Transition Metal Complexes as Drugs and Chemotherapeutic Agents

Metals in Medicine.- Chemotherapeutic Agents and Drugs.- Mechanisms of Toxicity.- Metal Accumulation and Activation.- Biochemical Targets for Metal Complexes.- Summary.- References.- 1. Interaction of Metal Complexes with DNA.- 1.1. DNA and Conformation.- 1.1.1. Nucleases and DNA.- 1.2. Experimental Methods for the Study of Conformational Changes.- 1.2.1. Uvltraviolet Spectroscopy.- 1.2.2. Circular Dichroism and Optical Dispersion.- 1.2.3. Nuclear Magnetic Resonance.- 1.2.4. Hydrodynamic and Light Scattering Properties.- 1.3. Binding of Metal Complexes to DNA.- 1.3.1. Intercalation.- 1.3.1.1. Platinum—Terpyridine Complexes.- 1.3.1.2. Metal—(1, 10-Phenanthroline) Complexes.- 1.3.1.3. Porphyrins and Metalloporphyrins.- 1.3.1.4. Intercalators as Drugs.- 1.3.1.5. Redox Activity of Metallointercalators.- 1.3.2. Outer Sphere Binding.- 1.3.2.1. Metal—Amine Complexes.- 1.3.3. Inner Sphere (Covalent) Binding.- 1.3.3.1. Binding of Platinum—Amine Complexes.- 1.3.3.2. Platinum—Amine Complexes and Intercalators.- 1.3.3.3. Restriction Enzymes and Platinum Complexes.- 1.3.4. Strand Breakage.- 1.3.4.1. Copper—(1, 10-phenanthroline) Complexes.- 1.3.4.2. Cobalt—(1, 10-phenanthroline) Complexes.- 1.3.4.3. Iron—EDTA—(DNA-binder) Complexes.- 1.4. Summary.- References.- 2. Platinum—Amine Complexes as Anticancer Agents.- 2.1. The Discovery of Cisplatin as an Antitumour Agent.- 2.2. Clinical Properties of Cisplatin.- 2.3. Development of Cisplatin Analogues.- 2.3.1. Clinical trials of Cisplatin Analogues.- 2.4. Biochemical Mechanism of Action of Platinum Complexes.- 2.4.1. Biological Effects Implying DNA as Target.- 2.4.2. Biological Effects not Involving DNA.- 2.5. Summary.- References.- 3. Structure—Activity Relationships of Platinum— Amine Complexes.- 3.1. The Requirement for Neutrality.- 3.2. Complexes of Pt(IV).- 3.3. Nature of the Leaving Group.- 3.3.1. Bisplatinum Complexes Containing Bridging Dicarboxylates.- 3.3.2. Sulfoxides as Leaving groups.- 3.4. Nature of the Nonleaving Group.- 3.4.1. Stereospecific Effects in Amine Complexes.- 3.5. Novel and Targeted Approaches to [PtX2(am)2] Complexes.- 3.5.1. Ternary Complexes.- 3.5.2. Amines as Carrier Ligands.- 3.6. Quantitative Structure—Activity Relationships.- 3.7. Chemistry of Platinum—Amine Complexes.- 3.7.1. Reactions with Biomolecules Other Than DNA.- 3.8. Summary.- References.- 4. Interactions of Platinum Complexes with DNA Components.- 4.1. Structural Aspects of Metal—Nucleobase Binding.- 4.1.1. Binding in Solution.- 4.1.1.1. Basicity and pH.- 4.1.1.2. Hard—Soft Relationship of Donor Atom and Metal Ion.- 4.1.1.3. Steric Effects Including Hydrogen Bonding.- 4.1.1.4. Base Stacking and Chelation.- 4.1.2. Binding of Platinum Complexes in Solution.- 4.2. Reactivity of Platinum Metal—Base Complexes.- 4.2.1. Effect of Metallation on Acidity of Noncoordinated Atoms.- 4.2.1.1. The Platinum—N7, O6 Chelate.- 4.2.2. Effect of Metallation on C—H Exchange.- 4.2.3. Susceptibility to Oxidation of Metal—Base Complexes.- 4.2.4. Reactivity of Nucleoside and Nucleotide Linkages.- 4.2.5. Reactivity of Metal—Base Complexes toward Nucleophiles.- 4.2.6. Linkage Isomerization.- 4.2.7. Rotation around Metal—Purine Bonds.- 4.3. Solid State Structural Studies.- 4.4. Structural Studies on Di- and Oligonucleotide Complexes.- 4.4.1. Studies on Dinucleotide Complexes.- 4.4.2. Studies on Trinucleotides.- 4.4.3. Studies on Oligonucleotides.- 4.4.3.1. Structural Studies on Oligonucleotides.- 4.5. Platinum Adducts from DNA Degradation.- 4.6. On the Molecular Mechanism of Antitumour Action of Cisplatin.- 4.7. Summary.- References.- 5. The Platinum—Pyrimidine Blues.- 5.1. Properties of the Platinum—Pyrimidine Blues.- 5.2. Platinum Blues not Derived from Pyrimidines.- 5.3. X-Ray Structure of Platinum—Pyrimidine and ?-Pyridone Blues.- 5.4. Formation of Platinum—Pyrimidine and ?-Pyridone Blues.- 5.4.1. Monomeric Complexes.- 5.4.2. Dimeric Complexes.- 5.4.3. Complexes of Pt(III).- 5.5. Studies of Crystalline Blues.- 5.6. Biological Studies on Platinum—Pyrimidine Blue Precursors.- 5.7. Summary.- References.- 6. Antitumour Activity of Metal Complexes.- 6.1. Platinum Group Metal Complexes.- 6.1.1. Palladium Complexes.- 6.1.2. Rhodium Complexes.- 6.1.2.1. Studies on Rhodium Carboxylates.- 6.1.3. Ruthenium Complexes.- 6.1.3.1. Studies on Ruthenium—Amine Complexes.- 6.2. Copper Complexes.- 6.2.1. Bis(Thiosemicarbazone) Complexes.- 6.2.2. Thiosemicarbazone Complexes.- 6.2.3. Nitrogen Chelates.- 6.2.4. Copper Salicylates.- 6.3. Silver and Gold.- 6.4. Organometallic Complexes.- 6.5. Summary.- References.- 7. Metal-Mediated Antibiotic Action.- 7.1. Discovery and Pharmacology of Bleomycin.- 7.2. Structure of Bleomycin and Analogues.- 7.3. Metal Complexes of Bleomycin.- 7.3.1. Copper Bleomycin.- 7.3.2. Cobalt Bleomycin.- 7.3.3. Manganese Bleomycin.- 7.4. Mechanism of Action of Bleomycin.- 7.4.1. DNA—Bleomycin Interactions.- 7.4.2. Iron and Iron—Oxygen Adducts.- 7.5. Other Metal Binding Antibiotics.- 7.5.1. Anthracyclines.- 7.5.1.1. Biochemical Aspects of Metal—Anthracyclines.- 7.5.2. Streptonigrin.- 7.6. Summary.- References.- 8. Metals, Metal Complexes, and Radiation.- 8.1. Interaction of Radiation and Biological Tissue.- 8.2. Chemical Modification of Radiation Damage.- 8.2.1. Oxygen Mimics and Electron Affinity.- 8.3. Metal Complexes as Radiation Sensitizers.- 8.3.1. Radiosensitization by Metal Salts.- 8.3.2. Cobalt—Amine Complexes.- 8.3.3. Radiosensitization by Electron Affinity.- 8.3.3.1. Metal—Radiosensitizer Complexes.- 8.3.3.2. Metal Chelates.- 8.3.4. Potentiation of Radiation Damage by Platinum—Amines. Differential Repair Processes.- 8.3.4.1. Mechanism of Action of Platinum—Amine Complexes.- 8.3.5. Radiosensitization by Thiol Depletion.- 8.4. Metal Complexes and Radioprotection.- 8.4.1. Metal Complexes as Radioprotectors.- 8.5. Activation of Metal Complexes.- 8.6. Summary.- References.- 9. Antibacterial Effects of Metal Complexes.- 9.1. Mercury and Silver Salts as Antibacterial Agents.- 9.1.1. Mercury.- 9.1.2. Silver.- 9.2. Antibacterial Activity of Chelating Agents and Metal Chelates.- 9.3. Antibacterial Activity of Metal—Amine Complexes.- 9.4. Redox Activity and Antibacterial Activity.- 9.5. Summary.- References.- 10. Antiviral and Antiparasitic Effects of Metal Complexes.- 10.1. Antiviral Therapy.- 10.2. Chelating Agents and Metal Complexes as Antiviral Agents.- 10.2.1. Chelating Agents.- 10.2.2. Metal—(1, 10-Phenanthroline) Complexes.- 10.2.3. Platinum— and Palladium—Amine Complexes.- 10.2.4. Zinc Complexes.- 10.2.5. Other Metal Complexes.- 10.3 Metal Complexes as Antiprotozoal Agents.- 10.3.1. Metal Complexes in Trypanosomiasis.- 10.3.2. Platinum—Amine Complexes as Trypanocides.- 10.3.3. Other Metal Complexes.- 10.3.4. Porphyrins and Metalloporphyrins as Trypanocides. Metal Sequestration.- 10.3.5. Metal Complexes with Trypanocidal Drugs. Dual-Function Agents.- 10.3.6. Metal Complexes in American Trypanosomiasis.- 10.4. Summary.- References.- 11 Metal Complexes in Arthritis.- 11.1. Gold Complexes in the Treatment of Rheumatoid Arthritis.- 11.1.1. Activity and Toxicity of Gold Drugs.- 11.1.2. Structures of Gold Complexes.- 11.1.3. Chemistry and Biochemistry of Gold Drugs.- 11.1.4. Mechanism of Action of Gold Drugs.- 11.2. Copper in Arthritis.- 11.2.1. Copper Complexes in Arthritis.- 11.2.2. Copper Bracelets.- 11.2.3. Copper and D-Penicillamine.- 11.2.4. Mechanism of Action of Copper Complexes.- 11.3. Other Metals.- 11.4. Summary.- References.- 12. Miscellaneous Uses of Metal Complexes.- 12.1. Mercurial Diuretics.- 12.2. Neuromuscular Effects of Metal Complexes.- 12.3. Nitroprusside as Vasodilator.- 12.3.1. Activity and Toxicity of Nitroprusside.- 12.3.2. Mechanism of Action of Nitroprusside.- 12.4. Summary.- References.- Names and Abbreviations.- Glossary of Terms and Definitions.- Appendix 1.- Appendix 2.- Index of Subjects.