Current Medicinal Chemistry

ISSN: 0929-8673




Current Medicinal Chemistry
Volume 16, Number 36, 2009

Contents


Role of the Transglutaminase Enzymes in the Nervous System and their Possible Involvement in Neurodegenerative Diseases Pp. 4767-4773
G. De Vivo, R. Di Lorenzo, M. Ricotta and V. Gentile
[Abstract] [Purchase Article] [PMID: 19929789 PubMed - indexed for MEDLINE]


Mepolizumab and Eosinophil-Mediated Disease Pp. 4774-4778
G.M. Walsh
[Abstract] [Purchase Article] [PMID: 19929788 PubMed - indexed for MEDLINE]


Peptide-Based Anticancer Vaccines: Recent Advances and Future Perspectives Pp. 4779-4796
S. Mocellin, P. Pilati and D. Nitti
[Abstract] [Purchase Article] [PMID: 19929787 PubMed - indexed for MEDLINE]


Overview of Naphthalimide Analogs as Anticancer Agents Pp. 4797-4813
Min Lv and Hui Xu
[Abstract] [Purchase Article] [PMID: 19929786 PubMed - indexed for MEDLINE]


The Potential of Embryonic Stem Cells Combined with -omics Technologies as Model Systems for Toxicology Pp. 4814-4827
J. Winkler, I. Sotiriadou, S. Chen, J. Hescheler and A. Sachinidis
[Abstract] [Purchase Article] [PMID: 19929785 PubMed - indexed for MEDLINE]


Syntheses, Transformations and Pharmaceutical Applications of Kynurenic Acid Derivatives Pp. 4828-4842
F. Fülöp, I. Szatmári, E. Vámos, D. Zádori, J. Toldi and L. Vécsei
[Abstract] [Purchase Article] [PMID: 19929784 PubMed - indexed for MEDLINE]


Branched-Chain Amino Acids and Pigment Epithelium-Derived Factor: Novel Therapeutic Agents for Hepatitis C Virus-Associated Insulin Pp. 4843-4857
T. Kawaguchi, S. Yamagishi and M. Sata
[Abstract] [Purchase Article] [PMID: 19929783 PubMed - indexed for MEDLINE]


Monoclonal Antibodies in the Treatment of Multiple Sclerosis Pp. 4858-4868
F. Di Pauli, T. Berger and M. Reindl
[Abstract] [Purchase Article] [PMID: 19929782 PubMed - indexed for MEDLINE]


Recent Research in Selective Cyclin-Dependent Kinase 4 Inhibitors for Anti-Cancer Treatment Pp. 4869-4888
N. Liu, H. Fang, Y. Li and W. Xu
[Abstract] [Purchase Article] [PMID: 19929781 PubMed - indexed for MEDLINE]



Abstracts


[Back to top] [Purchase Article] [PMID: 19929789 PubMed - indexed for MEDLINE]
Role of the Transglutaminase Enzymes in the Nervous System and their Possible Involvement in Neurodegenerative Diseases
G. De Vivo, R. Di Lorenzo, M. Ricotta and V. Gentile

Transglutaminases are a large family of related and ubiquitous enzymes which catalyze the cross linking of a glutaminyl residue of a protein/peptide substrate to a lysyl residue of a protein/peptide co-substrate. In addition to lysyl residues, other second nucleophilic co-substrates may include monoamines or polyamines (to form mono- or bisubstituted /crosslinked adducts) or -OH groups (to form ester linkages). In absence of co-substrates, the nucleophile may be water, resulting in the net deamidation of the glutaminyl residue. These enzymes are also capable of catalyzing other reactions important for cell viability. The distribution and the physiological roles of human transglutaminases have been widely studied in numerous cell types and tissues and their roles in several diseases have begun to be identified. Recently, "tissue" transglutaminase (TG2) has been shown to be involved in the molecular mechanisms responsible for a very wide-spread human pathology, celiac disease (CD). Transglutaminase activity has also been hypothesized to be directly involved in the pathogenetic mechanisms responsible for several human neurodegenerative diseases, which are character-ized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains, such as Alzheimer's disease (AD), Parkinson's disease (PD), supranuclear palsy, Huntington's disease (HD) and the other re-cently identified polyglutamine diseases, and others. In this review we discuss the biological role of the transglutaminases in the nervous system, with particular interest in the molecular mechanisms, which could involve these enzymes in the pathophysiological processes responsible for human neurodegenerative diseases.


[Back to top] [Purchase Article] [PMID: 19929788 PubMed - indexed for MEDLINE]
Mepolizumab and Eosinophil-Mediated Disease
G.M. Walsh

Eosinophils are major pro-inflammatory cells that make a major contribution to diseases that affect the upper and lower airways, skin and gastrointestinal tract. Interleukin (IL)-5 is central to their maturation and release from the bone marrow together with their subsequent accumulation and activation in the tissues. Mepolizumab is a humanized monoclonal antibody (mAb) with potent IL-5 neutralizing effects that represents a potential treatment for eosinophilic diseases. Several clinical trials with mepolizumab reported that treatment of patients with mild to severe asthma resulted in a substantial reduction in blood and sputum eosinophil numbers. However, clinical outcomes were disappointing as there were no significant effects on airway hyper-reactivity or the late asthmatic reaction to inhaled allergen challenge. More recently two studies, one in patients with refractory eosinophilic asthma with a history of recurrent severe exacerbations and the other in patients with persistent sputum eosinophilia and symptoms despite systemic treatment with prednisone treatment, reported that monthly intravenous mepolizumab reduced sputum/blood eosinophilia, asthma exacerbations together with improvments in quality of life. Mepolizumab also appears to be an effective therapy for hypereosinophilic syndrome while other trials have shown efficacy of mepolizumab therapy in eosinophilic esophagitis. This review will consider the current status of the clinical development of mepolizumab for diseases with a significant eosinophilic component to their pathology.


[Back to top] [Purchase Article] [PMID: 19929787 PubMed - indexed for MEDLINE]
Peptide-Based Anticancer Vaccines: Recent Advances and Future Perspectives
S. Mocellin, P. Pilati and D. Nitti

Anticancer active immunotherapy embodies the ideal antitumor therapy, as it theoretically combines target specificity with long-term disease control. Peptide-based cancer vaccines represent the most specific approach to polarize the immune system against malignant cells, since they are preparations made of single epitopes, the minimal immunogenic region of an antigen. Despite the strong rational, the promising preclinical results and the frequent induction of antigen-specific immune responses, peptide-based cancer vaccines have yielded relatively poor results in the clinical setting, a phenomenon likely due to the immunosuppressive properties of the tumor microenvironment that allow malignant cells to evade both naturally occurring and therapeutically induced immune surveillance. Nevertheless, advances in the engineering of peptides and in our understanding of the molecular mechanisms underlying an effective immune response against tumors have renewed the enthusiasm for peptide-based vaccination regimens in the setting of cancer, and a variety of clinical trials are being conducted based on the use of peptides. This review will describe the most recent insights in the rational design of peptide-based cancer vaccines, as well as the challenges to successful anticancer immunotherapy based on these short amino acid chains.


[Back to top] [Purchase Article] [PMID: 19929786 PubMed - indexed for MEDLINE]
Overview of Naphthalimide Analogs as Anticancer Agents
Min Lv and Hui Xu

Cancer, which accounted for 7.9 million deaths (around 13% of all deaths) in 2007, is a leading cause of death in the world. Deaths from cancer worldwide are projected to continue rising, with an estimated 12 million deaths in 2030. Therefore, the rapid increase in the cancer burden represents a real crisis for public health and health systems worldwide. Although cancer chemotherapy will cause side effects and drug resistance, it is still recognized as the first choice for the treatment of many cancers. To our knowledge, naphthalimide (1H-benzo[de]isoquinoline-1,3-(2H)-dione) analogs have been considered as one promising and potential class of anticancer agents against human tumor cells, such as amonafide (Quinamed®) was the first naphthalimide analog that reached the clinical trial stage and exhibited excellent antitumour activity against advanced breast cancer. In this review, we make attempts to report recent advances on the synthesis of naphthalimide analogs, including mononaphthalimides, bisnaphthalimides, and naphthalimide-other heterocycles conjugates; in the meantime, the relationships between the structures of the naphthalimides and the antitumour activity are investigated in detail. It will pave the way for the design and development of naphthalimide analogs as anticancer agents.


[Back to top] [Purchase Article] [PMID: 19929785 PubMed - indexed for MEDLINE]
The Potential of Embryonic Stem Cells Combined with -omics Technologies as Model Systems for Toxicology
J. Winkler, I. Sotiriadou, S. Chen, J. Hescheler and A. Sachinidis

The derivation of pluripotent embryonic stem (ES) cell lines has opened up new areas of research in basic and applied science, most significantly in developmental biology and regenerative medicine. While application-oriented research has for the most part focussed on obtaining differentiated, organotypic cells from ES cells for future cell grafting therapies, ES cells have more immediate potential for use in toxicological in vitro assays used during drug development.

ES cells are derived from blastocyst-stage embryos and offer an in vitro model for early development, thus enabling tests for teratogenicity testing in a human cell culture system and avoiding the pitfalls of inter-species differences. Differentiated, organotypic cells obtained from ES cells can potentially replace the primary cells and cell lines currently used for in vitro toxicology by offering a more consistent and potentially limitless source of differentiated cells. This can facilitate the establishment of comprehensive toxicogenomics and -proteomics databases and complement current databases that rely on data obtained from animal experiments. More recently, induced pluripotent stem (iPS) cells with ES cell-like properties have been obtained through reprogramming of somatic cells, thus enabling the generation of disease-specific cell lines.

We review the potential of combining ES cells and ES cell-derived somatic cells with “omics” technologies for in vitro toxicology with a particular emphasis on the development of toxicogenomics and toxicoproteomics signatures. A separate section describes the potential of iPS cells for toxicology.


[Back to top] [Purchase Article] [PMID: 19929784 PubMed - indexed for MEDLINE]
Syntheses, Transformations and Pharmaceutical Applications of Kynurenic Acid Derivatives
F. Fülöp, I. Szatmári, E. Vámos, D. Zádori, J. Toldi and L. Vécsei

The syntheses and transformations of 4-hydroxyquinoline-2-carboxylic acid, kynurenic acid, are reviewed, and special attention is paid to the pharmacological activities and pharmaceutical applications of its derivatives.


[Back to top] [Purchase Article] [PMID: 19929783 PubMed - indexed for MEDLINE]
Branched-Chain Amino Acids and Pigment Epithelium-Derived Factor: Novel Therapeutic Agents for Hepatitis C Virus-Associated Insulin
T. Kawaguchi, S. Yamagishi and M. Sata

Recent clinical studies have shown that patients with chronic liver disease are insulin resistant. Of all etiologies of chronic liver disease including non-alcoholic fatty liver disease, the one that causes the most sever insulin resistance is hepatitis C virus (HCV) infection. Since insulin resistance promotes inflammatory and fibrogenic reactions in the liver, thus leading to the development of liver cirrhosis and hepatocellular carcinoma (HCC) in patients with HCV infection, amelioration of insulin sensitivity may inhibit the progression of HCV-associated liver disease, and could improve the survival of these patients. HCV directly causes insulin resistance through HCV core protein-elicited proteasomal degradation of insulin receptor substrates and subsequent inactivation of intracellular insulin signaling molecules such as Akt. Furthermore, tumor necrosis factor-alpha (TNF-α) and/or triglyceride accumulation-induced nuclear factor-κB (NF-κB) activation in the liver is shown to play a role in insulin resistance in patients with HCV-related chronic liver disease as well. We, along with others, have recently found that branched-chain amino acids (BCAAs) and pigment epithelium-derived factor (PEDF) could improve the HCV-associated insulin resistance via suppression of NF-κB and preservation of insulin signaling pathway. In this review, we discuss the mechanisms for the actions of BCAAs and PEDF, and their clinical implications in insulin resistance of chronic liver disease in patients with HCV infection. We also discuss here which chemical structures could contribute to insulin-sensitization in patients with HCV infection.


[Back to top] [Purchase Article] [PMID: 19929782 PubMed - indexed for MEDLINE]
Monoclonal Antibodies in the Treatment of Multiple Sclerosis
F. Di Pauli, T. Berger and M. Reindl

Multiple sclerosis (MS), a chronic demyelinating disorder, is characterized by recurrent neurological deficits or progressive impairment with a high risk of permanent disability. Since the exact pathophysiology and etiology remain still unclear, no curing therapy is currently available. However, several treatments with beneficial effect on relapse rate such as the first line therapies interferon-beta and glatiramer acetate were approved for relapsing-remitting MS. One new important tool in the therapy of MS is the use of monoclonal antibodies. Natalizumab is the first and so far only monoclonal antibody that is approved for MS treatment by the US Food and Drug Administration and the European Medicines Agency. In addition to natalizumab other monoclonal antibodies previously used in cancer and other autoimmune disorders or even newly developed for MS are now being tested in clinical trials. With their high target specificity and efficacy monoclonal antibodies are a promising treatment approach in MS. This review summarizes the present knowledge on the use, effectiveness and safety of monoclonal antibodies in MS treatment.


[Back to top] [Purchase Article] [PMID: 19929781 PubMed - indexed for MEDLINE]
Recent Research in Selective Cyclin-Dependent Kinase 4 Inhibitors for Anti-Cancer Treatment
N. Liu, H. Fang, Y. Li and W. Xu

It is well known that cyclins and cyclin-dependent kinases (CDKs) play essential roles in regulation of the cell cycle. In past two decades, the scientific researches suggest that the cyclin D1/ CDK4 complex is a key regulator of the transition through the G1 phase of the cell cycle. Moreover, deregulation of the cyclin D /CDK4 pathway has been identified in multiple tumor types. Thus, CDK4 is a genetically validated therapeutic target; hence, there has been a surge of interests in finding selective CDK4 inhibitors as anti-cancer agents. This review will give the recent progress in the studies of structure, functions of CDK4 and highly selective and potent CDK4 inhibitors.