Polyamine drug discovery

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.

Author Notes

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.

Patrick M. WosterShridhar Bale and Steven E. EalickNigel Yarlett and Mary MoradaAnthony E. PeggPatrick M. Woster and Robert A. CaseroAndrew C. Goodwin and Tracy R. Murray-Stewart and Robert A. CaseroOtto Phanstiel IV and Jennifer Julian ArcherYun Qu and Joseph J. Moniodis and Amanda L. Harris and Xiaohong Yang and Alex Hegmans and Lawrence F. Povirk and Susan J. Berners-Price and Nicholas P. FarrellIan S. Blagbrough and Abdelkader A. Metwally and Osama A. A. AhmedYi Huang and Laurence J. Marton and Patrick M. WosterAndré S. Bachmann and Victor A. Levin

Chapter 1 Polyamine Drug Discovery: Synthetic Approaches to Therapeutic Modulators of Polyamine Metabolism	p. 1
1.1 Introduction	p. 1
1.2 Polyamine Metabolism as a Drug Target	p. 2
1.3 Synthetic Approaches to Modulators of Polyamine Metabolism and Function	p. 3
1.3.1 Ornithine Decarboxylase (ODC)	p. 3
1.3.2 S-Adenosylmethionine Decarboxylase (AdoMet-DC)	p. 6
1.3.3 Spermidine Synthase and Spermine Synthase	p. 15
1.3.4 Terminally Alkylated Polyamine Analogs	p. 17
1.3.5 Polyamine-Based Epigenetic Modulators	p. 19
1.4 Conclusion	p. 24
References	p. 24
Chapter 2 Structural Biology in Polyamine Drug Discovery	p. 28
2.1 Structural Biology and Drug Design	p. 28
2.2 Structural Biology of Polyamine-Related Enzymes	p. 29
2.3 S-Adenosylmethionine Decarboxylase	p. 32
2.4 Early Inhibitors of Human AdoMetDC	p. 34
2.5 Crystal Structure of Human AdoMetDC and Mutants	p. 35
2.6 Inhibitor Design for Active Site of AdoMetDC	p. 37
2.6.1 Role of the Central Nitrogen/Sulfonium Atom	p. 37
2.6.2 Role of the Linker Length and Terminal Group	p. 38
2.6.3 Effect of 8-Substitution	p. 40
2.7 Search for New Inhibitors by Virtual Screening	p. 41
2.8 Inhibitor Design for the Putrescine-Binding Site and Proenzyme	p. 41
2.9 Interspecies Correlations	p. 43
2.9.1 Classification of AdoMetDC	p. 43
2.9.2 Ligand Binding in Prokaryotic AdoMetDC	p. 44
2.9.3 Implications of the Prozyme	p. 45
References	p. 46
Chapter 3 Antiparasitic Drug Discovery for the Polyamine Pathway	p. 50
3.1 Ornithine Decarboxylase	p. 50
3.2 S-Adenosylmethionine Decarboxylase	p. 53
3.3 Spermidine Synthase	p. 55
3.4 Trypanothione Synthase	p. 57
3.5 Trypanothione Reductase	p. 61
3.5.1 Tricyclics	p. 61
3.5.2 Polyamine Analogs	p. 62
3.5.3 Redox Inhibitors	p. 62
3.5.4 Substrate Analogs	p. 64
3.5.5 Compounds Identified Through Screening of a Library of Drug-Like Compounds	p. 65
3.6 Hypusine	p. 66
3.7 Polyamine Retroconversion Pathways: SSAT/PAO/SMO	p. 68
References	p. 72
Chapter 4 Inhibitors of Polyamine Biosynthetic Enzymes	p. 78
4.1 Introduction	p. 78
4.2 Inhibition of ODC	p. 79
4.2.1 ¿-Difluoromethylornithine (DFMO)	p. 79
4.2.2 Other ODC Inhibitors	p. 83
4.3 Inhibition of AdoMetDC	p. 84
4.3.1 MGBG, SAM686A and Related Compounds	p. 84
4.3.2 AbeAdo and Other AdoMet Derivatives	p. 86
4.3.3 AbeAdo and Other AdoMetDC Inhibitors	p. 87
4.3.4 Therapeutic Potential of AdoMetDC Inhibitors	p. 87
4.4 Inhibition of Aminopropyltransferases	p. 89
4.4.1 Product Inhibition of Aminopropyltransferases	p. 89
4.4.2 SpdSyn Inhibitors	p. 89
4.4.3 SpmSyn Inhibitors	p. 91
4.5 Conclusions	p. 92
References	p. 93
Chapter 5 Symmetrical- and Unsymmetrical Terminally Alkylated Polyamines	p. 104
5.1 Introduction	p. 104
5.2 Symmetrical, Terminally Alkylated Polyamines	p. 106
5.3 Unsymmetrical, Terminally Alkylated Polyamines	p. 112
5.4 Polyamine Isosteres and Epigenetic Activity	p. 122
5.5 Future Directions	p. 129
References	p. 129
Chapter 6 Targeting the Polyamine Catabolic Enzymes Spermine Oxidase, N 1 -Acetylpolyamine Oxidase and Spermidine/Spermine N 1 -Acetyltransferase	p. 135
6.1 Introduction	p. 135
6.2 Structure, Mechanism of Action arid Function of Polyamine Catabolic Enzymes	p. 136
6.2.1 Spermidine/Spermine N 1 -Acetyltransferase (SSAT)	p. 136
6.2.2 N 1 -Acetylpolyamine Oxidase (APAO) and Spermine Oxidase (SMO)	p. 139
6.3 Modulation of SMO, APAO and SSAT as a Therapeutic Strategy	p. 144
6.3.1 Polyamine Catabolic Enzymes as Rational Drug Targets in Parasitic Diseases	p. 144
6.3.2 Cytotoxic Polyamine Analogs as Selective Chemotherapeutic Agents	p. 145
6.4 Inhibition of Polyamine Catabolism as a Therapeutic Approach	p. 147
6.4.1 Role of SMO in Inflammation-Associated Tumorigenesis	p. 147
6.4.2 Polyamine Catabolism in Ischemic Injuries	p. 149
6.4.3 Association of Polyamine Catabolic Enzymes With Other Human Diseases	p. 149
6.5 Conclusions	p. 150
References	p. 150
Chapter 7 Design of Polyamine Transport Inhibitors as Therapeutics	p. 162
7.1 Introduction	p. 162
7.2 Models of Polyamine Transport	p. 163
7.2.1 Homeostasis, Antizyme and Polyamine Transport	p. 164
7.3 Transportons and Anti-Transportons, New Words and Definitions	p. 165
7.4 Role of Polyamine Transportons	p. 166
7.5 Anti-Transportons	p. 167
7.5.1 Polypyridinium Quaternary Salts	p. 167
7.5.2 Irreversible and Sulfur-Containing PAT Inhibitors	p. 169
7.5.3 Dimeric Branched Polyamine Motifs	p. 170
7.5.4 Acridinyl Linear Polyamine Conjugates	p. 171
7.5.5 Aryl-Based Anti-Transportons	p. 172
7.5.6 Trimeric Polyamine Scaffolds	p. 174
7.5.7 Polyamine-Glutaraldehyde Polymers	p. 174
7.5.8 Linear Spermine-Amide Dimers	p. 177
7.5.9 Amino Acid-Spermine Conjugates	p. 177
7.5.10 Heparin Sulfate (HS)-Binding Agents	p. 181
7.5.11 Lipophilic Polyamine Conjugates	p. 182
7.6 Conclusions	p. 187
References	p. 187
Chapter 8 Non-Covalent Polynuclear Platinum Compounds as Polyamine Analogs	p. 191
8.1 Introduction	p. 191
8.2 Covalently Binding Polynuclear Platinum Complexes	p. 192
8.3 Non-Covalent Polynuclear Platinum Complexes	p. 193
8.3.1 Global DNA-Binding Profile	p. 194
8.3.2 Solid-State Studies: A New Mode of DNA Binding	p. 195
8.3.3 Solution Studies: Comparison With Minor Groove Binders	p. 196
8.3.4 Solution Studies: Binding Location of Pre-Associated BBR3464	p. 196
8.4 Biochemical Consequences of Non-Covalent Polynuclear Platinum Association	p. 198
8.4.1 Melphalan Protection Assay	p. 198
8.4.2 Cellular Accumulation and Cellular Effects	p. 199
8.4.3 Cytotoxicity of Non-Covalent Polynuclear Platinum Compounds	p. 200
8.5 Conclusions	p. 202
Acknowledgements	p. 202
References	p. 202
Chapter 9 Polyamine-Based Agents for Gene and siRNA Transfer	p. 205
9.1 Introduction	p. 205
9.2 Barriers to Polynucleotide Delivery	p. 209
9.2.1 DNA Condensation	p. 209
9.2.2 Cell Targeting	p. 213
9.2.3 Cell Membrane Entry	p. 215
9.2.4 Endosomal Escape	p. 215
9.2.5 Nuclear Entry	p. 216
9.2.6 Decomplexation	p. 216
9.2.7 Transcription and Translation	p. 217
9.3 Polyamines Used in Non-Viral Polynucleotide Formulation	p. 217
9.3.1 Cationic Polymers	p. 218
9.3.2 Cationic Peptides	p. 221
9.3.3 Cationic Lipids	p. 223
Acknowledgments	p. 228
References	p. 228
Chapter 10 The Design and Development of Polyamine-Based Analogs with Epigenetic Targets	p. 238
10.1 Polyamine-Nucleic Acid Interaction as a Potential Epigenetic Target for Cancer Therapy	p. 238
10.2 Polyamine Analogs as HDAC Inhibitors	p. 239
10.2.1 HDAC Inhibitors	p. 239
10.2.2 Polyaminohydroxamic Acid (PAHA) and Polyaminobenzamide (PABA) Polyamine Derivatives as HDAC Inhibitors	p. 240
10.3 Histone Lysine-Specific Histone Demethylase 1 (LSD1)	p. 242
10.3.1 Discovery of LSD1	p. 242
10.3.2 LSD1 is an Amine Oxidase Homolog	p. 244
10.3.3 LSD1 Complex is Implicated in Tumorigenesis	p. 245
10.4 Identification of Polyamine Analogs as LSD1 Inhibitors	p. 245
10.4.1 Bisguanidine and Biguanide Polyamine Analogs as LSD1 Inhibitors	p. 245
10.4.2 Oligoamine Polyamine Analogs as LSD1 Inhibitors	p. 248
10.5 Inhibition of LSD1 by Polyamine Analogs Reactivates Aberrantly Silenced Gene Expressions in Cancer Cells	p. 248
10.6 Polyamine Analogs Increase Activating Chromatin Marks and Decrease Repressive Marks at the Promoters of Re-Expressed Genes with Retention of DNA Hypermethylation	p. 251
10.7 Combination of LSD1 Inhibitors with Other Agents Targeting Epigenetic Regulation of Gene Expression	p. 251
10.8 In Vivo Effects of Polyamine Analogs on LSD1 and Tumor Growth	p. 252
10.9 Conclusion	p. 252
Acknowledgment	p. 253
References	p. 253
Chapter 11 Clinical Applications of Polyamine-Based Therapeutics	p. 257
11.1 Introduction	p. 257
11.2 Polyamine Inhibitors in Therapeutic Clinical Trials	p. 258
11.2.1 Cancer	p. 258
11.2.2 Other Diseases	p. 267
11.3 Polyamine Inhibitors in Chemoprevention Trials	p. 268
11.3.1 Cancer	p. 268
11.4 Polyamine Analogs in Therapeutic Clinical Trials	p. 269
11.4.1 Cancer	p. 269
11.5 Future Directions	p. 270
Acknowledgments	p. 271
References	p. 271
Subject Index	p. 277

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