Polyamine Drug Discovery

, by Woster, Patrick M.; Casero, Robert A., Jr.

Note: Supplemental materials are not guaranteed with Rental or Used book purchases.

ISBN: 9781849731904 | 184973190X
Cover: Hardcover
Copyright: 11/30/2011

Rent

(Recommended)

$120.70

Term

Due

Price

Semester

Dec 13

$134.11

Quarter

Aug 31

$127.40

Short Term

Jul 26

$120.70

*This item is part of an exclusive publisher rental program and requires an additional convenience fee. This fee will be reflected in the shopping cart.
Buy Used

Usually Ships in 2-4 Business Days

$136.71
Buy New

Usually Ships in 3-5 Business Days

$183.22
eBook

Available Instantly

Online: 1825 Days

Downloadable: Lifetime Access

$209.25

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.

Polyamine Drug Discovery: Synthetic Approaches to Therapeutic Modulators of Polyamine Metabolism	p. 1
Introduction	p. 1
Polyamine Metabolism as a Drug Target	p. 2
Synthetic Approaches to Modulators of Polyamine Metabolism and Function	p. 3
Ornithine Decarboxylase (ODC)	p. 3
S-Adenosylmethionine Decarboxylase (AdoMet-DC)	p. 6
Spermidine Synthase and Spermine Synthase	p. 15
Terminally Alkylated Polyamine Analogs	p. 17
Polyamine-Based Epigenetic Modulators	p. 19
Conclusion	p. 24
References	p. 24
Structural Biology in Polyamine Drug Discovery	p. 28
Structural Biology and Drug Design	p. 28
Structural Biology of Polyamine-Related Enzymes	p. 29
S-Adenosylmethionine Decarboxylase	p. 32
Early Inhibitors of Human AdoMetDC	p. 34
Crystal Structure of Human AdoMetDC and Mutants	p. 35
Inhibitor Design for Active Site of AdoMetDC	p. 37
Role of the Central Nitrogen/Sulfonium Atom	p. 37
Role of the Linker Length and Terminal Group	p. 38
Effect of 8-Substitution	p. 40
Search for New Inhibitors by Virtual Screening	p. 41
Inhibitor Design for the Putrescine-Binding Site and Proenzyme	p. 41
Interspecies Correlations	p. 43
Classification of AdoMetDC	p. 43
Ligand Binding in Prokaryotic AdoMetDC	p. 44
Implications of the Prozyme	p. 45
References	p. 46
Antiparasitic Drug Discovery for the Polyamine Pathway	p. 50
Ornithine Decarboxylase	p. 50
S-Adenosylmethionine Decarboxylase	p. 53
Spermidine Synthase	p. 55
Trypanothione Synthase	p. 57
Trypanothione Reductase	p. 61
Tricyclics	p. 61
Polyamine Analogs	p. 62
Redox Inhibitors	p. 62
Substrate Analogs	p. 64
Compounds Identified Through Screening of a Library of Drug-Like Compounds	p. 65
Hypusine	p. 66
Polyamine Retroconversion Pathways: SSAT/PAO/SMO	p. 68
References	p. 72
Inhibitors of Polyamine Biosynthetic Enzymes	p. 78
Introduction	p. 78
Inhibition of ODC	p. 79
¿-Difluoromethylornithine (DFMO)	p. 79
Other ODC Inhibitors	p. 83
Inhibition of AdoMetDC	p. 84
MGBG, SAM686A and Related Compounds	p. 84
AbeAdo and Other AdoMet Derivatives	p. 86
AbeAdo and Other AdoMetDC Inhibitors	p. 87
Therapeutic Potential of AdoMetDC Inhibitors	p. 87
Inhibition of Aminopropyltransferases	p. 89
Product Inhibition of Aminopropyltransferases	p. 89
SpdSyn Inhibitors	p. 89
SpmSyn Inhibitors	p. 91
Conclusions	p. 92
References	p. 93
Symmetrical- and Unsymmetrical Terminally Alkylated Polyamines	p. 104
Introduction	p. 104
Symmetrical, Terminally Alkylated Polyamines	p. 106
Unsymmetrical, Terminally Alkylated Polyamines	p. 112
Polyamine Isosteres and Epigenetic Activity	p. 122
Future Directions	p. 129
References	p. 129
Targeting the Polyamine Catabolic Enzymes Spermine Oxidase, N¹-Acetylpolyamine Oxidase and Spermidine/Spermine N¹-Acetyltransferase	p. 135
Introduction	p. 135
Structure, Mechanism of Action arid Function of Polyamine Catabolic Enzymes	p. 136
Spermidine/Spermine N¹-Acetyltransferase (SSAT)	p. 136
N¹-Acetylpolyamine Oxidase (APAO) and Spermine Oxidase (SMO)	p. 139
Modulation of SMO, APAO and SSAT as a Therapeutic Strategy	p. 144
Polyamine Catabolic Enzymes as Rational Drug Targets in Parasitic Diseases	p. 144
Cytotoxic Polyamine Analogs as Selective Chemotherapeutic Agents	p. 145
Inhibition of Polyamine Catabolism as a Therapeutic Approach	p. 147
Role of SMO in Inflammation-Associated Tumorigenesis	p. 147
Polyamine Catabolism in Ischemic Injuries	p. 149
Association of Polyamine Catabolic Enzymes With Other Human Diseases	p. 149
Conclusions	p. 150
References	p. 150
Design of Polyamine Transport Inhibitors as Therapeutics	p. 162
Introduction	p. 162
Models of Polyamine Transport	p. 163
Homeostasis, Antizyme and Polyamine Transport	p. 164
Transportons and Anti-Transportons, New Words and Definitions	p. 165
Role of Polyamine Transportons	p. 166
Anti-Transportons	p. 167
Polypyridinium Quaternary Salts	p. 167
Irreversible and Sulfur-Containing PAT Inhibitors	p. 169
Dimeric Branched Polyamine Motifs	p. 170
Acridinyl Linear Polyamine Conjugates	p. 171
Aryl-Based Anti-Transportons	p. 172
Trimeric Polyamine Scaffolds	p. 174
Polyamine-Glutaraldehyde Polymers	p. 174
Linear Spermine-Amide Dimers	p. 177
Amino Acid-Spermine Conjugates	p. 177
Heparin Sulfate (HS)-Binding Agents	p. 181
Lipophilic Polyamine Conjugates	p. 182
Conclusions	p. 187
References	p. 187
Non-Covalent Polynuclear Platinum Compounds as Polyamine Analogs	p. 191
Introduction	p. 191
Covalently Binding Polynuclear Platinum Complexes	p. 192
Non-Covalent Polynuclear Platinum Complexes	p. 193
Global DNA-Binding Profile	p. 194
Solid-State Studies: A New Mode of DNA Binding	p. 195
Solution Studies: Comparison With Minor Groove Binders	p. 196
Solution Studies: Binding Location of Pre-Associated BBR3464	p. 196
Biochemical Consequences of Non-Covalent Polynuclear Platinum Association	p. 198
Melphalan Protection Assay	p. 198
Cellular Accumulation and Cellular Effects	p. 199
Cytotoxicity of Non-Covalent Polynuclear Platinum Compounds	p. 200
Conclusions	p. 202
Acknowledgements	p. 202
References	p. 202
Polyamine-Based Agents for Gene and siRNA Transfer	p. 205
Introduction	p. 205
Barriers to Polynucleotide Delivery	p. 209
DNA Condensation	p. 209
Cell Targeting	p. 213
Cell Membrane Entry	p. 215
Endosomal Escape	p. 215
Nuclear Entry	p. 216
Decomplexation	p. 216
Transcription and Translation	p. 217
Polyamines Used in Non-Viral Polynucleotide Formulation	p. 217
Cationic Polymers	p. 218
Cationic Peptides	p. 221
Cationic Lipids	p. 223
Acknowledgments	p. 228
References	p. 228
The Design and Development of Polyamine-Based Analogs with Epigenetic Targets	p. 238
Polyamine-Nucleic Acid Interaction as a Potential Epigenetic Target for Cancer Therapy	p. 238
Polyamine Analogs as HDAC Inhibitors	p. 239
HDAC Inhibitors	p. 239
Polyaminohydroxamic Acid (PAHA) and Polyaminobenzamide (PABA) Polyamine Derivatives as HDAC Inhibitors	p. 240
Histone Lysine-Specific Histone Demethylase 1 (LSD1)	p. 242
Discovery of LSD1	p. 242
LSD1 is an Amine Oxidase Homolog	p. 244
LSD1 Complex is Implicated in Tumorigenesis	p. 245
Identification of Polyamine Analogs as LSD1 Inhibitors	p. 245
Bisguanidine and Biguanide Polyamine Analogs as LSD1 Inhibitors	p. 245
Oligoamine Polyamine Analogs as LSD1 Inhibitors	p. 248
Inhibition of LSD1 by Polyamine Analogs Reactivates Aberrantly Silenced Gene Expressions in Cancer Cells	p. 248
Polyamine Analogs Increase Activating Chromatin Marks and Decrease Repressive Marks at the Promoters of Re-Expressed Genes with Retention of DNA Hypermethylation	p. 251
Combination of LSD1 Inhibitors with Other Agents Targeting Epigenetic Regulation of Gene Expression	p. 251
In Vivo Effects of Polyamine Analogs on LSD1 and Tumor Growth	p. 252
Conclusion	p. 252
Acknowledgment	p. 253
References	p. 253
Clinical Applications of Polyamine-Based Therapeutics	p. 257
Introduction	p. 257
Polyamine Inhibitors in Therapeutic Clinical Trials	p. 258
Cancer	p. 258
Other Diseases	p. 267
Polyamine Inhibitors in Chemoprevention Trials	p. 268
Cancer	p. 268
Polyamine Analogs in Therapeutic Clinical Trials	p. 269
Cancer	p. 269
Future Directions	p. 270
Acknowledgments	p. 271
References	p. 271
Subject Index	p. 277
Table of Contents provided by Ingram. All Rights Reserved.

Please wait while the item is added to your bag...

FREE SHIPPING

Amazon no longer offers textbook rentals. We do!

Polyamine Drug Discovery

Summary

Table of Contents

Supplemental Materials