Transition Metal Complexes as Drugs and Chemotherapeutic Agents

When this book was first conceived as a project the expanding interest in the clinical use of platinum and gold complexes made a survey of the relevant biological properties of metal complexes timely and appropriate. This timeliness has not diminished during the gestation and final publica­ tion of the manuscript. The introduction contains an explanation of the layout and approach to the book, which I wrote as an overall survey of the wide variety of biological properties of metal complexes. Hopefully, the reader will see the parallels in mechanisms and behavior, even in different organisms. The writing was considerably helped by the enthusiasm and confidence (totally unearned on my part) in the project of Professor Brian James and lowe him my special thanks. I also owe a great debt of gratitude to my colleagues, and especially to Eucler Paniago, of the Universidade Federal de Minas Gerais, for their comprehension and for the initial leave of absence which allowed me to begin the project. To those who read some or all of the manuscript and made suggestions, Bernhard Lippert, Kirsten Skov, and Tom Tritton, as well as the editor's reviewer I am also grateful. As usual, the final responsibility for errors or otherwise rests with the author.

Inhalt

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 Meta…