Polyamine drug discovery

303 Pages·2011·7.85 MB·English

by  Patrick M Woster

RSC Drug Discovery
Edited by Patrick M. Woster and Robert A. Casero, Jr.
Polyamine Drug Discovery
Polyamine Drug Discovery
RSC Drug Discovery Series
Editor-in-Chief:
Professor David Thurston, London School of Pharmacy, UK
Series Editors:
Dr David Fox, Pfizer Global Research and Development, Sandwich, UK
Professor Salvatore Guccione, University of Catania, Italy
Professor Ana Martinez, Instituto de Quimica Medica-CSIC, Spain
Dr David Rotella, Montclair State University, USA
Advisor to the Board:
Professor Robin Ganellin, University College London, UK
Titles in the Series:
1:Metabolism,PharmacokineticsandToxicityofFunctionalGroups:Impact
of Chemical Building Blocks on ADMET
2:Emerging Drugs and Targets for Alzheimer’s Disease; Volume 1: Beta-
Amyloid, Tau Protein and Glucose Metabolism
3:EmergingDrugsandTargetsforAlzheimer’sDisease;Volume2:Neuronal
Plasticity, Neuronal Protection and Other Miscellaneous Strategies
4: Accounts in Drug Discovery: Case Studies in Medicinal Chemistry
5: New Frontiers in Chemical Biology: Enabling Drug Discovery
6: Animal Models for Neurodegenerative Disease
7: Neurodegeneration: Metallostasis and Proteostasis
8: G Protein-Coupled Receptors: From Structure to Function
9: Pharmaceutical Process Development: Current Chemical and Engineering
Challenges
10: Extracellular and Intracellular Signaling
11: New Synthetic Technologies in Medicinal Chemistry
12: New Horizons in Predictive Toxicology: Current Status and Application
13: Drug Design Strategies: Quantitative Approaches
14: Neglected Diseases and Drug Discovery
15:BiomedicalImaging:TheChemistryofLabels,ProbesandContrastAgents
16: Pharmaceutical Salts and Cocrystals
17: Polyamine Drug Discovery
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Polyamine Drug Discovery
Edited by
Patrick M. Woster
Medical University of South Carolina, Charleston, SC, USA
Robert A. Casero, Jr.
John Hopkins University, Baltimore, MD, USA
RSCDrugDiscoverySeriesNo.17
ISBN: 978-1-84973-190-4
ISSN: 2041-3203
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rRoyalSocietyofChemistry2012
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Preface
There have been many significant advances in polyamine research since the
field was brought to the forefront of biological and biomedical research in
the 1970s. Many of the significant findings since that time, whether in plant
research, cell biology, the development of therapeutics, genetics or another
related field, have been aided by the availability of synthetic compounds
specifically designed to inhibit enzymes in the polyamine pathway or other-
wise disrupt polyamine metabolism. For example, a search of PubMed using
the terms difluoromethylornithine AND dfmo AND eflornithine produces
1179 references dating to 1980, and including research in diverse areas such
as plant biochemistry, cancer cell biology, parasitology, insect biochemistry,
synthetic chemistry, drug development and human clinical trials. Despite the
diversity of fields of endeavor within polyamine research and the significant
impact of modulators of polyamine metabolism, a book dedicated to the
discovery and development of synthetic compounds targeting polyamine
metabolism as drugs has never been produced. The purpose of this book is
to fill that void by presenting an overview of drug-discovery research within
the polyamine field.
The impetus for a significant portion of polyamine research has been pro-
vided by the availability of synthetic analogs that produce defined effects on
polyaminemetabolisminvitroandinvivo.Thisbookbeginswithachapterthat
outlines the synthetic approaches to these analogs, covering areas such as
nucleotide synthesis and synthetic routes used to access various polyamine
analogs. The structural biology aspects of polyamine drug discovery are
detailed, as are efforts to design and discover specific inhibitors of enzymes in
the polyamine pathway. Chapters are also included that address the role of
polyamineanalogsasantiparasiticagents,antineoplasticagentsandepigenetic
modulators. In addition, the important role played by polyamine oxidation is
detailed.Otherimportantareaswithinpolyaminedrugdiscoveryresearch,such
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vi Preface
as polyamine transport, the development of polyamine–metal complexes as
antitumoragentsandthedesignofpolyamine-basedgenetransferreagents,are
discussed. Finally, a chapter is included that describes the promising results
from recent human clinical trials involving drugs targeting polyamine meta-
bolism. The result is a broad overview of polyamine drug discovery and the
translation of new chemical entities from basic chemistry to studies involving
patients.
Those of us who have a long history in polyamine drug discovery research
know that it is a cyclic endeavor, with drug discovery successes appearing
periodically and clinical successes appearing steadily but infrequently. How-
ever, recent clinical research with existing compounds, including DFMO and
the bis(ethyl)polyamine analogs PG-11093 and PG-11144, bode well for the
future. In particular, DFMO has found utility as a chemopreventative agent
in combination with sulindac, and the bis(ethyl)polyamines have produced
promising results in combination antitumor studies. Not since the advent of
DFMO has the field of polyamine drug discovery research been so close to
bringing a drug to market. We hope that after perusing this book, the reader
will have gained an appreciation for polyamine drug discovery effortsthat are
occurring on multiple fronts. We also hope that you will share the confidence
inherent in modern polyamine researchers that significant successes in poly-
amine drug discovery are on the horizon.
Patrick M. Woster
Robert A. Casero, Jr
Contents
Chapter 1 Polyamine Drug Discovery: Synthetic Approaches to
Therapeutic Modulators of Polyamine Metabolism 1
Patrick M. Woster
1.1 Introduction 1
1.2 Polyamine Metabolism as a Drug Target 2
1.3 Synthetic Approaches to Modulators of Polyamine
Metabolism and Function 3
1.3.1 Ornithine Decarboxylase (ODC) 3
1.3.2 S-Adenosylmethionine Decarboxylase
(AdoMet-DC) 6
1.3.3 Spermidine Synthase and Spermine Synthase 15
1.3.4 Terminally Alkylated Polyamine Analogs 17
1.3.5 Polyamine-Based Epigenetic Modulators 19
1.4 Conclusion 24
References 24
Chapter 2 Structural Biology in Polyamine Drug Discovery 28
Shridhar Bale and Steven E. Ealick
2.1 Structural Biology and Drug Design 28
2.2 Structural Biology of Polyamine-Related Enzymes 29
2.3 S-Adenosylmethionine Decarboxylase 32
2.4 Early Inhibitors of Human AdoMetDC 34
2.5 CrystalStructureofHumanAdoMetDCandMutants 35
2.6 Inhibitor Design for Active Site of AdoMetDC 37
2.6.1 RoleoftheCentralNitrogen/SulfoniumAtom 37
2.6.2 RoleoftheLinkerLengthandTerminalGroup 38
2.6.3 Effect of 8-Substitution 40
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2.7 Search for New Inhibitors by Virtual Screening 41
2.8 Inhibitor Design for the Putrescine-Binding Site and
Proenzyme 41
2.9 Interspecies Correlations 43
2.9.1 Classification of AdoMetDC 43
2.9.2 Ligand Binding in Prokaryotic AdoMetDC 44
2.9.3 Implications of the Prozyme 45
References 46
Chapter 3 Antiparasitic Drug Discovery for the Polyamine Pathway 50
Nigel Yarlett and Mary Morada
3.1 Ornithine Decarboxylase 50
3.2 S-Adenosylmethionine Decarboxylase 53
3.3 Spermidine Synthase 55
3.4 Trypanothione Synthase 57
3.5 Trypanothione Reductase 61
3.5.1 Tricyclics 61
3.5.2 Polyamine Analogs 62
3.5.3 Redox Inhibitors 62
3.5.4 Substrate Analogs 64
3.5.5 CompoundsIdentifiedThroughScreeningofa
Library of Drug-Like Compounds 65
3.6 Hypusine 66
3.7 PolyamineRetroconversionPathways:SSAT/PAO/SMO 68
References 72
Chapter 4 Inhibitors of Polyamine Biosynthetic Enzymes 78
Anthony E. Pegg
4.1 Introduction 78
4.2 Inhibition of ODC 79
4.2.1 a-Difluoromethylornithine (DFMO) 79
4.2.2 Other ODC Inhibitors 83
4.3 Inhibition of AdoMetDC 84
4.3.1 MGBG, SAM686A and Related Compounds 84
4.3.2 AbeAdo and Other AdoMet Derivatives 86
4.3.3 AbeAdo and Other AdoMetDC Inhibitors 87
4.3.4 Therapeutic Potential of AdoMetDC
Inhibitors 87
4.4 Inhibition of Aminopropyltransferases 89
4.4.1 Product Inhibition of
Aminopropyltransferases 89
4.4.2 SpdSyn Inhibitors 89
4.4.3 SpmSyn Inhibitors 91
Contents ix
4.5 Conclusions 92
References 93
Chapter 5 Symmetrical- and Unsymmetrical Terminally Alkylated
Polyamines 104
Patrick M. Woster and Robert A. Casero, Jr
5.1 Introduction 104
5.2 Symmetrical, Terminally Alkylated Polyamines 106
5.3 Unsymmetrical, Terminally Alkylated Polyamines 112
5.4 Polyamine Isosteres and Epigenetic Activity 122
5.5 Future Directions 129
References 129
Chapter 6 Targeting the Polyamine Catabolic Enzymes Spermine
Oxidase, N1-Acetylpolyamine Oxidase and Spermidine/
Spermine N1-Acetyltransferase 135
Andrew C. Goodwin, Tracy R. Murray-Stewart and
Robert A. Casero, Jr
6.1 Introduction 135
6.2 Structure, Mechanism of Action and Function
of Polyamine Catabolic Enzymes 136
6.2.1 Spermidine/Spermine N1-Acetyltransferase
(SSAT) 136
6.2.2 N1-Acetylpolyamine Oxidase (APAO) and
Spermine Oxidase (SMO) 139
6.3 Modulation of SMO, APAO and SSAT as a
Therapeutic Strategy 144
6.3.1 Polyamine Catabolic Enzymes as Rational
Drug Targets in Parasitic Diseases 144
6.3.2 Cytotoxic Polyamine Analogs as Selective
Chemotherapeutic Agents 145
6.4 Inhibition of Polyamine Catabolism as a Therapeutic
Approach 147
6.4.1 Role of SMO in Inflammation-Associated
Tumorigenesis 147
6.4.2 Polyamine Catabolism in Ischemic Injuries 149
6.4.3 Association of Polyamine Catabolic Enzymes
With Other Human Diseases 149
6.5 Conclusions 150
References 150