Medicinal chemistry of anticancer drugs

Antitumor chemotherapy is nowadays a very active field of research, and a huge amount of information on the topic is generated every year. Although many books are available that deal with clinical aspects of cancer chemotherapy, this book addresses the need for an updated treatment from the point of view of medicinal chemistry and drug design. The focus of Medicinal Chemistry of Anticancer Drugs is on the mechanism of action of antitumor drugs from the molecular point of view and on the relationship between chemical structure and chemical and biochemical reactivity of antitumor agents, aiming at the rationalization of the action of this type of drug, which would allow the design of new active structures.

Author Notes

Carmen Avendano and J. Carlos Menendez Departamento de Quimica Organica y Farmaceutica Facultad de Farmacia, Universidad Complutense Madrid, Spain

Preface	p. ix
Abbreviations	p. xi
1 Introduction	p. 1
1 Some General Remarks About Cancer and Cancer Chemotherapy	p. 1
2 A Brief Account of the Role of Chemistry in Cancer Chemotherapy	p. 3
3 Natural Products in Cancer Chemotherapy	p. 5
4 A Brief Comment About Cancer Nanotechnology	p. 6
5 Conclusion	p. 7
References	p. 7
2 Antimetabolites	p. 9
1 Introduction	p. 10
2 Inhibitors of the Biosynthesis of Uridylic Acid	p. 10
3 Inhibitors of the Biosynthesis of 2'-Deoxyribonucleotides by Ribonucleotide Reductase (RNR)	p. 11
4 Inhibitors of the Biosynthesis of Thymidilic Acid	p. 18
5 Inhibitors of Dihydrofolate Reductase (DHFR)	p. 32
6 Inhibitors of the De Novo Purine Biosynthesis Pathway	p. 36
7 Inhibitors of Adenosine Deaminase	p. 42
8 Inhibitors of Late Stages in DNA Synthesis	p. 45
9 Antimetabolite Enzymes	p. 50
References	p. 51
3 Anticancer Drugs That Inhibit Hormone Action	p. 53
1 Introduction	p. 54
2 Estrogens and Their Involvement in Carcinogenesis	p. 54
3 Antiestrogens as Antitumor Drugs	p. 58
4 Aromatase Inhibitors	p. 65
5 Steroid Sulfatase Inhibitors	p. 73
6 Androgen-Related Antitumor Agents	p. 75
7 Regulation of Steroidal Hormone Synthesis as a Target for Antitumor Drugs	p. 79
8 Miscellaneous Steroid Hormone-Related Anticancer Therapy	p. 85
9 Compounds Acting on Other Proteins of the Nuclear Receptor Superfamily: Retinoids	p. 86
References	p. 90
4 Anticancer Drugs Acting via Radical Species, Photosensitizers and Photodynamic Therapy of Cancer	p. 93
1 Introduction: Radicals and Other Reactive Oxygen Species	p. 93
2 Biological Effects of ROS	p. 95
3 Anthracyclines and Their Analogs	p. 102
4 Mitoxantrone and Related Quinones	p. 112
5 Actinomycin D	p. 114
6 Chartreusin, Elsamicin A, and Related Compounds	p. 116
7 Bleomycins	p. 116
8 Enediyne Antibiotics	p. 122
9 Tirapazamine	p. 126
10 Penclomedine	p. 128
11 Radiosensitizers	p. 129
12 Photodynamic Therapy of Cancer	p. 132
References	p. 135
5 DNA Alkylating Agents	p. 139
1 Introduction	p. 139
2 Nitrogen Mustards	p. 141
3 Aziridines (Ethyleneimines)	p. 154
4 Epoxides	p. 158
5 Methanesulfonates	p. 159
6 Nitrosoureas	p. 160
7 Triazenes	p. 165
8 Methylhydrazines	p. 166
9 1,3,5-Triazines: Hexamethylmelamine and Trimelamol	p. 168
10 Platinum Complexes	p. 169
11 Miscellaneous Alkylating and Acylating Antitumor Agents	p. 173
References	p. 174
6 Alkylating and Non-Alkylating Compounds Interacting with the DNA Minor Groove	p. 177
1 Introduction	p. 177
2 Netropsin, Distamycin, and Related Compounds	p. 178
3 Mitomycins	p. 182
4 Tetrahydroisoquinoline Alkaloids	p. 189
5 Cyclopropylindole Alkylating Agents	p. 193
6 Pyrrolo[1,4]Benzodiazepines	p. 195
References	p. 196
7 DNA Intercalators and Topoisomerase Inhibitors	p. 199
1 DNA Intercalation and Its Consequences	p. 200
2 Monofunctional Intercalating Agents	p. 201
3 Bifunctional Intercalating Agents	p. 206
4 DNA Topoisomerases	p. 209
5 Topoisomerase II Poisons	p. 213
6 Topoisomerase II Catalytic Inhibitors	p. 218
7 Specific Topoisomerase I Inhibitors	p. 220
References	p. 225
8 Anticancer Drugs Targeting Tubulin and Microtubules	p. 229
1 Introduction	p. 229
2 Drugs That Inhibit Microtubule Polymerization at High Concentrations	p. 231
3 Microtubule-Stabilizing Agents: Compounds Binding at the Taxane Site	p. 237
4 Miscellaneous Anticancer Drugs Acting on Novel Sites on Tubuline	p. 245
5 Antivascular Effects of Microtubule-Targeted Agents	p. 245
6 Mitotic Kinesin Inhibitors	p. 246
References	p. 247
9 Drugs That Inhibit Signalling Pathways for Tumor Cell Growth and Proliferation	p. 251
1 Introduction: The Role of Protein Kinases in Cancer	p. 252
2 Signalling Pathways Related to Kinases	p. 254
3 Inhibitors of Tyrosine Kinases (TKs)	p. 254
4 Inhibitors of Serine-Threonine Kinases	p. 275
5 Inhibitors of the RAS-RAF-MEK Signalling Pathway and Farnesyl Transferase	p. 286
6 Inhibitors of Farnesyldiphosphate Synthase and Geranylgeranyldiphosphate Synthase	p. 295
7 Anticancer Drugs Acting on Apoptotic Signalling Pathways	p. 296
8 Inhibitors of Heat-Shock Proteins (HSP 90)	p. 299
References	p. 302
10 Other Approaches to Targeted Therapy	p. 307
1 Proteasome Inhibitors	p. 307
2 Antiangiogenic Agents Unrelated to Kinase Signaling	p. 312
3 Epigenetic Therapy of Cancer	p. 323
4 Inhibitors of Other DNA-Associated Enzymes	p. 337
5 Therapy Directed at Other Targets	p. 341
References	p. 347
11 Drug Targeting in Anticancer Chemotherapy	p. 351
1 Introduction	p. 351
2 Prodrug-Based Anticancer Drug Targeting: Small-Molecule Prodrugs	p. 352
3 Polymer-Protein Conjugates	p. 368
4 Macromolecular Small-Drug Carrier Systems	p. 369
5 Polymer-Directed Enzyme Prodrug Therapy (PDEPT)	p. 377
6 Folate Receptor-Targeted Chemotherapy and Immunotherapy of Cancer	p. 378
7 Liposomes and Nanoparticles in Anticancer Drug Targeting	p. 380
References	p. 383
12 Drugs That Modulate Resistance to Antitumor Agents	p. 387
1 ATP-Binding Cassette Efflux Pumps in Anticancer Drug Resistance	p. 388
2 Glutathione and Glutathione-S-Transferase in Anticancer Drug Resistance	p. 397
3 Chemosensitizers Targeting DNA-Repair Systems	p. 401
4 Antitumor Drug Resistance Related to Extracellular pH: Tumor-Associated Carbonic Anhydrase as an Anticancer Target	p. 412
References	p. 414
13 Cancer Chemoprevention	p. 417
1 Introduction	p. 417
2 Ligands for Nuclear Receptors in Cancer Chemoprevention	p. 418
3 Anti-Inflammatory Agents and Antioxidants in Cancer Chemoprevention	p. 421
4 Chromatin Modifiers in Cancer Chemoprevention	p. 425
5 Miscellaneous Agents for Chemoprevention	p. 426
6 Cancer Vaccines	p. 428
References	p. 428
Index	p. 431

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