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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 |
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