Abstracts


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Imatinib (STI571) resistance in chronic myelogenous leukemia: Molecular basis of the underlying mechanisms and potential strategies for treatment
Cowan-Jacob, SW; Guez, V; Fendrich, G; Griffin, JD; Fabbro, D; Furet, P; Liebetanz, J; Mestan, J; Manley, PW

Following the paradigm set by ST1571, protein tyrosine kinase inhibitors are emerging as a promising class of drugs, capable of modulating intracellular signaling and demonstrating therapeutic potential for the treatment of proliferative diseases. Although the majority of chronic phase CML patients treated with ST1571 respond, some patients, especially those with more advanced disease, relapse. This article reviews the reasons for relapse and, in particular, analyses resistance resulting from Bcr-Abl tyrosine kinase domain mutations at the molecular level. Arguments are based upon the structure of the ST1571-Abl complex, which is compared to the crystal structures of PD173955-Abl and PD180970-Abl, which bind to the kinase differently. Strategies to potentially circumvent or overcome resistance are discussed.


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The wide pharmacological versatility of semicarbazones, thiosemicarbazones and their metal complexes
Beraldo, H; Gambino, D

The more significant bioactivities of a variety of semicarbazones (anti-protozoa, anticonvulsant) and thiosemicarbazones (antibacterial, antifungal, antitumoral, antiviral) and their metal complexes are reviewed together with proposed mechanisms of action and structure-activity relationships. Clinical or potential pharmacological applications of these versatile compounds are discussed.


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Nitrogen-containing bisphosphonate mechanism of action
Reszka, AA; Rodan, GA

The current paradigm for drug discovery requires the identification of a target involved in the disease process (e.g. enzyme or receptor) and the development of an appropriate ligand (activator, inhibitor or selective modulator). Selection of ligands for clinical development is based on the therapeutic window between efficacy vs. safety and ADME (absorption, distribution, metabolism and elimination) considerations. For bisphosphonates (BPs) the process has not followed that paradigm. BPs have very low absorption and are retained in bone, their target tissue. A few have been used on a limited basis for over 20 years in diseases of rapid bone destruction (e.g. post-menopausal osteoporosis, Paget's disease, bone metastases, etc.), without understanding their molecular mechanism of action. The nitrogen-containing BPs (N-BPs) are the latest and most potent addition to this family of compounds and have the widest use. They have high potency, are specifically targeted to the osteoclast on bone and are used at very low doses (5-10 mg clinically). Over the last four years, there was significant progress in elucidating the mechanism of action of BPs, both lacking and containing nitrogen. This review will focus on the mechanism of action of the N-BPs, specifically alendronate (ALN) and risedronate (RIS), the two agents most widely used. For these and all other N-BPs, the molecular target is the isoprenoid biosynthetic enzyme, farnesyl diphosphate synthase, in the cholesterol biosynthesis pathway. Although inhibition of this enzyme by N-BPs results in the suppression of sterol biosynthesis, it is actually disruption of a branch pathway, isoprenylation, that is responsible for N-BP pharmacological activity. Isoprenylation involves covalent linkage of the 15 or 20 carbon isoprene moiety farnesyl diphosphate or geranylgeranyl diphosphate, respectively, to the carboxy-terminus of regulatory proteins, including the small GTPases Ras, Rac, Rho and Cdc42. The latter three, as well as numerous others, are geranylgeranylated and play a rate-limiting role in the activity of the bone-resorbing osteoclast. This targeted osteoclast inhibition accounts for the potency of the N-BPs and for their ability to elicit the desired therapeutic response of suppressing bone turnover. The occasional gastrointestinal irritation caused by N-BPs appears to be mechanism-based and is also briefly reviewed.


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Structural requirements of acetylcholinesterase reactivators
Kuca, K; Jun, D; Musilek, K

Nerve agents (sarin, soman, cyclosarin, tabun and VX agent) and pesticides (paraoxon, chlorpyrifos, TEPP) represent extremely toxic group of organophosphorus compounds (OPCs). These compounds inhibit enzyme acetylcholinesterase (ACNE, EC 3.1.1.7) via its phosphorylation or phosphonylation at the serine hydroxy group in its active site. Afterwards, ACNE is not able to serve its physiological function and intoxicated organism is died due to overstimulation of cholinergic nervous system. The current standard treatment of poisoning with highly toxic OPCs usually consists of the combined administration of anticholinergic drugs (preferably atropine) and ACNE reactivators (called "oximes"). Anticholinergic drugs block effects of accumulated neurotransmitter acetylcholine at nicotinic and muscarinic receptor sites, while oximes reactivate ACNE inhibited by OPCs. Unfortunately, none from the currently used oximes is sufficiently effective against all known nerve agents and pesticides. Therefore, to find new oximes able to sufficiently reactivate inhibited ACNE (regardless of the type of OPCs) is still very important task for medicinal chemistry with the aim to improve the efficacy of antidotal treatment of the acute poisonings mentioned. In this paper, the relationship between chemical structure of ACNE reactivators and their ability to reactivate ACNE inhibited by several nerve agents and pesticides is summarized. It is shown that there are several structural fragments possibly involving in the structure of proposed ACNE reactivators. Finally, an attempt of a future course of new ACNE reactivators development is discussed.


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Description, distribution, activity and phylogenetic relationship of ribosome-inactivating proteins in plants, fungi and bacteria
Girbes, T; Ferreras, JM; Arias, FJ; Stirpe, F

Ribosome-Inactivating Proteins (RIPs) are enzymes that trigger the catalytic inactivation of ribosomes and other substrates. They are present in a large number of plants and have been found also in fungi, algae and bacteria. RIPs are currently classified as type 1, those formed by a single polypeptide chain with the enzymatic activity, and type 2, those formed by 2 types of chains, i.e. A chains equivalent to a type I RIPs and B chains with lectin activity. Type 2 RIPs usually contain the formulae A-B, (A-B)2 and less frequent (A-B)4 and polymeric forms of type 2 RIPs lectins. RIPs are broadly distributed in plants, and are present also in fungi, bacteria, at least in one alga; recently RIP-type activity has been described in mammalian tissues. The highest number of RIPs has been found in Caryophyllaceae, Sambucaceae, Cucurbitaceae, Euphorbiaceae, Phytolaccaceae and Poaceae. However there are no systematic screening studies to allow generalisations about occurrence. The most known activity of RIPs is the translational inhibitory activity, which seems a consequence of a N-glycosidase on the 28 S rRNA of the eukaryotic ribosome that triggers the split of the A(4324) (or an equivalent base in other ribosornes), which is key for translation. This activity seems to be part of a general adenine polynucleotide glycosylase able to act on several substrates other than ribosornes, such as tRNA, mRNA, viral RNA and DNA. Other enzymatic activities found in RIPs are lipase, chitinase and superoxide dismutase. RIPs are phylogenetically related. In general RIPs from close families share good amino acid homologies. Type 1 RIPs and the A chains of type 2 RIPs from Magnoliopsida (dicotyledons) are closely related. RIPs from Liliopsida (monocotyledons) are at the same time closely related and distant from Magnoliopsida. Concerning the biological roles played by RIPs there are several hypotheses, but the current belief is that they could play significant roles in the antipathogenic (viruses and fungi), stress and senescence responses. In addition, roles as antifeedant and storage proteins have been also proposed. Future research will approach the potential biological roles played by RIPs and their use as toxic effectors in the construction of immunotoxins and conjugates for target therapy.


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Aryloxy phosphoramidate triesters as pro-tides
Cahard, D; McGuigan, C; Balzarini, J

We herein describe the development of aryloxy phosphoramidate triesters as an effective pro-tide motif for the intracellular delivery of charged bio-active antiviral nucleoside monophosphates. The review covers the discovery Of Such aryl phosphoramidates, their mechanism of action and structure-activity relationships. The application of this strategy to a range of antiviral nucleosides is highlighted.


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Allosterism at muscarinic receptors: Ligands and mechanisms
Birdsall, NJM; Lazareno, S

The evaluation of allosteric ligands at muscarinic receptors is discussed in terms of the ability of the experimental data to be interpreted by the allosteric ternary complex model. The compilation of useful SAR information of allosteric ligands is not simple, especially for muscarinic receptors, where there are multiple allosteric sites and complex interactions.


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Beta-lactams in the new millennium. Part-I: Monobactams and carbapenems
Singh, GS

Beta-lactam ring-containing compounds such as penicillins, ampicillin, amoxicillin, cephalosporins and carbapenem are among the most famous antibiotics. This article reviews the recent developments in the study of such compounds. The introductory paragraph, which highlights the significance of the subject and cites most of the leading references of the previous century, is followed by an overview of beta-lactams and some novel methodologies for the synthesis of bi-, tri- and polycyclic derivatives. The rest of the sections deal with design, synthesis and biological activity of monobactams and carbapenems. Many of them have potential antibacterial activity, even against some resistant strains, and enzyme inhibitory activity.


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Naturally occurring NF-kappa B inhibitors
Nam, NH

NF-kappa B is a ubiquitous and well-characterised protein responsible for the regulation of complex phenomena, with a pivotal role in controlling cell signalling in the body under certain physiological and pathological conditions. Among other functions, NF-kappa B controls the expression of genes encoding the pro-inflammatory cytokines (e. g., IL-1, IL2, IL-6, TNF-alpha, etc.), chemokines (e. g., IL-8, MIP-1 alpha, MCPI, RANTES, eotaxin, etc.), adhesion molecules (e. g., ICAM, VCAM, E-selectin), inducible enzymes (COX-2 and iNOS), growth factors, some of the acute phase proteins, and immune receptors, all ofwhich play critical roles in controlling most inflammatory processes. Since NF-kappa B represents an important and very attractive therapeutic target for drugs to treat many inflammatory diseases, including arthritis, asthma, and the auto-immune diseases, most attention has been paid in the last decade to the identification of compounds that selectively interfere with this pathway. Recently, a great number of plant-derived substances have been evaluated as possible inhibitors of the NF-kappa B pathway. These include a wide range of compound classess, such as lignans (manassantins, (+)-saucemetin, (-)-saucemeol methyl ether), sesquiterpenes (costunolide, parthenolide, celastrol, celaphanol A), diterpenes (excisanin, kamebakaurin), triterpenes (avicin, oleandrin), polyphenols (resveratrol, epigallocatechin gallate, quercetin), etc. In this mini-review we will discuss the medicinal chemistry of these compounds with regards to the NF-kappa B inhibition.


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The role of Genistein and synthetic derivatives of isoflavone in cancer prevention and therapy
Sarkar, FH; Adsule, S; Padhye, S; Kulkarni, S; Li

Genistein, one of the predominant soy isoflavones. has been shown to compete with 17 beta-estradiol for estrogen receptor binding because of its structural similarity, resulting in agonistic or antagonistic activity. It causes inhibition of cell growth in breast and prostate cancers in vivo and in vitro. From gene expression profiles, genistein has been found to regulate the genes that are critical for the control of cell proliferation, cell cycle, apoptosis, oncogenesis, transcription regulation, and cell signal transduction pathways. It has been reported that genistein induces apoptosis and inhibits activation of NF-kappa B and Akt signaling pathways, both of which are known to maintain a balance between cell survival and apoptosis. Recently, we found that genistein sensitized cancer cells to apoptosis induced by chemotherapeutic agents including docetaxel, gemcitabine and cisplatin through inactivation of NF-kappa beta in multiple cancer cell lines. To enhance the anti-cancer activity of genistein, we have synthesized structurally-modified derivatives of isoflavone based oil the structural requirements for optimal anti-cancer effect. We found that these synthetic derivatives of isoflavone exerted higher anti-cancer activity with lower IC50. These derivatives of isoflavone also induced more apoptosis compared to genistein. These results suggest that genistein and synthetic structurally-modified derivatives of isoflavone may be promising agents for cancer chemoprevention and therapy either alone or in combination with existing chemotherapeutic agents.