Medicinal Chemistry of Anticancer Drugs (eBook)

Front Cover 1
Medicinal Chemistry of Anticancer Drugs 4
Copyright Page 5
Preface 10
Abbreviations 12
Chapter 1: Introduction 18
1. Some General Remarks About Cancer and Cancer Chemotherapy 18
2. A Brief Account of the Role of Chemistry in Cancer Chemotherapy 20
3. Natural Products in Cancer Chemotherapy 22
4. A Brief Comment About Cancer Nanotechnology 23
5. Conclusion 24
References 24
Chapter 2: Antimetabolites 26
1. Introduction 27
2. Inhibitors of the Biosynthesis of Uridylic Acid 27
3. Inhibitors of the Biosynthesis of 2'-Deoxyribonucleotides by Ribonucleotide Reductase (RNR) 28
4. Inhibitors of the Biosynthesis of Thymidilic Acid 35
5. Inhibitors of Dihydrofolate Reductase (DHFR) 49
6. Inhibitors of the De Novo Purine Biosynthesis Pathway 53
7. Inhibitors of Adenosine Deaminase 59
8. Inhibitors of Late Stages in DNA Synthesis 62
9. Antimetabolite Enzymes 67
References 68
Chapter 3: Anticancer Drugs That Inhibit Hormone Action 70
1. Introduction 71
2. Estrogens and Their Involvement in Carcinogenesis 71
3. Antiestrogens as Antitumor Drugs 75
4. Aromatase Inhibitors 82
5. Steroid Sulfatase Inhibitors 90
6. Androgen-Related Antitumor Agents 92
7. Regulation of Steroidal Hormone Synthesis as a Target for Antitumor Drugs 96
8. Miscellaneous Steroid Hormone-Related Anticancer Therapy 102
9. Compounds Acting on Other Proteins of the Nuclear Receptor Superfamily: Retinoids 103
References 107
Chapter 4: Anticancer Drugs Acting via Radical Species, Photosensitizers and Photodynamic Therapy of Cancer 110
1. Introduction: Radicals and Other Reactive Oxygen Species 110
2. Biological Effects of ROS 112
3. Anthracyclines and Their Analogs 119
4. Mitoxantrone and Related Quinones 129
5. Actinomycin D 131
6. Chartreusin, Elsamicin A, and Related Compounds 133
7. Bleomycins 133
8. Enediyne Antibiotics 139
9. Tirapazamine 143
10. Penclomedine 145
11. Radiosensitizers 146
12. Photodynamic Therapy of Cancer 149
References 152
Chapter 5: DNA Alkylating Agents 156
1. Introduction 156
2. Nitrogen Mustards 158
3. Aziridines (Ethyleneimines) 171
4. Epoxides 175
5. Methanesulfonates 176
6. Nitrosoureas 177
7. Triazenes 182
8. Methylhydrazines 183
9. 1,3,5-Triazines: Hexamethylmelamine and Trimelamol 185
10. Platinum Complexes 186
11. Miscellaneous Alkylating and Acylating Antitumor Agents 190
References 191
Chapter 6: Alkylating and Non-Alkylating Compounds Interacting with the DNA Minor Groove 194
1. Introduction 194
2. Netropsin, Distamycin, and Related Compounds 195
3. Mitomycins 199
4. Tetrahydroisoquinoline Alkaloids 206
5. Cyclopropylindole Alkylating Agents 210
6. Pyrrolo[1,4]Benzodiazepines 212
References 213
Chapter 7: DNA Intercalators and Topoisomerase Inhibitors 216
1. DNA Intercalation and Its Consequences 217
2. Monofunctional Intercalating Agents 218
3. Bifunctional Intercalating Agents 223
4. DNA Topoisomerases 226
5. Topoisomerase II Poisons 230
6. Topoisomerase II Catalytic Inhibitors 235
7. Specific Topoisomerase I Inhibitors 237
References 242
Chapter 8: Anticancer Drugs Targeting Tubulin and Microtubules 246
1. Introduction 246
2. Drugs That Inhibit Microtubule Polymerization at High Concentrations 248
3. Microtubule-Stabilizing Agents: Compounds Binding at the Taxane Site 254
4. Miscellaneous Anticancer Drugs Acting on Novel Sites on Tubuline 262
5. Antivascular Effects of Microtubule-Targeted Agents 262
6. Mitotic Kinesin Inhibitors 263
References 264
Chapter 9: Drugs That Inhibit Signalling Pathways for Tumor Cell Growth and Proliferation 268
1. Introduction: The Role of Protein Kinases in Cancer 269
2. Signalling Pathways Related to Kinases 271
3. Inhibitors of Tyrosine Kinases (TKs) 271
4. Inhibitors of Serine-Threonine Kinases 292
5. Inhibitors of the RAS-RAF-MEK Signalling Pathway and Farnesyl Transferase 303
6. Inhibitors of Farnesyldiphosphate Synthase and Geranylgeranyldiphosphate Synthase 312
7. Anticancer Drugs Acting on Apoptotic Signalling Pathways 313
8. Inhibitors of Heat-Shock Proteins (HSP 90) 316
References 319
Chapter 10: Other Approaches to Targeted Therapy 324
1. Proteasome Inhibitors 324
2. Antiangiogenic Agents Unrelated to Kinase Signaling 329
3. Epigenetic Therapy of Cancer 340
4. Inhibitors of Other DNA-Associated Enzymes 354
5. Therapy Directed at Other Targets 358
References 364
Chapter 11: Drug Targeting in Anticancer Chemotherapy 368
1. Introduction 368
2. Prodrug-Based Anticancer Drug Targeting: Small-Molecule Prodrugs 369
3. Polymer-Protein Conjugates 385
4. Macromolecular Small-Drug Carrier Systems 386
5. Polymer-Directed Enzyme Prodrug Therapy (PDEPT) 394
6. Folate Receptor-Targeted Chemotherapy and Immunotherapy of Cancer 395
7. Liposomes and Nanoparticles in Anticancer Drug Targeting 397
References 400
Chapter 12: Drugs That Modulate Resistance to Antitumor Agents 404
1. ATP-Binding Cassette Efflux Pumps in Anticancer Drug Resistance 405
2. Glutathione and Glutathione-S-Transferase in Anticancer Drug Resistance 414
3. Chemosensitizers Targeting DNA-Repair Systems 418
4. Antitumor Drug Resistance Related to Extracellular pH: Tumor-Associated Carbonic Anhydrase as an Anticancer Target 429
References 431
Chapter 13: Cancer Chemoprevention 434
1. Introduction 434
2. Ligands for Nuclear Receptors in Cancer Chemoprevention 435
3. Anti-Inflammatory Agents and Antioxidants in Cancer Chemoprevention 438
4. Chromatin Modifiers in Cancer Chemoprevention 442
5. Miscellaneous Agents for Chemoprevention 443
6. Cancer Vaccines 445
References 445
Index 448