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
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 8 1.1. DNA and Conformation 10 1.1.1. Nucleases and DNA 14 1.2. Experimental Methods for the Study of Conformational Changes 16 1.2.1. Ultraviolet Spectroscopy 16 1.2.2. Circular Dichroism and Optical Dispersion 16 1.2.3. Nuclear Magnetic Resonance. 17 1.2.4. Hydrodynamic and Light Scattering Properties 17 1.3. Binding of Metal Complexes to DNA 17 1.3.1. Intercalation 18 1.3.1.1. Platinum Terpyridine Complexes 20 1.3.1.2. Metal (1,10-Phenanthroline) Complexes 22 1.3.1.3. Porphyrins and Metalloporphyrins 24 1.3.1.4. Intercalators as Drugs 25 1.3.1.5. Redox Activity of Metallointercalators 26 1.3.2. Outer Sphere Binding 27 1.3.2.1. Metal Amine Complexes 27 1.3.3. Inner Sphere (Covalent) Binding 29 1.3.3.1. Binding of Platinum Amine Complexes 30
VI CONTENTS 1.3.3.2. Platinum Amine Complexes and Intercalators 33 1.3.3.3. Restriction Enzymes and Platinum Complexes 35 1.3.4. Strand Breakage 36 1.3.4.1. Copper (1,10-phenanthroline) Complexes 36 1.3.4.2. Cobalt (1,10-phenanthroline) Complexes 37 1.3.4.3. Iron EDTA (DNA-binder) Complexes 37 1.4. Summary 40 40 CHAPTER 2. Platinum Amine Complexes as Anticancer Agents 2.1. The Discovery of Cisplatin as an Antitumour Agent 46 2.2. Clinical Properties of Cisplatin 49 2.3. Development of Cisplatin Analogues 54 2.3.1. Clinical trials of Cisplatin Analogues 58 2.4. Biochemical Mechanism of Action of Platinum Complexes 59 2.4.1. Biological Effects Implying DNA as Target 60 2.4.2. Biological Effects not Involving DNA 62 2.5. Summary 62 63 CHAPTER 3. Structure Activity Relationships of Platinum Amine Complexes 67 3.1. The Requirement for Neutrality 68 3.2. Complexes of Pt(IV) 70 3.3. Nature of the Leaving Group 72 3.3.1. Bisplatinum Complexes Containing Bridging Dicarboxylates 74 3.3.2. Sulfoxides as Leaving groups 74 3.4. Nature of the Nonleaving Group 76 3.4.1. Stereospecific Effects in Amine Complexes 77 3.5. Novel and Targeted Approaches to [PtX 2 (am) 2 ] Complexes 80 3.5.1. Ternary Complexes 80 3.5.2. Amines as Carrier Ligands 82 3.6. Quantitative Structure Activity Relationships 84 3.7. Chemistry of Platinum Amine Complexes 85 3.7.1. Reactions with Biomolecules Other Than DNA 88 3.8. Summary 90 90
CONTENTS vii CHAPTER 4. Interactions of Platinum Complexes with DNA Components 95 4.1. Structural Aspects of Metal Nucleobase Binding 95 4.1.1. Binding in Solution 96 4.1.1.1. Basicity and ph 96 4.1.1.2. Hard Soft Relationship of Donor Atom and Metal Ion 96 4.1.1.3. Steric Effects Including Hydrogen Bonding 97 4.1.1.4. Base Stacking and Chelation 97 4.1.2. Binding of Platinum Complexes in Solution 97 4.2. Reactivity of Platinum Metal Base Complexes 100 4.2.1. Effect of Metallation on Acidity of Noncoordinated Atoms 101 4.2.1.1. ThePlatinum-N 7,O 6 Chelate 102 4.2.2. Effect of Metallation on C-H Exchange 102 4.2.3. Susceptibility to Oxidation of Metal Base Complexes 103 4.2.4. Reactivity of Nucleoside and Nucleotide Linkages 104 4.2.5. Reactivity of Metal Base Complexes toward Nucleophiles 104 4.2.6. Linkage Isomerization 105 4.2.7. Rotation around Metal Purine Bonds 106 4.3. Solid State Structural Studies 106 4.4. Structural Studies on Di- and Oligonucleotide Complexes 110 4.4.1. Studies on Dinucleotide Complexes 110 4.4.2. Studies on Trinucleotides 113 4.4.3. Studies on Oligonucleotides 114 4.4.3.1. Structural Studies on Oligonucleotides 115 4.5. Platinum Adducts from DNA Degradation 117 4.6. On the Molecular Mechanism of Antitumour Action of Cisplatin 118 4.7. Summary 121 121 CHAPTER 5. The Platinum Pyrimidine Blues 127 5.1. Properties of the Platinum Pyrimidine Blues 127 5.2. Platinum Blues not Derived from Pyrimidines 128 5.3. X-Ray Structure of Platinum Pyrimidine and a- Pyridone Blues 128 5.4. Formation of Platinum Pyrimidine and a-pyridone Blues 131
viii CONTENTS 5.4.1. 5.4.2. 5.4.3. 5.5. 5.6. 5.7. 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 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 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 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 131 133 136 138 138 139 139 142 143 144 144 145 147 150 151 151 153 155 155 157 160 163 163 168 168 169 170 171 171 172 172 173 173 175 176 177 178 179 179
CONTENTS CHAPTER 8. Metals, Metal Complexes, and Radiation 8.1. 8.2. 8.2.1. 8.3. 8.3.1. 8.3.2. 8.3.3. 8.3.3.1. 8.3.3.2. 8.3.4. 8.3.4.1. 8.3.5. 8.4. 8.4.1. 8.5. 8.6. 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 9.1. 9.1.1. 9.1.2. 9.2. 9.3. 9.4. 9.5. 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 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 IX 183 183 187 188 190 190 192 193 193 196 197 198 200 201 201 202 203 204 208 209 209 211 214 217 219 219 220 222 222 225 225 226 226 228 229 230
X CONTENTS 10.3.1. Metal Complexes in Trypanosomiasis 231 10.3.2. Platinum Amine Complexes as Trypanocides 232 10.3.3. Other Metal Complexes 233 10.3.4. Porphyrins and Metalloporphyrins as Trypanocides. Metal Sequestration 234 10.3.5. Metal Complexes with Trypanocidal Drugs. Dual-Function Agents 236 10.3.6. Metal Complexes in American Trypanosomiasis 238 10.4. Summary 239 239 CHAPTER 11 Metal Complexes in Arthritis 243 11.1. Gold Complexes in the Treatment of Rheumatoid Arthritis 243 11.1.1. Activity and Toxicity of Gold Drugs 244 11.1.2. Structures of Gold Complexes 245 11.1.3. Chemistry and Biochemistry of Gold Drugs 246 11.1.4. Mechanism of Action of Gold Drugs 247 11.2. Copper in Arthritis 248 11.2.1. Copper Complexes in Arthritis 249 11.2.2. Copper Bracelets 250 11.2.3. Copperand D-Penicillamine 250 11.2.4. Mechanism of Action of Copper Complexes 251 11.3. Other Metals 252 11.4. Summary 252 253 CHAPTER 12. Miscellaneous Uses of Metal Complexes 257 12.1. Mercurial Diuretics 257 12.2. Neuromuscular Effects of Metal Complexes 259 12.3. Nitroprusside as Vasodilator 261 12.3.1. Activity and Toxicity of Nitroprusside 261 12.3.2. Mechanism of Action of Nitroprusside 262 12.4. Summary 263 263 NAMES AND ABBREVIATIONS 266 GLOSSARY OF TERMS AND DEFINITIONS 270 APPENDIX 1 274
CONTENTS XI APPENDIX 2 279 INDEX OF SUBJECTS 281