Metallotherapeutic Drugs and Metal-Based Diagnostic Agents : The Use of Metals in Medicine

There are an astonishing number and variety of roles that metals play in contemporary medicine. This book contains information on the medicinal uses of inorganics, that is, of elements such as boron, lithium, selenium, to name a few, as well as metal-containing species. In keeping with the notion that healthy mammals rely on (bio-essential) metals for the normal functioning of approximately a third of their proteins and enzymes, a large number of drugs are metal-based and considerable effort is being devoted to developing both second- and third-generation drugs as well as generating novel metal-based drugs. While there is no doubt that there is an emphasis on 'Metallotherapeutics' throughout the volume, the use of metals in medicine is not restricted to metal-based drugs. The following are also covered: non-invasive radiopharmaceuticals Magnetic Resonance Imaging (MRI) mineral supplements From the foregoing and, more importantly, from the contents of the various Chapters, the reader will gain an appreciation of the very real role metal-based drugs play in modern medicine and of the considerable effort being devoted to the development of novel complexes with greater efficacy as therapeutic and diagnostic agents. METALLOTHERAPEUTIC DRUGS AND METAL-BASED DIAGNOSTIC AGENTS......Page 3 Contents......Page 7 List of Contributors......Page 28 Preface......Page 39 1.1 Introduction......Page 43 1.2 The Inorganic Chemistry of Lithium......Page 44 1.3.1 The history of lithium therapeutics......Page 45 1.3.2 Lithium and the body......Page 46 1.4.1 Glycogen synthase kinase-3......Page 47 1.4.2 Inositol phosphate signalling......Page 50 1.5.1 Bipolar disorder and schizophrenia......Page 52 1.5.2 Alzheimer’s disease......Page 54 1.5.4 Adverse effects......Page 56 References......Page 57 2.1 Boron Neutron Capture Therapy......Page 61 2.2.1 DNA binders......Page 64 2.2.2 Boron-containing amino acids and related peptides......Page 66 2.2.3 Boron-containing nucleic acid precursors......Page 69 2.3 Phosphates, Phosphonates and Phosphoramidates......Page 73 2.5 Boron Analogues of Pyrophosphates......Page 75 2.6 Boronated Polyamines......Page 76 2.8 Lipoproteins......Page 78 2.9 Lipids and Phospholipids......Page 79 2.11 Cyclic Thiourea Derivatives......Page 80 2.13 Hydantoins and Barbiturates......Page 81 2.14 Oligonucleotide Antisense Agents......Page 82 2.15 Hormones......Page 84 2.16 Liposomes......Page 86 2.17 Conclusions......Page 87 References......Page 88 3.1 Introduction......Page 93 3.2.1 Gestational hypertension, preeclampsia and eclampsia......Page 95 3.2.2 Asthma......Page 96 3.2.3 Stroke......Page 97 3.2.4 Acute myocardial infarction......Page 99 3.2.5 Arrhythmias......Page 102 3.2.6 Miscellaneous......Page 103 References......Page 104 4.1 Introduction......Page 107 4.2.1 Alum......Page 108 4.2.2 Al(OH)(3)......Page 109 4.3.1 Aluminum hydroxide......Page 111 4.3.3 Peptic ulcer disease......Page 112 4.4 Phosphate Binders......Page 115 4.5 Alginate Raft Formulations......Page 117 4.7 Metabolic Diseases and Aluminum......Page 119 4.8 Anti-malarial Substances......Page 120 4.9 Potential Aluminum Toxicity......Page 121 References......Page 122 5.1 Introduction......Page 125 5.2.1 O-, S- and N-Silylation......Page 126 5.2.2 C-Silylation......Page 131 5.3 Sila Analogues......Page 134 5.4 Specific Organosilicon Compounds......Page 136 References......Page 138 6.1 Introduction......Page 151 6.2 Calcium Homeostasis......Page 152 6.3 Hormonal Regulation of Calcium Metabolism......Page 153 6.4 Optimal Amount of Dietary Calcium Intake and Benefits of Calcium Supplementation......Page 154 6.5 Osteoporosis......Page 157 6.6 Hypertension......Page 158 6.7 Hypertension in Pregnancy and Preeclampsia......Page 160 6.9 Weight Control and Regulation of Body Fat......Page 161 6.10 Periodontal Disease......Page 162 6.12 Calcium Supplements: Side Effects......Page 163 6.13 Conclusions......Page 164 References......Page 165 7.1 Introduction......Page 167 7.2 The Biochemistry of Titanium......Page 168 7.3 Titanium Anti-cancer Drugs......Page 169 7.4.1 Chemistry and anti-cancer activity......Page 172 7.4.2 Isomer abundance of budotitane......Page 173 7.4.3 Reaction with biomolecules......Page 175 7.4.5 Clinical investigations......Page 176 7.5.1 Chemistry and anti-cancer activity......Page 177 7.5.2 Reaction with biomolecules......Page 178 7.5.3 Animal studies......Page 179 7.5.5 Perspectives of titanocene dichloride......Page 180 7.6 Conclusions......Page 181 References......Page 182 8.1 Chemistry of Vanadium......Page 185 8.3 The Role of Insulin in Glucose Metabolism......Page 186 8.4 Vanadium Complexes with Biological Activity......Page 187 8.5 Biological Activity and Toxicity of Various Vanadium(IV/V) Compounds......Page 190 8.6 Speciation of VI(IV) Complexes in Biological Fluids......Page 191 8.7 Possible Mechanism for in vivo Vanadium Action......Page 195 8.8 Conclusion......Page 197 References......Page 198 9.1 Prevalence in the Environment......Page 201 9.4 MnSOD......Page 202 9.5.1 Animals......Page 203 9.6 Toxicity......Page 204 9.7 Therapeutic Manganese-Related Agents......Page 205 9.8.1 Arthritis......Page 207 9.8.2 Cancer......Page 208 9.8.3 Cardiovascular diseases......Page 209 9.8.5 Diabetes......Page 210 9.8.7 Human immunodeficiency virus......Page 211 9.8.8 Inflammatory pain and response......Page 212 9.8.10 Osteoporosis......Page 213 9.8.12 Premenstrual syndrome......Page 214 9.8.13 Shortened life span (premature aging)......Page 215 9.9 Magnetic Resonance Imaging (MRI)......Page 216 Acknowledgements......Page 217 References......Page 218 10.1 Introduction......Page 221 10.2 Ferrocene......Page 222 10.4 Ferrocene in Drug Design......Page 223 10.4.1 Examples where introduction of ferrocene has resulted in a loss or no change in activity......Page 224 10.4.2 Examples where introduction of ferrocene has resulted in enhanced activity or a change in activity profile......Page 225 10.5 Ferrochloroquine......Page 227 10.6 Other Ferrocenyl Anti-plasmodial Agents......Page 233 10.7 Organoiron as Anti-cancer Agents......Page 235 10.8 Conclusions......Page 239 References......Page 240 11.1 Introduction......Page 243 11.2.2 Topoisomerase II inhibitors......Page 244 11.2.3 Heme oxygenase-1 inducers......Page 245 11.3.1 Cobalt(III) polypyridyl complexes......Page 246 11.3.2 Cobalt(III) bleomycin complexes......Page 248 11.3.3 Cobalt(III) polyamine complexes......Page 250 11.4.1 Cobalamin conjugates as drug delivery devices......Page 251 11.4.2 Hypoxic selective agents......Page 253 11.4.3 PET imaging agents......Page 255 References......Page 256 12.1 Introduction......Page 261 12.2 Copper-Purine Derivatives Complexes......Page 262 12.3 Copper-Thiosemicarbazone Complexes......Page 265 12.5 Copper-Imidazole Derivatives Complexes......Page 272 12.6 Copper-Polycarboxylate Complexes......Page 275 Acknowledgements......Page 276 References......Page 277 13.2 Functions......Page 279 13.3 Zinc Deficiency......Page 280 13.3.3 Growth retardation......Page 281 13.4.3 Malaria......Page 282 13.5.2 Intake recommendations......Page 283 13.6.3 Human immunodeficiency virus (HIV) infection......Page 285 13.6.5 Wound healing......Page 286 13.8 Zinc Status and Its Relevance to Cancer......Page 287 13.8.1 Zinc deficiency and oxidative stress......Page 288 13.8.2 Zinc and DNA repair......Page 289 13.8.3 Zinc and prostate cancer......Page 291 13.9.1 Toxicity......Page 293 References......Page 294 14.1 Introduction......Page 301 14.2.1 Aqueous biochemistry......Page 302 14.2.2 Gallium and iron......Page 303 14.2.3 Mechanisms of action......Page 306 14.3.1 Gallium nitrate and citrated gallium nitrate......Page 307 14.3.3 Gallium 8-quinolinolate......Page 311 14.3.4 Gallium maltolate......Page 312 14.3.5 Other gallium compounds......Page 313 References......Page 315 15.1 Introduction......Page 321 15.2.1 2-Carboxyethylgermanium sesquioxide......Page 324 15.2.2 Spirogermanium......Page 327 15.2.3 Germatranes......Page 328 15.2.4 Germanium modified organic compounds......Page 330 References......Page 332 16.1 Introduction......Page 339 16.2 Chemistry of Arsenic......Page 341 16.3 Mechanisms of Action......Page 342 16.3.1 Modulation of PML and PML–RARa genes......Page 343 16.3.2 Induction of intracellular reactive oxygen species (ROS)......Page 344 16.3.4 Roles of glutathione......Page 345 16.3.6 Involvement of p53......Page 346 16.3.8 Other mechanisms of arsenic-induced apoptosis......Page 347 16.4.2 Metabolism......Page 348 16.5 Toxic Side Effects of As(2)O(3)......Page 349 16.7 Summary and Conclusions......Page 350 References......Page 351 17.1 Introduction to Selenium and its Biochemistry......Page 355 17.2 Diseases Associated with Selenium Deficiency......Page 357 17.2.2 Keshan disease......Page 358 17.3.1 Arsenism......Page 359 17.3.2 Cancer prevention......Page 360 17.4.1 Anti-oxidants and anti-inflammatory agents......Page 363 17.4.2 Anti-cancer......Page 366 17.4.4 Anti-virals and anti-bacterials......Page 369 References......Page 370 18.1 Overview......Page 375 18.2 Technetium: Historical Accounts and Properties Relevant to Nuclear Medicine......Page 376 18.3.1 Tc-essential compounds......Page 378 18.3.2 Tc-tagged compounds......Page 380 18.4 Peptide-Targeted Radiopharmaceuticals......Page 385 18.5.1 Bioorganometallic chemistry......Page 386 18.5.2 Tc and solid supports......Page 387 18.5.3 Technetium-94m......Page 391 18.6 Outlook......Page 392 References......Page 394 19.1 Introduction......Page 401 19.2 Ruthenium Complexes that Mimic Platinum Drugs......Page 402 19.2.1 Chloro-ammino derivatives......Page 403 19.2.2 Dimethyl-sulfoxide complexes......Page 404 19.2.3 Complexes with mixed chloride and heterocyclic ligands......Page 406 19.3 Design of New Anti-cancer Compounds based on the Photoreactivity of Polyazaaromatic Ruthenium(II) Complexes......Page 407 19.3.1 Energy transfer processes leading to photo-cleavages......Page 409 19.3.2 Photoelectron transfer processes leading to DNA cleavages......Page 410 19.3.3 Photoelectron transfer processes leading to photoadduct formation......Page 413 19.4 Targeting Base Residues of Specific Sequences......Page 415 19.5 Conclusions......Page 417 References......Page 418 20.2 Anti-tumor Activity of Rhodium Complexes......Page 421 20.2.1 Rhodium(I) complexes......Page 422 20.2.2 Rhodium(II) complexes......Page 423 20.2.3 Rhodium(III) complexes......Page 427 20.3 Anti-bacterial and Anti-parasitic Activity......Page 430 20.4 Radiorhodium Agents......Page 432 20.5 Photochemotherapy......Page 433 20.6 Toxicity of Rhodium Complexes......Page 434 References......Page 436 21.1 Introduction......Page 441 21.2.1 Sulfur-donor ligands......Page 442 21.2.2 Metal complexes of drugs used as ligands......Page 446 21.2.3 Palladium(II) complexes with Schiff base ligands......Page 447 21.2.4 Miscellaneous......Page 448 21.3.1 Sulfur-donor ligands......Page 449 21.3.2 Nitrogen and other donor atoms......Page 452 21.4 Concluding Remarks......Page 456 References......Page 457 22.1 Introduction......Page 463 22.3 Anti-tumour Pre-screening......Page 464 22.4 Early In Vitro Cytotoxicity Testing of Diorganotin Carboxylates......Page 465 22.5 The Di-n-Butyltin Analogue of Carboplatin......Page 467 22.6 Anti-tumour Potential of Triorganotin Carboxylates......Page 468 22.7 Anti-tumour Screening of Organotin Derivatives of Biologically Relevant Substrates......Page 469 22.9 Anti-tumour Potential of Boron-Containing Organotin Carboxylates......Page 470 22.10 Anti-tumour Potential of Organotin Carboxylates-Containing Polyoxaalkyl Moieties......Page 472 22.12 Other Therapeutic Potential of Organotin Compounds......Page 473 22.13 Therapeutic Potential of Tin Compounds Without Tin-to-Carbon Bonds......Page 475 References......Page 477 23.2 The Chemistry of Antimony......Page 483 23.3.1 Historic view of antimony drugs......Page 485 23.3.2 Applications of antimony drugs as anti-leishmanial agents......Page 486 23.3.3 Other medicinal applications......Page 487 23.4.1 Pharmacology and human toxicology of antimony drugs......Page 489 23.4.2 Pharmacokinetics studies and clinical aspect of antimony drugs......Page 490 23.5.2 In vitro and in vivo reduction of antimony(V) drugs......Page 491 23.5.3 Interaction of antimony(III) compounds with thiolate molecules......Page 492 23.5.4 Inhibition of topoisomerase I from Leishmania donovani and formation of DNA-protein complexes by Sb(V)......Page 495 23.5.6 Interference of the exclusive purine scavenge pathway of Leishmania......Page 496 23.5.7 Modulation and increase of cellular signaling of the host macrophage as a means of intracellular Leishmania elimination......Page 497 References......Page 499 24.1 Introduction......Page 505 24.2 Synthetic Aspects of Rhenium Radiopharmaceuticals......Page 508 24.3.1 Complexes with oxo-cores......Page 509 24.3.2 Complexes with cores containing metal–nitrogen multiple bonds......Page 514 24.3.3 Complexes of the Re(I) tricarbonyl core......Page 516 24.3.4 Organometallic approaches......Page 521 24.3.5 Miscellaneous approaches......Page 522 24.4.1 Bone-targeting phosphonate complexes......Page 524 24.4.2 [Re(V)-oxo(DMSA)]......Page 525 24.4.3 Rhenium agents for endovascular radiation therapy......Page 526 24.5 Summary......Page 527 References......Page 528 25.1 Introduction, Anti-tumor Activity of Cisplatin......Page 531 25.2 Anti-tumor Activity of Carboplatin, Oxaliplatin and Nedaplatin......Page 532 25.3 Mechanism of Action of Cisplatin......Page 533 25.4 Mechanism of Action of Carboplatin, Oxaliplatin and Nedaplatin......Page 536 25.5 Activation of trans Geometry......Page 537 25.6 Polynuclear Platinum Compounds......Page 540 25.7 Platinum(IV) Compounds......Page 541 25.8 Targeted Analogues......Page 542 25.9 Anti-viral Activity......Page 543 25.11 Conclusions......Page 544 References......Page 545 26.2.1 Physical properties of the element......Page 549 26.2.3 Oxidation states and stereochemistries of gold complexes......Page 550 26.3.1 Historical perspective......Page 552 26.3.2 Gold therapy for rheumatoid arthritis......Page 553 26.4.2 Gold in cells: The thiol-shuttle model......Page 556 26.4.3 Cyanide metabolites......Page 557 26.5.1 Motivation for drug development......Page 558 26.5.2 Anti-tumour properties of gold drugs......Page 559 26.5.4 Auranofin analogues......Page 560 26.5.5 Gold(III) complexes......Page 562 26.6.1 Anti-microbial activity......Page 563 26.6.2 Anti-malaria activity......Page 564 26.6.3 Treatment of bronchial asthma......Page 565 References......Page 566 27.2 Bismuth-Based Therapeutics......Page 571 27.3 Fundamental Aspects of Bismuth Chemistry and Methods of Characterization......Page 572 27.4 Hydroxycarboxylate Complexes of Bismuth......Page 573 27.5 Development of Bioactive Bismuth Compounds......Page 576 27.6 Interactions of Bismuth Compounds with Biological Molecules......Page 579 References......Page 581 28.1 Generalities on Magnetic Resonance Imaging (MRI) and Paramagnetic Contrast Agents......Page 583 28.2 Determinants of the Relaxivity of Paramagnetic Metal Complexes......Page 586 28.3 Responsive Agents......Page 590 28.3.1 pH sensitive agents......Page 591 28.3.2 Agents sensitive to the redox potential......Page 593 28.3.3 Enzyme responsive agents......Page 594 28.4 Targeting Cells with Gd(III) Chelates......Page 596 References......Page 601 Index......Page 603

There are an astonishing number and variety of roles that metals play in contemporary medicine. This book contains information on the medicinal uses of inorganics, that is, of elements such as boron, lithium, selenium, to name a few, as well as metal-containing species.

In keeping with the notion that healthy mammals rely on (bio-essential) metals for the normal functioning of approximately a third of their proteins and enzymes, a large number of drugs are metal-based and considerable effort is being devoted to developing both second- and third-generation drugs as well as generating novel metal-based drugs. While there is no doubt that there is an emphasis on 'Metallotherapeutics' throughout the volume, the use of metals in medicine is not restricted to metal-based drugs. The following are also covered:

• non-invasive radiopharmaceuticals
• Magnetic Resonance Imaging (MRI)
• mineral supplements

From the foregoing and, more importantly, from the contents of the various Chapters, the reader will gain an appreciation of the very real role metal-based drugs play in modern medicine and of the considerable effort being devoted to the development of novel complexes with greater efficacy as therapeutic and diagnostic agents.

"This book contains information on the medicinal uses of inorganics, that is, of elements such as boron, lithium, selenium, to name a few, as well as metal-containing species." "From this book, the reader will gain an appreciation of the very real role metal-based drugs play in modern medicine and of the considerable effort being devoted to the development of novel complexes with greater efficacy as therapeutic and diagnostic agents."--Jacket