Polyamine Drug Discovery: Rsc (Rsc Drug Discovery, 17) - Hardcover

Hardcover

ISBN 10: 184973190X ISBN 13: 9781849731904

Verlag: ROYAL SOCIETY OF CHEMISTRY, 2011

Inhaltsangabe

Polyamines are ubiquitous molecules that are involved in a number of important cellular processes. Aberrations in their function or metabolism play a role in diseases such as cancer and parasitic infection. A number of validated drug targets have been identified, including enzymes in the polyamine biosynthetic and catabolic pathways and the S-adenosylmethionine synthetic and salvage pathways. Polyamine Drug Discovery is the first comprehensive volume to cover all aspects of the design and development of potential therapeutics targeting polyamine metabolism. The book details research progress from 1975 to the present date and discusses the design and use of polyamine metabolism inhibitors as therapeutic agents. Various polyamine-containing drugs are described that can be used in chemotherapy, and as treatments for infections including trypanosomiasis, leishmaniasis and malaria. Finally, the roles of polyamine analogues in chemoprevention, polyamine-containing vectors for gene delivery, and the design of polyamine-based epigenetic modulators are detailed. Each chapter addresses a different aspect of polyamine drug discovery and all are written by medicinal and biological chemists with particular expertise in developing agents that modulate polyamine metabolism or function. The book will increase the visibility of polyamine drug discovery among pharmaceutical researchers and provide a valuable reference for everyone working in the field.

Über diesen Titel

Über die Autorin bzw. den Autor

Patrick M. Woster, Ph.D. is Professor and Center for Economic Excellence Endowed Chair in the Department of Pharmaceutical and Biomedical Sciences at the Medical University of South Carolina. He is a medicinal chemist with an interest in the synthesis of molecules that modulate polyamine metabolism or chromatin remodeling as potential antitumor agents. Dr. Woster also maintains a program in antiparasitic drug discovery with a particular emphasis on malaria and trypanosomiasis. He has produced a number of inhibitors that target enzymes in the polyamine biosynthetic pathway, and synthesized the first unsymmetrically substituted alkylpolyamine analogues. Molecules developed in the Woster laboratory have been shown to produce dramatic effects on a variety of tumor cells by initiating apoptosis, binding to DNA and by producing epigenetic changes in gene expression. Robert A. Casero, Jr., Ph.D. is a Professor of Oncology in the Johns Hopkins University School of Medicine. Dr. Casero is a molecular pharmacologist who has spent most of the last 30 years studying the role of polyamines in normal and tumour cell growth, and devising strategies to target polyamine function and metabolism for therapeutic benefit. His laboratory was responsible for cloning several genes involved in human polyamine catabolism; genes whose expression are thought to play a role in determining cellular responses to specific polyamine analogues.

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Polyamine Drug Discovery

By Patrick M. Woster, Robert A. Casero Jr.

The Royal Society of Chemistry

Copyright © 2012 Royal Society of Chemistry
All rights reserved.

ISBN: 978-1-84973-190-4

Contents

Chapter 1 Polyamine Drug Discovery: Synthetic Approaches to Therapeutic Modulators of Polyamine Metabolism Patrick M. Woster, 1, 
Chapter 2 Structural Biology in Polyamine Drug Discovery Shridhar Bale and Steven E. Ealick, 28, 
Chapter 3 Antiparasitic Drug Discovery for the Polyamine Pathway Nigel Yarlett and Mary Morada, 50, 
Chapter 4 Inhibitors of Polyamine Biosynthetic Enzymes Anthony E. Pegg, 78, 
Chapter 5 Symmetrical-and Unsymmetrical Terminally Alkylated Polyamines Patrick M. Woster and Robert A. Casero, Jr, 104, 
Chapter 6 Targeting the Polyamine Catabolic Enzymes Spermine Oxidase, N1-Acetylpolyamine Oxidase and Spermidine/Spermine N1-Acetyltransferase Andrew C. Goodwin, Tracy R. Murray-Stewart and Robert A. Casero, Jr, 135, 
Chapter 7 Design of Polyamine Transport Inhibitors as Therapeutics Otto Phanstiel IV and Jennifer Julian Archer, 162, 
Chapter 8 Non-Covalent Polynuclear Platinum Compounds as Polyamine Analogs Yun Qu, Joseph J. Moniodis, Amanda L. Harris, Xiaohong Yang, Alex Hegmans, Lawrence F. Povirk, Susan J. Berners-Price and Nicholas P. Farrell, 191, 
Chapter 9 Polyamine-Based Agents for Gene and siRNA Transfer Ian S. Blagbrough, Abdelkader A. Metwally and Osama A. A. Ahmed, 205, 
Chapter 10 The Design and Development of Polyamine-Based Analogs with Epigenetic Targets Yi Huang, Laurence J. Marton and Patrick M. Woster, 238, 
Chapter 11 Clinical Applications of Polyamine-Based Therapeutics André S. Bachmann and Victor A. Levin, 257, 
Subject Index, 277, 

CHAPTER 1

Polyamine Drug Discovery: Synthetic Approaches to Therapeutic Modulators of Polyamine Metabolism

PATRICK M. WOSTER

Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, 70 President St., Charleston, SC 29425, USA

1.1 Introduction

In the following chapters, a complete description of the design, bioevaluation and development of modulators of polyamine metabolism is presented. There are numerous synthetic approaches to these inhibitors, and as such a comprehensive review of the chemical literature in this area is beyond the scope of this book. In this chapter, specific examples of synthetic approaches to nucleosides, analogs of the natural polyamines and other agents that affect polyamine metabolism are described. The reader should bear in mind that the literature is replete with alternative strategies for the synthesis of compounds described herein. However, the examples provided will allow the reader to appreciate the vast chemical diversity that is available to medicinal chemists working in the polyamine field.

1.2 Polyamine Metabolism as a Drug Target

The mammalian polyamine biosynthetic pathway is shown in Figure 1.1. Ornithine is converted to putrescine by the action of the enzyme ornithine decarboxylase (ODC). Mammalian ODC, a dimeric enzyme with a molecular weight of about 80 000, is a typical pyridoxal phosphate-requiring amino acid decarboxylase that has been studied quite extensively. ODC is known to be one of the control points in the polyamine biosynthetic pathway, producing a product that is committed to polyamine biosynthesis. The synthesis and degradation of ODC are controlled by a number of factors including degradation assisted by a specific ODC antizyme, a polyamine-induced protein that binds to ODC and promotes ubiquitin-independent degradation by the 26S proteasome. As a result, ODC has a functional half-life of about 10 min. Putrescine is next converted to spermidine via an aminopropyltransferase known as spermidine synthase, which requires decarboxylated S-adenosylmethionine as a co-substrate. A second closely related but distinct aminopropyltransferase, spermine synthase, then adds an additional aminopropyl group to spermidine to yield spermine, the longest polyamine occurring in mammalian systems. The by-product for the spermidine and spermine synthase reactions is 5'-methyl-thioadenosine (MTA), a potent product inhibitor for the aminopropyl transfer process. In mammalian systems, MTA is rapidly hydrolyzed by the enzyme MTA-phosphorylase, and the components are converted to adenosine and methionine via salvage pathways. The aminopropyl donor for both amino- propyltransferases is decarboxylated S-adenosylmethionine (dc-AdoMet), produced from S-adenosylmethionine (AdoMet) by S-adenosylmethionine decarboxylase (AdoMet-DC). AdoMet-DC, like ODC, is a highly regulated enzyme in mammalian cells, and also serves as a regulatory point in the path- way. However, unlike ODC, AdoMet-DC belongs to a class of pyruvoyl enzymes that do not require pyridoxal phosphate as a cofactor (see below).

Polyamine metabolism is tightly controlled by a combination of inducible enzymes and the import/export of cellular polyamines. In addition to the enzymes mentioned above, intracellular polyamine content is modulated by a pair of acetyltransferases. Spermidine in the cell nucleus is acetylated on the four-carbon end by spermidine-N8-acetyltransferase, possibly altering the compound's binding affinity for DNA. A specific deacetylase can then reverse this enzymatic acetylation. Cytoplasmic spermidine and spermine serve as substrates for spermidine/spermine-N1-acetyltransferase (SSAT), resulting in acetylation on the three-carbon end of each molecule (Figure 1.1). The acetylated spermidine or spermine then acts as a substrate for acetylpolyamine oxidase (APAO), which catalyzes the formation of 3-acetamidopropionaldehyde and either putrescine or spermidine, respectively. Excess acetylated polyamines can also be exported from the cell via the polyamine transport system. More recently, a second polyamine oxidase, the inducible spermine oxidase (SMO) was discovered and characterized. Thus, SSAT, APAO and SMO together serve as a reverse route for the interconversion of polyamines. An additional mechanism for control of cellular polyamines is provided by the polyamine transport system, which has been well characterized in some organisms (bacteria, yeast), but has not been well characterized in mammalian organisms. The function of enzymes in polyamine metabolism and the polyamine transport system, and the consequences of modulating their activity, are described in more detail elsewhere in this book.

1.3 Synthetic Approaches to Modulators of Polyamine Metabolism and Function

1.3.1 Ornithine Decarboxylase (ODC)

Mammalian ODC is a highly unstable protein, and cellular levels of ODC depend on rates of synthesis and degradation as outlined above. For this reason, reversible and irreversible inhibitors of ODC have proven to be of limited value, since the synthesis of new protein occurs very rapidly in response to reduced polyamine levels in the cell. The catalytic mechanism of ODC involves the formation of a Schiff's base between the amino group of ornithine and the pyridoxal phosphate cofactor which is tightly bound to ODC. The most useful inhibitor of ODC to date, α-difluoromethylornithine (DFMO, 1, Scheme 1.1), takes advantage of this aspect of the mechanism, and belongs to a group of rationally designed mechanism-based inactivators specifically targeted to individual amino acid decarboxylases. The chemical synthesis of DFMO is shown in Scheme 1.1. The (bis)benzylidene-protected amino ester 2 is treated with lithium diisopropylamide (LDA) followed by...

Details zur Ausgabe

• Verlag: ROYAL SOCIETY OF CHEMISTRY
• Erscheinungsdatum: 2011
• Sprache: Englisch
• ISBN 10: 184973190X
• ISBN 13: 9781849731904
• Einband: Gebundene Ausgabe
• Anzahl der Seiten: 289
• Herausgeber: Woster Patrick, Casero Robert
• Kontakt zum Hersteller: Nicht verfügbar
• Verantwortliche Person: Nicht verfügbar