TRANSITION METAL COMPLEXES AS DRUGS AND CHEMOTHERAPEUTIC AGENTS

Transcription

1 TRANSITION METAL COMPLEXES AS DRUGS AND CHEMOTHERAPEUTIC AGENTS by NICHOLAS FARRELL The University of Vermont, Burlington, Vermont, U.S.A. KLUWER ACADEMIC PUBLISHERS DORDRECHT/ BOSTON / LONDON

2 CONTENTS PREFACE xii INTRODUCTION 1 Metals in Medicine 2 Chemotherapeutic Agents and Drugs 4 Mechanisms of Toxicity 4 Metal Accumulation and Activation 4 Biochemical Targets for Metal Complexes 5 Summary 6 6 CHAPTER 1. Interaction of Metal Complexes with DNA DNA and Conformation Nucleases and DNA Experimental Methods for the Study of Conformational Changes Ultraviolet Spectroscopy Circular Dichroism and Optical Dispersion Nuclear Magnetic Resonance Hydrodynamic and Light Scattering Properties Binding of Metal Complexes to DNA Intercalation Platinum Terpyridine Complexes Metal (1,10-Phenanthroline) Complexes Porphyrins and Metalloporphyrins Intercalators as Drugs Redox Activity of Metallointercalators Outer Sphere Binding Metal Amine Complexes Inner Sphere (Covalent) Binding Binding of Platinum Amine Complexes 30

3 VI CONTENTS Platinum Amine Complexes and Intercalators Restriction Enzymes and Platinum Complexes Strand Breakage Copper (1,10-phenanthroline) Complexes Cobalt (1,10-phenanthroline) Complexes Iron EDTA (DNA-binder) Complexes Summary CHAPTER 2. Platinum Amine Complexes as Anticancer Agents 2.1. The Discovery of Cisplatin as an Antitumour Agent Clinical Properties of Cisplatin Development of Cisplatin Analogues Clinical trials of Cisplatin Analogues Biochemical Mechanism of Action of Platinum Complexes Biological Effects Implying DNA as Target Biological Effects not Involving DNA Summary CHAPTER 3. Structure Activity Relationships of Platinum Amine Complexes The Requirement for Neutrality Complexes of Pt(IV) Nature of the Leaving Group Bisplatinum Complexes Containing Bridging Dicarboxylates Sulfoxides as Leaving groups Nature of the Nonleaving Group Stereospecific Effects in Amine Complexes Novel and Targeted Approaches to [PtX 2 (am) 2 ] Complexes Ternary Complexes Amines as Carrier Ligands Quantitative Structure Activity Relationships Chemistry of Platinum Amine Complexes Reactions with Biomolecules Other Than DNA Summary 90 90

4 CONTENTS vii CHAPTER 4. Interactions of Platinum Complexes with DNA Components Structural Aspects of Metal Nucleobase Binding Binding in Solution Basicity and ph Hard Soft Relationship of Donor Atom and Metal Ion Steric Effects Including Hydrogen Bonding Base Stacking and Chelation Binding of Platinum Complexes in Solution Reactivity of Platinum Metal Base Complexes Effect of Metallation on Acidity of Noncoordinated Atoms ThePlatinum-N 7,O 6 Chelate Effect of Metallation on C-H Exchange Susceptibility to Oxidation of Metal Base Complexes Reactivity of Nucleoside and Nucleotide Linkages Reactivity of Metal Base Complexes toward Nucleophiles Linkage Isomerization Rotation around Metal Purine Bonds Solid State Structural Studies Structural Studies on Di- and Oligonucleotide Complexes Studies on Dinucleotide Complexes Studies on Trinucleotides Studies on Oligonucleotides Structural Studies on Oligonucleotides Platinum Adducts from DNA Degradation On the Molecular Mechanism of Antitumour Action of Cisplatin Summary CHAPTER 5. The Platinum Pyrimidine Blues Properties of the Platinum Pyrimidine Blues Platinum Blues not Derived from Pyrimidines X-Ray Structure of Platinum Pyrimidine and a- Pyridone Blues Formation of Platinum Pyrimidine and a-pyridone Blues 131

5 viii CONTENTS Monomenc Complexes Dimeric Complexes Complexes of Pt(III) Studies of Crystalline Blues Biological Studies on Platinum Pyrimidine Blue Precursors Summary CHAPTER 6. Antitumour Activity of Metal Complexes 6.1. Platinum Group Metal Complexes Palladium Complexes Rhodium Complexes Studies on Rhodium Carboxylates Ruthenium Complexes Studies on Ruthenium Amine Complexes 6.2. Copper Complexes Bis(Thiosemicarbazone) Complexes Thiosemicarbazone Complexes Nitrogen Chelates Copper Salicylates 6.3. Silver and Gold 6.4. Organometallic Complexes 6.5. Summary CHAPTER 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 Copper Bleomycin Cobalt Bleomycin Manganese Bleomycin 7.4. Mechanism of Action of Bleomycin DNA Bleomycin Interactions Iron and Iron Oxygen Adducts 7.5. Other Metal Binding Antibiotics Anthracyclines Biochemical Aspects of Metal Anthracyclines Streptonigrin 7.6. Summary

6 CONTENTS CHAPTER 8. Metals, Metal Complexes, and Radiation Interaction of Radiation and Biological Tissue Chemical Modification of Radiation Damage Oxygen Mimics and Electron Affinity Metal Complexes as Radiation Sensitizers Radiosensitization by Metal Salts Cobalt Amine Complexes Radiosensitization by Electron Affinity Metal Radiosensitizer Complexes Metal Chelates Potentiation of Radiation Damage by Platinum Amines. Differential Repair Processes Mechanism of Action of Platinum Amine Complexes Radiosensitization by Thiol Depletion Metal Complexes and Radioprotection Metal Complexes as Radioprotectors Activation of Metal Complexes Summary CHAPTER 9. Antibacterial Effects of Metal Complexes Mercury and Silver Salts as Antibacterial Agents Mercury Silver Antibacterial Activity of Chelating Agents and Metal Chelates Antibacterial Activity of Metal Amine Complexes Redox Activity and Antibacterial Activity Summary CHAPTER 10. Antiviral and Antiparasitic Effects of Metal Complexes Antiviral Therapy Chelating Agents and Metal Complexes as Antiviral Agents Chelating Agents Metal (1,10-Phenanthroline) Complexes Platinum and Palladium Amine Complexes Zinc Complexes Other Metal Complexes 10.3 Metal Complexes as Antiprotozoal Agents IX

7 X CONTENTS Metal Complexes in Trypanosomiasis Platinum Amine Complexes as Trypanocides Other Metal Complexes Porphyrins and Metalloporphyrins as Trypanocides. Metal Sequestration Metal Complexes with Trypanocidal Drugs. Dual-Function Agents Metal Complexes in American Trypanosomiasis Summary CHAPTER 11 Metal Complexes in Arthritis Gold Complexes in the Treatment of Rheumatoid Arthritis Activity and Toxicity of Gold Drugs Structures of Gold Complexes Chemistry and Biochemistry of Gold Drugs Mechanism of Action of Gold Drugs Copper in Arthritis Copper Complexes in Arthritis Copper Bracelets Copperand D-Penicillamine Mechanism of Action of Copper Complexes Other Metals Summary CHAPTER 12. Miscellaneous Uses of Metal Complexes Mercurial Diuretics Neuromuscular Effects of Metal Complexes Nitroprusside as Vasodilator Activity and Toxicity of Nitroprusside Mechanism of Action of Nitroprusside Summary NAMES AND ABBREVIATIONS 266 GLOSSARY OF TERMS AND DEFINITIONS 270 APPENDIX 1 274

8 CONTENTS XI APPENDIX INDEX OF SUBJECTS 281