Current Medicinal Chemistry

ISSN: 0929-8673




Current Medicinal Chemistry
Volume 17, Number 9, 2010


Contents

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The Bcl-2 Family as a Rational Target for the Treatment of B-Cell Chronic Lymphocytic Leukaemia Pp. 801-811
N. Capitani and C.T. Baldari
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Natural Polyphenols that Display Anticancer Properties through Inhibition of Kinase Activity Pp. 812-825
D. Lamoral-Theys, L. Pottier, F. Dufrasne, J. Nève, J. Dubois, A. Kornienko, R. Kiss and L. Ingrassia
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Homodimeric Enzymes as Drug Targets Pp. 826-846
D. Cardinale, O.M.H. Salo-Ahen, S. Ferrari, G. Ponterini, G. Cruciani, E. Carosati, A.M. Tochowicz, S. Mangani, R.C. Wade and M.P. Costi
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Pediatric Idiopathic Nephrotic Syndrome: Treatment Strategies in Steroid Dependent and Steroid Resistant Forms Pp. 847-853
T. Ulinski and B. Aoun
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Recent Insights into the Biosynthesis and Biological Activities of Natural Xanthones Pp. 854-901
H.R. El-Seedi, M.A. El-Barbary, D.M. H. El-Ghorab, L. Bohlin, Anna-Karin Borg-Karlson, U. Göransson and R. Verpoorte
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Abstracts


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The Bcl-2 Family as a Rational Target for the Treatment of B-Cell Chronic Lymphocytic Leukaemia
N. Capitani and C.T. Baldari

B-cell chronic lymphocytic leukaemia (B-CLL) is the most common lymphoid malignancy in the Western world, characterized by clonal growth and accumulation of monoclonal CD5⁺ B-cells in peripheral blood, bone marrow and peripheral lymphoid organs. Although the clinical course in B-CLL patients is highly variable, the most conserved feature is the prolonged survival of malignant B-cells, which has been associated to defects in the apoptotic machinery. The apoptosis defects are mainly determined by a defective balance among pro- and anti-apoptotic members of the Bcl-2 family, often related to resistance of CLL B-cells to chemotherapy. Purine nucleoside analogs or alkylating agents, alone or in combination, are the first-line treatment for B-CLL patients. Alternative, more specifically tailored therapeutics have been developed in recent years, including humanized monoclonal antibodies and kinase inhibitors. Here we shall review the drugs which are commonly used or are currently being assessed in clinical trials on B-CLL patients, their chemical structure, mechanisms of action, pharmacological properties, molecular targets, clinical efficacy and side effects, with a focus on drugs designed to promote apoptosis of malignant B-cells by targeting the Bcl-2 family.


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Natural Polyphenols that Display Anticancer Properties through Inhibition of Kinase Activity
D. Lamoral-Theys, L. Pottier, F. Dufrasne, J. Nève, J. Dubois, A. Kornienko, R. Kiss and L. Ingrassia

Over eleven hundred publications reporting anticancer activities of polyphenols have appeared in the peer-reviewed literature. In addition, a search of the PubMed database using “polyphenols – cancer – review” as keywords produced over 320 hits for review articles (July 2009). Polyphenol anticancer activities include, among others, anti-oxidative, pro-apoptotic, DNA damaging, anti-angiogenic, and immunostimulatory effects. Targeting specific protein kinases to combat cancer represents a major focus of oncology research within the so-called targeted therapy approach. An exhaustive search of the PubMed database (July 2009) using “polyphenols – cancer - kinases” as keywords resulted in more than 130 hits, half of them having been published within the past five years. Furthermore, the PubMed database contains 25 reviews on the subject of anti-kinase activity of some specific polyphenols, including mainly curcumin and the green tea polyphenol (-)-epigallocatechin 3-gallate (EGCG). However, no attempt has been made yet to review this area of research in a comprehensive, general manner. The current review therefore aims to highlight those anticancer polyphenols that target specific kinases in various types of cancer. The present review also provides an in-depth analysis of polyphenol structure-activity relationships in relation to their anticancer activities and specific kinase targeting. Lastly, a number of polyphenols are identified as potential antitumor agents that could be used to combat biologically aggressive cancers, including metastasizing cancers, through the targeting of specific kinases.


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Homodimeric Enzymes as Drug Targets
D. Cardinale, O.M.H. Salo-Ahen, S. Ferrari, G. Ponterini, G. Cruciani, E. Carosati, A.M. Tochowicz, S. Mangani, R.C. Wade and M.P. Costi

Many enzymes and proteins are regulated by their quaternary structure and/or by their association in homo- and/or hetero-oligomer complexes. Thus, these protein-protein interactions can be good targets for blocking or modulating protein function therapeutically. The large number of oligomeric structures in the Protein Data Bank (http://www.rcsb. org/) reflects growing interest in proteins that function as multimeric complexes. In this review, we consider the particular case of homodimeric enzymes as drug targets. There is intense interest in drugs that inhibit dimerization of a functionally obligate homodimeric enzyme. Because amino acid conservation within enzyme interfaces is often low compared to conservation in active sites, it may be easier to achieve drugs that target protein interfaces selectively and specifically. Two main types of dimerization inhibitors have been developed: peptides or peptidomimetics based on sequences involved in protein-protein interactions, and small molecules that act at hot spots in protein-protein interfaces. Examples include inhibitors of HIV protease and HIV integrase. Studying the mechanisms of action and locating the binding sites of such inhibitors requires different techniques for different proteins. For some enzymes, ligand binding is only detectable in vivo or after unfolding of the complexes. Here, we review the structural features of dimeric enzymes and give examples of inhibition through interference in dimer stability. Several techniques for studying these complex phenomena will be presented.


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Pediatric Idiopathic Nephrotic Syndrome: Treatment Strategies in Steroid Dependent and Steroid Resistant Forms
T. Ulinski and B. Aoun

Idiopathic nephrotic syndrome (INS) is defined as massive proteinuria and hypoalbuminemia associated with dyslipidemia and generalized oedema in most cases. It is thought to be due to a plasma factor of immunologic origin. Most cases are steroid responsive. However, a considerable proportion of children run a steroid dependent course. Calcineurin inhibitors and alkylating agents have been classical treatment strategies for such cases, but specific toxicity limits the use of these drugs.

Mycophenolate mofetil (MMF) is an inhibitor of inosine monophosphate dehydrogenase and thus de novo purine synthesis. Several uncontrolled clinical trials have demonstrated the efficacy of MMF in steroid dependent NS with or without prior use of CyP and in children with nephrotoxicity due to prolonged CyA treatment.

Non-compliance to steroid therapy can be responsible for multiple relapses and may be misinterpreted as steroid dependency and may therefore lead to unjustified increase of immunosuppressive treatment. Triamcinolone acetonide, a long acting steroid for intramuscular injection, can replace the usual oral prednisone treatment if non-compliance is suspected.

Whereas the treatment of the primary course of INS is well established, steroid dependent and steroid resistant forms are still a challenge for pediatric nephrologists. Both under-treatment with multiple relapses with disease or steroid associated morbidity on the one hand and over-treatment with specific side effects of immunosuppressive drugs may have severe consequences for the patients.


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Recent Insights into the Biosynthesis and Biological Activities of Natural Xanthones
H.R. El-Seedi, M.A. El-Barbary, D.M. H. El-Ghorab, L. Bohlin, Anna-Karin Borg-Karlson, U. Göransson and R. Verpoorte

This review focuses on recent advances in our understanding of the complex biosynthetic pathways and diverse biological activities of naturally occurring xanthones. The biosynthesis section covers studies published from 1989 to 2008 on xanthone production in plants and fungi, while the bioactivity review presents tabulated activities of more than 250 xanthones described in studies published from 2001 to 2008, together with structural information and indications of their wide-ranging potential uses as pharmacological tools. A large number of relevant papers have been published on these subjects (128 cited here), illustrating the diversity of the xanthones and their possible uses.