonstrate that each type of tumor has its specific “Achilles heel”, and that suitable targets of cancer diagnosis and therapy must be found for each kind of neoplasm. This implies that membrane-associated proteins for each type of tumor cell need to be investigated. This review describes the current technologies of membrane protein characterization in a first part and subsequently summarizes the membrane associated proteins currently being tested as targets for diagnosis and treatment in breast, prostate, thyroid, and colon cancer. Their function will be explained and their role in tumor biology will be discussed.

The Role of Survivin for Radiation Oncology: Moving Beyond Apoptosis Inhibition

The Role of Survivin for Radiation Oncology: Moving Beyond Apoptosis Inhibition, 2011, 18(2) Pp. 191-199
F. Rodel, S. Reichert, T. Sprenger, U. S. Gaipl, J. Mirsch, T. Liersch, S. Fulda and C. Rodel

Alterations in the expression of apoptosis-related proteins, like the inhibitor of apoptosis (IAP) protein family, display a pivotal pathway by which cancer cells acquire resistance to therapeutic treatment. Among this family, survivin, the smallest and structural unique member, deserves growing attention due to its universal over-expression in human tumors, and its prominent role in disparate networks of cellular division, intracellular signaling and apoptosis. Several preclinical studies have demonstrated that targeting survivin expression by the use of small interfering RNAs, dominant negative mutants, antisense-oligonucleotides and small molecule repressors sensitized tumor cells towards chemotherapy and irradiation and reduced tumor growth potential. Due to these properties, survivin has been proposed as a molecular target for anticancer therapies. Recent studies further revealed that radio-sensitization achieved by survivin inhibition seems to be multifaceted and involves caspase-dependent and caspase-independent mechanisms. In general, an enhanced rate of apoptosis, and pronounced cell cycle arrest have been observed. More recently, a hampered DNA-damage response has been noted, indicating a distinct role of the protein in radiation-induced double strand break repair. These properties were linked to a nuclear import and physical interrelationship with members of the DNA-DSB repair machinery such as phospho-histone H2AX and DNA dependent Protein Kinase (DNA-PKcs). The applicability of survivin-driven strategies in clinical practice is currently under investigation as the first survivin inhibitors successfully entered phase I/II trials. Although these trials do not include radiation therapy at present, survivin inhibitors may represent a novel type of molecular antagonists to improve the effectiveness of radiation therapy or chemoradio- therapy.

Role of Natural Killer Cell Activity in the Pathogenesis of Endometriosis

Role of Natural Killer Cell Activity in the Pathogenesis of Endometriosis, 2011, 18(2) Pp. 200-208
Justyna Sikora, Aleksandra Mielczarek-Palacz and Zdzislawa Kondera-Anasz

Natural Killer (NK) cells are cytotoxic effector lymphocytes with the ability to lyse target cells in a major histocompatibility complex (MHC) class I-independent manner and without the need for prior antigen exposure. Data strongly suggested that NK cells play an important role in human reproduction and disturbance in their function can favor development of the gynecological disorders. In our study the role of NK cells in pathogenesis of endometriosis is reviewed and summarized from available literature. Endometriosis is related to a defect of NK cell cytotoxicity function in the ability to eliminate endometrial cells in ectopic sites. Alternations of the innate immunity mediated by NK cells may promote impairments or disrupt functions of adaptive immunity, which can contribute to development and progression of endometriosis and infertility associated with endometriosis. Aberrant immune responses by NK cells in affected women may represent risk factors for endometriosis and the repaired function can be a new treatment target of the affected women.

The Toxicogenetics of Antirretroviral Therapy: The Evil Inside

The Toxicogenetics of Antirretroviral Therapy: The Evil Inside, 2011, 18(2) Pp. 209-219
M del M. Gutierrez, M G. Mateo, F. Vidal and P. Domingo

The most important factor limiting the success of an antiretroviral therapy regimes is toxicity. Toxicity can depend on a number of factors; some of these are intrinsic to the host and may not only affect the latter's outward appearance, but also determine the intensity these toxic effects may reach. The former is exemplified by idiosyncratic or hypersensitivity reactions, whereas the latter is usually appreciated in metabolic disturbances or fat redistribution syndromes. Some of the determinants of antiretroviral toxicity are genetic in origin and have been the subject of intense study in recent years. Some of these are linked to a single nucleotide polymorphism (SNP), whereas others depend on a complex interaction between multiple genes variations. One of these tests (HLA B*5701) is now being applied in clinical practice and widely used to prevent the risk of hypersensitivity reactions to abacavir. Many other genetic determinants of antiretroviral drug toxicity have been suggested as an explanation for nucleoside analogue toxicity; these include lactic acidosis, peripheral neuropathy and pancreatitis, and have also been suggested as a potential basis for the non-nucleoside toxicity derived from immunogenetic factors involved in nevirapine hypersensitivity to SNPs in efavirenz enzyme metabolism, amongst other things. Metabolic toxicity, mainly due to protease inhibitors (PIs) is far more complex and depends on the interaction of various genes. The same seems to be true for fat redistribution syndromes and atherosclerosis, although a clear picture of the genetic factors operating in these syndromes is yet to emerge. The ultimate goal of pharmacogenetics is to customize antiretroviral therapy by identifying the genes that can maximise efficacy whilst helping avoid known side effects of antiretroviral drugs.

Computational Insights into Binding of Bisphosphates to Farnesyl Pyrophosphate Synthase

Computational Insights into Binding of Bisphosphates to Farnesyl Pyrophosphate Synthase, 2011, 18(2) Pp. 220-233
K. Ohno, K. Mori, M. Orita and M. Takeuchi

Bisphosphonates (BPs) are the most widely used and effective treatment for osteoporosis and Paget's disease. Non-nitrogen containing BPs (non-N-BPs), namely etidronate, clodronate, tiludronate, as well as nitrogen-containing BPs (N-BPs), namely pamidronate, alendronate, ibandronate, risedronate, zoledronate and minodronate have been launched on the market to date. N-BPs act by inhibiting the enzyme farnesyl pyrophosphate synthase (FPPS), and several crystal structures of complexes between FPPS and N-BPs have been revealed. Understanding the physical basis of the binding between protein and small molecules is an important goal in both medicinal chemistry and structural biology. In this review, we analyze in detail the energetic basis of molecular recognition between FPPS and N-BPs. First, we summarize the interactions between ligands and proteins observed in N-BPs-FPPS complexes in the Protein Data Bank (PDB). Second, we present an interaction energy analysis on the basis of full quantum mechanical calculation of FPPS and N-BP complexes using the fragment molecular orbital (FMO) method. The FMO result revealed that not only hydrogen bond and electrostatic interaction but also CH-O and π-πinteraction with FPPS are important for N-BP's potency. Third, we describe a binding site analysis of FPPS on the basis of the inhomogeneous solvation theory which, by clustering the results from an explicit solvent molecular dynamics simulation (MD), is capable of describing the entropic and enthalpic contributions to the free energies of individual hydration sites. Finally, we also discuss the structure-activity relationship (SAR) of the series of minodronate derivatives.

Targeting the Nogo Receptor Complex in Diseases of the Central Nervous System

Targeting the Nogo Receptor Complex in Diseases of the Central Nervous System, 2011, 18(2) Pp. 234-244
C. L. McDonald, C. Bandtlow and M. Reindl

After injury to the central nervous system intrinsic factors such as myelin associated inhibitory factors inhibit cellular and axonal regeneration resulting in permanent disability. Three of these factors (Nogo-A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein) bind to a common receptor: the Nogo-66 receptor (NgR1). NgR1 is expressed mainly on neurons and is usually associated in a trimolecular complex. The second member of the complex, LINGO-1, is often connected to NgR1 function and is further found to function independently as a negative regulator of oligodendrocyte proliferation and differentiation. The third member of the NgR complex is either the p75 neurotrophin receptor, TROY, or an as yet unidentified co-receptor. Targeting of factors contained in this complex has been described to lead to the promotion of neurite outgrowth, oligodendrocyte proliferation and differentiation and inhibition of cell death. In the current review, we aim to describe the mechanisms of action of the chemical and biological compounds used in targeting NgR1 and LINGO-1. This will be achieved using three examples: blocking of ligand binding to NgR1 in treatment of spinal cord injury, antibody-mediated inhibition of LINGO-1 to promote oligodendrocyte differentiation in multiple sclerosis, and the use of soluble NgR1 to sequester Abeta peptide in the periphery in Alzheimer's disease.

Inflammatory and Neurodegenerative Pathways in Depression: A New Avenue for Antidepressant Development?

Inflammatory and Neurodegenerative Pathways in Depression: A New Avenue for Antidepressant Development?, 2011, 18(2) Pp. 245-255
M. Catena-Dell'Osso, C. Bellantuono, G. Consoli, S. Baroni, F. Rotella and D. Marazziti

The latest advancement in neurobiological research provided an increasing evidence that inflammatory and neurodegenerative pathways play a relevant role in depression. Preclinical and clinical studies on depression highlighted an increased production of inflammatory markers, such as interleukin (IL)-1, IL-6, tumor necrosis factor-α and interferon- αand γ. On the other hand, acute and chronic administration of cytokines or cytokine inducers were found to trigger depressive symptoms. According to the cytokine hypothesis, depression would be due to a stress-related increased production of pro-inflammatory cytokines that, in turn, would lead to increased oxidative and nitrosative brain damage and to indoleamine 2,3 dioxygenase (IDO) induction, with production of tryptophan (TRP) catabolites along the IDO pathway (TRYCATs) and consequent reduced availability of TRP and serotonin (5-HT). Cytokines would also play a role in the onset of the glucocorticoid resistance, underlying the overdrive of the hypothalamic-pituitary-adrenal axis. Therefore, the activation of the inflammatory and neurodegenerative pathways would lead to the brain damage observed in depression through both reduced neurogenesis and increased neurodegeneration. Besides the 5-HT system, other targets, possibly within the I&ND pathways, should be considered for the future treatment of depression: cytokines and their receptors, intracellular inflammatory mediators, IDO, TRYCATs, glucocorticoid receptors, neurotrophic factors may all represent possible therapeutic targets for novel antidepressants. In addition, it should be also clarified the role of the existing antiinflammatory drugs in the treatment of depression, and those compounds with the anti-inflammatory and anti-oxidative properties should be examined either as monotherapy or adjunctive therapy. In conclusion, the molecular inflammatory and neurodegenerative pathways might provide new targets for antidepressant development and might be crucial to establish a rational treatment of depression aimed, hopefully, to its causal factors.

Use of Antimicrobial Peptides Against Microbial Biofilms: Advantages and Limits

Use of Antimicrobial Peptides Against Microbial Biofilms: Advantages and Limits, 2011, 18(2) Pp. 256-279
Giovanna Batoni, Giuseppantonio Maisetta, Franca Lisa Brancatisano, Semih Esin and Mario Campa

The formation of surface-attached cellular agglomerates, the so-called biofilms, contributes significantly to bacterial resistance to antibiotics and innate host defenses. Bacterial biofilms are associated to various pathological conditions in humans such as cystic fibrosis, colonization of indwelling medical devices and dental plaque formation involved in caries and periodontitis. Over the last years, natural antimicrobial peptides (AMPs) have attracted considerable interest as a new class of antimicrobial drugs for a number of reasons. Among these, there are the broad activity spectrum, the relative selectivity towards their targets (microbial membranes), the rapid mechanism of action and, above all, the low frequency in selecting resistant strains. Since biofilm resistance to antibiotics is mainly due to the slow growth rate and low metabolic activity of bacteria in such community, the use of AMPs to inhibit biofilm formation could be potentially an attractive therapeutic approach. In fact, due to the prevalent mechanism of action of AMPs, which relies on their ability to permeabilize and/or to form pores within the cytoplasmic membranes, they have a high potential to act also on slow growing or even non-growing bacteria. This review will highlight the most important findings obtained testing AMPs in in vitro and in vivo models of bacterial biofilms, pointing out the possible advantages and limits of their use against microbial biofilm-related infections.

Peroxynitrite-Driven Mechanisms in Diabetes and Insulin Resistance the Latest Advances

Peroxynitrite-Driven Mechanisms in Diabetes and Insulin Resistance the Latest Advances, 2011, 18(2) Pp. 280-290
K. Stadler

Since its discovery, peroxynitrite has been known as a potent oxidant in biological systems, and a rapidly growing body of literature has characterized its biochemistry and role in the pathophysiology of various conditions. Either directly or by inducing free radical pathways, peroxynitrite damages vital biomolecules such as DNA, proteins including enzymes with important functions, and lipids. It also initiates diverse reactions leading eventually to disrupted cell signaling, cell death, and apoptosis. The potential role and contribution of this deleterious species has been the subject of investigation in several important diseases, including but not limited to, cancer, neurodegeneration, stroke, inflammatory conditions, cardiovascular problems, and diabetes mellitus. Diabetes, obesity, insulin resistance, and diabetes-related complications represent a major health problem at epidemic levels. Therefore, tremendous efforts have been put into investigation of the molecular basics of peroxynitrite-related mechanisms in diabetes. Studies constantly seek new therapeutical approaches in order to eliminate or decrease the level of peroxynitrite, or to interfere with its downstream mechanisms. This review is intended to emphasize the latest findings about peroxynitrite and diabetes, and, in addition, to discuss recent and novel advances that are likely to contribute to a better understanding of peroxynitrite-mediated damage in this disease.

Food Matrix Affecting Anthocyanin Bioavailability: Review

Food Matrix Affecting Anthocyanin Bioavailability: Review, 2011, 18(2) Pp. 291-300
M. Yang, S. I. Koo, W. O. Song and O. K. Chun

Anthocyanins, abundant in deep-colored fruits and vegetables, have received considerable attention due to their potential health benefits. However, the bioavailability of anthocyanins is relatively low compared to that of other flavonoids. While previous reviews focused on the absorption, metabolism and excretion of anthocyanins, little information is available on the effects of food matrix on anthocyanin bioavailability, particularly food matrices of the usual diet. The present review includes the recent studies on interactive effects of anthocyanins and certain food components. Evidence suggests that the bioavailability of anthocyanins varies markedly depending on food matrices, including other antioxidants and macronutrients present in foods consumed, which consequently affects the absorption and antioxidant capacity of anthocyanins. Further studies are needed to gain insight into the mechanisms underlying the interactive effects of anthocyanins and food components in their bioavailability and antioxidant capacity of anthocyanins at the physiological level.

Regulatory Mechanisms of Calcineurin Phosphatase Activity

Regulatory Mechanisms of Calcineurin Phosphatase Activity, 2011, 18(2) Pp. 301-315
R. E.A. Musson and N. P.M. Smit

Calcineurin (protein phosphatase 3, Cn) is best known for its central position in Ca2+-dependent T-cell signaling. Interest in calcineurin has, however, conserved its momentum as new Ca2+-dependent pathways have been steadily surfacing in several other cell types, such as brain, heart, skin cells and beta pancreatic cells, and Cn appears to serve as a central controller of stress, immune response, and cellular proliferation and differentiation. Calcineurin is the principal target of the immunosuppressive drugs cyclosporin A (CsA) and tacrolimus (TRL). Therapy based on these immunosuppressants has markedly reduced the incidence of transplant rejection in allograft recipients. In addition, these drugs have proven very useful for patients suffering from chronic inflammatory skin conditions. Unfortunately, their application is somewhat limited by a broad spectrum of toxic side-effects, affecting several organ systems. This calls for enhancements in the design of this class of immunosuppressants. An intricate constellation of regulatory systems allows for precise modulation and adaptation of calcineurin activity in vivo. The last few years have been very fruitful in elucidating several long-standing issues regarding the binding patterns of substrates and inhibitors to Cn. This new knowledge may enable more precise manipulation of the Ca2+-calcineurin pathway in the near future, preferably targeted towards one specific substrate or cell system. In this review, we will discuss the factors and mechanisms underlying calcineurin activity regulation and their exploitation in recent approaches towards better immunosuppressants.

Chemical and Pharmacological Chaperones: Application for Recombinant Protein Production and Protein Folding Diseases

Chemical and Pharmacological Chaperones: Application for Recombinant Protein Production and Protein Folding Diseases, 2011, 18(1) Pp. 1-15
Rahul S. Rajan, Kouhei Tsumoto, Masao Tokunaga, Hiroko Tokunaga, Yoshiko Kita and Tsutomu Arakawa

Since protein function depends on folding, successful development of active pharmaceutical proteins requires in vitro production of functional, properly folded proteins. In vitro protein folding and hence production can be assisted by co-solvents, including osmolytes and arginine. Osmolytes accumulate in the cytoplasm to raise the osmotic pressure against environmental water stresses, resulting in stabilization of proteins. They have shown to enhance in vitro and in vivo protein folding and suppress in vivo protein aggregation, thus called “chemical chaperones”. Requirement of high concentrations, however, eliminates possible applications of chemical chaperones to rescue in vivo misfolded proteins that cause various diseases. More specific ligands can serve a similar function at much lower concentrations and are called “pharmacological chaperones”. We will review here the applications of chemical chaperones for biotechnology product development and of pharmacological chaperones for in vivo protein folding, and the mechanism of their effects on protein folding. A specific case we review here is the mechanism of action of the polar amino acid arginine, which has been widely used in vitro as a chemical chaperone to assist protein folding and suppress aggregation.

New Therapeutic Approaches Targeted at the Late Stages of the HIV-1 Replication Cycle

New Therapeutic Approaches Targeted at the Late Stages of the HIV-1 Replication Cycle, 2011, 18(1) Pp. 16-28
Yan Jiang, Xinyong Liu and Erik De Clercq

Owing to the serious clinical consequences associated with acquisition of resistance to current antiretroviral drugs, discovery of new drug targets and development of novel anti-HIV-1 therapeutic agents have become a high research priority. The late stages of HIV-1 replication involve the processes of assembly, budding and maturation, and comprise several new potential therapeutic targets which have not (yet) been targeted by any of the antiretroviral drugs approved at present. The structural protein Gag plays a central role in these stages through its different regions and mature Gag proteins working in concert. In this article, we highlight a number of steps in the late stages of HIV-1 replication that represent promising targets for drug discovery. Recent progress in development of related inhibitors targeting at CA, zinc fingers of NC, p6-Tsg101 interaction, lipid rafts of plasma membrane, proteolytic cleavage sites in Gag and gp160 processing is also reviewed.

Functional Roles of Azoles Motif in Anti-HIV Agents

Functional Roles of Azoles Motif in Anti-HIV Agents, 2011, 18(1) Pp. 29-46
Peng Zhan, Dongyue Li, Xuwang Chen, Xinyong Liu and Erik De Clercq

Currently, there has been considerable interest in the discovery of original molecules with broad-spectrum anti- HIV activity and favourable pharmacokinetic profiles, to be used as an alternative to the approved anti-HIV/AIDS drugs, should they fail as therapeutics. Five-membered azole heterocycles represent an important class of lead structures for novel anti-HIV drug development. They can serve as versatile building blocks to introduce different new functional groups, (i) as scaffolds to anchor these groups into the optimal space for interactions with the target, (ii) as basic pharmacophore elements to make hydrogen bonds or hydrophobic interaction for facilitating the spatial filling at the binding site, (iii) as ester surrogates to improve metabolic stability, or (iv) as pharmacophoric motif of metal coordination to coordinate metal ions (i.e. magnesium) within the active site of target (i.e. integrase). This article will summarize recent progress in the development of some azoles derivatives that inhibit the replication of HIV-1 and will illustrate the possible functional role(s) of the azole motif in the search for new anti-HIV drugs.

Progress in the Developement of Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 2

Progress in the Developement of Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 2, 2011, 18(1) Pp. 47-68
A. A. Trabanco, J. M. Cid, H. Lavreysen, G. J. Macdonald and G. Tresadern

The metabotropic glutamate type 2 (mGlu2) receptor is a G-protein coupled receptor (GPCR) expressed on presynaptic nerve terminals where it negatively modulates glutamate and GABA release. Mixed mGlu2/mGlu3 orthosteric agonists such as LY354740 have shown activity in a range of preclinical animal models of anxiety and schizophrenia. Clinical work with LY354740 demonstrated activity in a CO2 inhalation study suggesting application in the treatment of anxiety related disorders. Subsequently, a related prodrug LY2140023 demonstrated improvements in positive and negative symptoms in patients suffering from schizophrenia. These molecules exhibit combined mGlu2/mGlu3 activity although there is evidence from knock-out studies that preclinical anti-psychotic effects may be mediated via the mGlu2 receptor. An alternative avenue for modulating GPCRs is to act via allosteric mechanisms, binding at a different site from the orthosteric agonist. Since the first discovery of mGlu2 positive allosteric modulators (PAMs) such as 2,2,2-TEMPS and BINA, multiple families of mGlu2 modulators have been reported and several have entered into clinical development. This review focuses on recent advances in the development of novel mGlu2 PAMs by analysis of compounds disclosed in research articles and patent literature between 2007 and 2010.

Regulation of Xanthine Oxidase Activity by Substrates at Active Sites via Cooperative Interactions between Catalytic Subunits: Implication to Drug Pharmacokinetics

Regulation of Xanthine Oxidase Activity by Substrates at Active Sites via Cooperative Interactions between Catalytic Subunits: Implication to Drug Pharmacokinetics, 2011, 18(1) Pp. 69-78
L. A. Tai and K. C. Hwang

Three xanthine oxidase substrates (i.e., xanthine, adenine, and 2-amino-4-hydroxypterin) show a “substrate inhibition” pattern (i.e., slower turnover rates at higher substrate concentrations), whereas another two substrates (i.e., xanthopterin and lumazine) show a “substrate activation” pattern (i.e., higher turnover rates at higher substrate concentrations). Binding of a 6-formylpterin at one of the two xanthine oxidase active sites slows down the turnover rate of xanthine at the adjacent active site from 17.0 s-1 to 10.5 s-1, and converts the V-[S] plot from “substrate inhibition” pattern to a classical Michaelis-Menten hyperbolic saturation pattern. In contrast, binding of xanthine at an active site accelerates the turnover rate of 6-formylpterin at the neighboring active site. The experimental results demonstrate that a substrate can regulate the activity of xanthine oxidase via binding at the active sites; or a xanthine oxidase catalytic subunit can simultaneously serve as a regulatory unit. Theoretical simulation based on the velocity equation derived from the extended Michaelis-Menten model shows that the substrate inhibition and the substrate activation behavior in the V-[S] plots could be obtained by introducing cooperative interactions between two catalytic subunits in homodimeric enzymes. The current work confirms that there exist very strong cooperative interactions between the two catalytic subunits of xanthine oxidase.

Bioprocess and Bioreactor: Next Generation Technology for Production of Potential Plant-based Antidiabetic and Antioxidant Molecules

Bioprocess and Bioreactor: Next Generation Technology for Production of Potential Plant-based Antidiabetic and Antioxidant Molecules, 2011, 18(1) Pp. 79-90
G. Sivakumar, F. Medina-Bolivar, J. O. Lay, M. C. Dolan, J. Condori, S. K. Grubbs, S. M. Wright, M. A. Baque, E. J. Lee and K. Y. Paek

Globally, diabetes and obesity are two of the most common metabolic diseases of the 21st century. Increasingly, not only adults but children and adolescents are being affected. New approaches are needed to prevent and treat these disorders and to reduce the impact of associated disease-related complications. Industrial-scale production using plant-root cultures can produce quantities and quality of inexpensive bioactive small molecules with nutraceutical and pharmaceutical properties. Using this approach, and targeting these diseases, a next generation approach to tackling this emerging global health crisis may be developed. Adventitious roots cultured in bioreactors under controlled and reproducible conditions have been shown effective for production of natural products. The liquid-phase airlift bioreactor in particular has been used successfully for culturing roots on an industrial-scale and thus may provide an economical production platform for expressing promising plant-based antidiabetic and antioxidant molecules. This review focuses on a next-generation, scalable, bioprocessing approach for adventitious and hairy root cultures that are a pesticide-free, seasonally-independent, plant-based source of three molecules that have shown promise for the therapeutic management of diabetes and obesity: corosolic acid, resveratrol and ginsenosides.

Impact of Genetic Variability in Nicotinic Acetylcholine Receptors on Nicotine Addiction and Smoking Cessation Treatment

Impact of Genetic Variability in Nicotinic Acetylcholine Receptors on Nicotine Addiction and Smoking Cessation Treatment, 2011, 18(1) Pp. 91-112
P. Russo, A. Cesario, S. Rutella, G. Veronesi, L. Spaggiari, D. Galetta, S. Margaritora, P. Granone and D. S. Greenberg

Nicotine dependence (ND) is one of the world's leading causes of preventable death. Nicotine addiction and other forms of drug addiction continue to be significant public health problems in the world. Evidence for a genetic influence on smoking behaviour and ND has prompted a search for susceptibility genes. Evidence has recently accumulated that single nucleotide polymorphisms (SNPs) in the genetic region encoding the nicotinic acetylcholine receptor (nAChR) subunits α6, α5, α3, and β4 are associated with smoking and ND. Brain nAChR are a heterogeneous family of ion channels expressed in the various parts of the brain. A number of studies suggest that brain nAChR are critical targets for the development of pharmacotherapy for nicotine and other drug addictions. In this review, we will discuss the nAChR subtypes, their function in response to endogenous brain transmitters, and how their functions are regulated in the presence of nicotine. Additionally, we will provide an overview of the three major pharmacotherapies for smoking cessation (which have demonstrated efficacy) such as: nicotine replacement therapy (NRT), bupropion, and varenicline. An appreciation of the complexity of nAChR and their regulation will be necessary for the development of nAChR modulators as potential pharmacotherapy for drug addiction. Prevention strategies should be tailored to carriers of SNPs located on chromosome 15q and that are strongly associated with nicotine dependence and risk of lung cancer.

Novel Rational Drug Design Strategies with Potential to Revolutionize Malaria Chemotherapy

Novel Rational Drug Design Strategies with Potential to Revolutionize Malaria Chemotherapy, 2011, 18(1) Pp. 113-143
F. W. Muregi, P. G. Kirira and A. Ishih

Efforts to develop an effective malaria vaccine are yet to be successful and thus chemotherapy remains the mainstay of malaria control strategy. Plasmodium falciparum, the parasite that causes about 90% of all global malaria cases is increasingly becoming resistant to most antimalarial drugs in clinical use. This dire situation is aggravated by reports from Southeast Asia, of the parasite becoming resistant to the “magic bullet” artemisinins, the last line of defense in malaria chemotherapy. Drug development is a laborious and time consuming process, and thus antimalarial drug discovery approaches currently being deployed largely include optimization of therapy with available drugs including combination therapy and developing analogues of the existing drugs. However, the latter strategy may be hampered by cross-resistance, since agents that are closely related chemically may share similar mechanisms of action and/or targets. This may render new drugs ineffective even before they are brought to clinical use. Evaluation of drug-resistance reversers (chemosensitizers) against quinoline-based drugs such as chloroquine and mefloquine is another approach that is being explored. Recently, evaluation of new chemotherapeutic targets is gaining new impetus as knowledge of malaria parasite biology expands. Also, single but hybrid molecules with dual functionality and/or targets have been developed through rational drug design approach, termed as “covalent bitherapy”. Since desperate times call for radical measures, this review aims to explore novel rational drug-design strategies potentially capable of revolutionizing malaria therapy. We thus explore malaria apoptosis machinery as a novel drug target, and also discuss the potential of hybrid molecules as well as prodrugs and double prodrugs in malaria chemotherapy.

Natural and Synthetic Naphthoquinones Active Against Trypanosoma Cruzi: An Initial Step Towards New Drugs for Chagas Disease

Natural and Synthetic Naphthoquinones Active Against Trypanosoma Cruzi: An Initial Step Towards New Drugs for Chagas Disease, 2011, 18(1) Pp. 144-161
Cristian O. Salas, Mario Faundez, Antonio Morello, Juan Diego Maya and Ricardo A. Tapia

Chagas disease is one of the most important endemic diseases in Latin America, caused by Trypanosoma cruzi. The drugs used for the treatment of this disease, nifurtimox and benznidazole, are toxic and present severe side effects. The need of effective drugs, without adverse effects, has stimulated the search for new compounds with potential clinical utility. An overview of a number of natural naphthoquinones tested against T. cruzi parasites is provided. Among natural naphthoquinones, lapachol, β-lapachone and its α-isomer have demonstrated useful trypanocidal activities. In the search for new trypanocidal agents, this review outlines different structural modifications of natural quinones, as well as synthetic quinones, which have been subjected to trypanocidal studies. This review summarizes the mechanism of action and structure-activity relationships of the quinone derivatives, including some theoretical calculations that discuss the correlation of stereo electronic properties with the trypanocidal activity. In this context, this review will be useful for the development of new antichagasic drugs based mainly on structural modification of natural quinones.