Boron Compounds as Therapeutic

Halki Diabetes Remedy

Diabetes Reversed

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Drugs 19

Geeta Rana, Kamesh Vyakaranam, John A. Maguire and Narayan S. Hosmane

2.1 Boron Neutron Capture Therapy 19

2.2 Classes of Boron Compounds for Potential Use in BNCT 22

2.2.1 DNA binders 22

2.2.2 Boron-containing amino acids and related peptides 24

2.2.3 Boron-containing nucleic acid precursors 27

2.3 Phosphates, Phosphonates and Phosphoramidates 31

2.4 Amines 33

2.5 Boron Analogues of Pyrophosphates 33

2.6 Boronated Polyamines 34

2.7 Carbohydrates 36

2.8 Lipoproteins 36

2.9 Lipids and Phospholipids 37

2.10 Radiation Sensitizers 38

2.11 Cyclic Thiourea Derivatives 38

2.12 Central Nervous System (CNS) Depressants: Promazines, Hydantoins and Barbiturates 39

2.13 Hydantoins and Barbiturates 39

2.14 Oligonucleotide Antisense Agents 40

2.15 Hormones 42

2.16 Liposomes 44

Contents 2.17

Conclusions 45

Acknowledgements 46

References 46

12Mg The Role of Magnesium as a

Metallotherapeutic Drug 51

Pietro Delva

Introduction 51

Magnesium as a Drug 53

3.2.1 Gestational hypertension, preeclampsia and eclampsia 53

3.2.2 Asthma 54

3.2.3 Stroke 55

3.2.4 Acute myocardial infarction 57

3.2.5 Arrhythmias 60

3.2.6 Miscellaneous 61

References 62

13Al Aluminum Metallotherapeutics 65

Thanos Salifoglou

Introduction 65

Adjuvants 66

4.2.3 Aluminum phosphate 69

Antacids 69

4.3.1 Aluminum hydroxide 69

4.3.2 Aluminum glycinate 70

4.3.3 Peptic ulcer disease 70

4.3.4 Bismuth aluminum carbonate 73

4.3.5 Bismuth-magnesium-sodium alumino-silicate 73

Phosphate Binders 73

4.4.1 Basic aluminum carbonate 75

4.4.2 Alumino-silicates 75

4.5 Alginate Raft Formulations 75

4.6 Blistering Diseases in the Elderly 77

4.7 Metabolic Diseases and Aluminum 77

4.8 Anti-malarial Substances 78

4.9 Potential Aluminum Toxicity 79

4.10 Conclusions 80 References 80

5 14Si Biological Activity of Organosilicon Compounds 83

Edmunds Lukevics and Luba Ignatovich

5.1 Introduction 83

5.2 Organosilicon Modification 84

5.2.2 C-Silylation 89

5.3 Sila Analogues 92

5.4 Specific Organosilicon Compounds 94 References 96

6 2ûCa The Role of Calcium as a Metallotherapeutic Drug 109

Mario Barbagallo and Ligia J. Dominguez

6.1 Introduction 109

6.2 Calcium Homeostasis 110

6.3 Hormonal Regulation of Calcium Metabolism 111

6.4 Optimal Amount of Dietary Calcium Intake and Benefits of Calcium Supplementation 112

Contents

,x

6.5

Osteoporosis

115

6.6

Hypertension

116

6.7

Hypertension in Pregnancy and Preeclampsia

118

6.8

Colon Cancer

119

6.9

Weight Control and Regulation of Body Fat

119

6.10

Periodontal Disease

120

6.11

Kidney Stones

121

6.12

Calcium Supplements: Side Effects

121

6.13

Conclusions

122

References

123

7

22Ti Anti-tumor Titanium Drugs

125

m

Erich Dubler

7.1

Introduction

125

7.2

The Biochemistry of Titanium

126

7.3

Titanium Anti-cancer Drugs

127

7.4

Budotitane

130

7.4.1 Chemistry and anti-cancer activity

130

7.4.2 Isomer abundance of budotitane

131

7.4.3 Reaction with biomolecules

133

7.4.4 Animal studies

134

7.4.5 Clinical investigations

134

7.5

Titanocene Dichloride

135

7.5.1 Chemistry and anti-cancer activity

135

7.5.2 Reaction with biomolecules

136

7.5.3 Animal studies

137

7.5.4 Clinical investigations

138

7.5.5 Perspectives of titanocene dichloride

138

7.6 Conclusions 139

Acknowledgements 140

References 140

8 23V Insulin-Mimetic Vanadium-Containing Compounds l43

Jamás Kiss and Jamás Jakusch

8.1 Chemistry of Vanadium 143

8.2 Biological and Medicinal Aspects of Vanadium 144

8.3 The Role of Insulin in Glucose Metabolism 144

8.4 Vanadium Complexes with Biological Activity 145

8.5 Biological Activity and Toxicity of Various Vanadium(IV/V) Compounds 148

8.6 Speciation of VI(IV) Complexes in Biological Fluids 149

8.7 Possible Mechanism for in vivo Vanadium Action 153

8.8 Conclusion iss Acknowledgements 156 References 156

9 25Mn Manganese Metallotherapeutics 159

Jeanne H. Freeland-Graves, Janushree Bose and Abbass Karbassian

9.1 Prevalence in the Environment 159

9.2 Diet and Water 160

9.3 Functions 160

9.4 MnSOD 160

9.5 Deficiency 161

9.5.1 Animals 161

9.5.2 Humans 162

9.6 Toxicity 162

9.7 Therapeutic Manganese-Related Agents 163

9.8 Therapeutic Uses 165

9.8.1 Arthritis 165

9.8.2 Cancer 166

9.8.3 Cardiovascular diseases 167

9.8.4 Dermatitis 168

9.8.5 Diabetes 168

9.8.6 Epilepsy 169

9.8.7 Human immunodeficiency virus 169

9.8.8 Inflammatory pain and response 170

9.8.9 Ischemia and reperfusion injury 171

9.8.10 Osteoporosis 171

9.8.11 Peritoneal adhesions 172

9.8.12 Premenstrual syndrome 172

9.8.13 Shortened life span (premature aging) 173

9.8.14 Other disorders 174

9.9 Magnetic Resonance Imaging (MRI) 174

9.10 Future Implications 175 Acknowledgements 175 References 176

10 26Fe The Use of Iron-Based Drugs in Medicine 179

Xiang Wu and Mei Lin Go

10.1 Introduction 179

10.2 Ferrocene 180

10.3 TMH Ferrocene 181

10.4 Ferrocene in Drug Design 181

10.4.1 Examples where introduction of ferrocene has resulted in a loss or no change in activity 182

10.4.2 Examples where introduction of ferrocene has resulted in enhanced activity or a change in activity profile 183

10.5 Ferrochloroquine 185

10.6 Other Ferrocenyl Anti-plasmodial Agents 191

10.7 Organoiron as Anti-cancer Agents 193

10.8 Conclusions 197 References 198

11 27Co Cobalt Complexes as Potential

Pharmaceutical Agents 201

Hui Chao and Liang-Nian Ji

11.1 Introduction 201

11.2 Enzyme Inhibition/Induction 202

11.2.1 Serine protease inhibitors 202

11.2.2 Topoisomerase II inhibitors 202

11.2.3 Heme oxygenase-1 inducers 203

11.3 Nucleic Acid Binding and Cleavage 204

11.3.1 Cobalt(III) polypyridyl complexes 204

11.3.2 Cobalt(III) bleomycin complexes 206

11.3.3 Cobalt(III) polyamine complexes 208

11.4 Miscellaneous 209

11.4.1 Cobalamin conjugates as drug delivery devices 209

11.4.2 Hypoxic selective agents 211

11.4.3 PET imaging agents 213

11.5 Conclusions 214

Acknowledgements 214

References 214

12 29Cu Chemotherapeutic Copper Compounds 219

Francisco Gonzâlez-VÎlchez and Rosario Vilaplana

12.1 Introduction 219

12.2 Copper-Purine Derivatives Complexes 220

12.3 Copper-Thiosemicarbazone Complexes 223

12.4 Copper-Benzohydroxamic Acid

Complexes 230

12.5 Copper-Imidazole Derivatives Complexes 230

12.6 Copper-Polycarboxylate Complexes 233 Acknowledgements 234 References 235

13 3oZn The Role of Zinc as a Metallotherapeutic Agent 237

Jane V. Higdon and Emily Ho

13.1 Introduction 237

13.2 Functions 237

13.2.1 Catalytic functions 238

13.2.2 Structural functions 238

13.2.3 Regulatory functions 238

13.3 Zinc Deficiency 238

13.3.1 Severe zinc deficiency 239

13.3.2 Mild zinc deficiency 239

13.3.3 Growth retardation 239

13.4

13.5

13.6

13.7

13.8

13.9

13.10

Increased Susceptibility to Infectious Disease 240

13.4.1 Diarrhea 240

13.4.2 Pneumonia 240

13.4.3 Malaria 240

Risk Factors for Zinc Deficiency 241

13.5.1 Dietary factors that decrease zinc absorption 241

13.5.2 Intake recommendations 241

Therapeutic Uses of Zinc 243

13.6.1 Wilson disease 243

13.6.2 Age-related macular degeneration 243

13.6.3 Human immunodeficiency virus

(HIV) infection 243

13.6.4 Type 1 diabetes 244

13.6.5 Wound healing 244

Common Cold 245

13.7.1 Oral zinc 245

13.7.2 Intranasal zinc 245

Zinc Status and Its Relevance to Cancer 245

13.8.1 Zinc deficiency and oxidative stress 246

13.8.2 Zinc and DNA repair 247

13.8.3 Zinc and prostate cancer 249

Safety 251

13.9.1 Toxicity 251

13.9.2 Drug interactions 252

Conclusions 252

References 252

31Ga Therapeutic Gallium

Compounds 259

Lawrence R. Bernstein

Introduction 259

Chemistry and Mechanisms of Action 260

14.2.1 Aqueous biochemistry 260

14.2.2 Gallium and iron 261

14.2.3 Mechanisms of action 264

14.3 Therapeutic Gallium Compounds 265

14.3.1 Gallium nitrate and citrated gallium nitrate 265

14.3.2 Gallium chloride 269

14.3.3 Gallium 8-quinolinolate 269

14.3.4 Gallium maltolate 270

14.3.5 Other gallium compounds 271

Abbreviations Used 273

References 273

15 32Ge Biological Activity of Organogermanium Compounds 279

Edmunds Lukevics and Luba Ignatovich

15.1 Introduction 279

15.2 Biological Activity 282

15.2.1 2-Carboxyethylgermanium sesquioxide 282

15.2.2 Spirogermanium 285

15.2.3 Germatranes 286

15.2.4 Germanium modified organic compounds 288

References 290

16 33As Metallotherapeutic Arsenic Compounds 297

Paul C. Ho

16.1 Introduction 297

16.2 Chemistry of Arsenic 299

16.3 Mechanisms of Action 300

16.3.1 Modulation of PML and PMLRARa genes 301

16.3.2 Induction of intracellular reactive oxygen species (ROS) 302

16.3.3 Collapse of the mitochondrial membrane potential 303

16.3.4 Roles of glutathione 303

16.3.5 Down-regulation of bcl-2 304

16.3.6 Involvement of p53 304

16.3.7 Activation of caspases 305

16.3.8 Other mechanisms of arsenic-induced apoptosis 305

16.4 Pharmacokinetic Profiles 306

16.4.1 Absorption, distribution and excretion 306

16.4.2 Metabolism 306

16.5 Toxic Side Effects of As2O3 307

16.6 Indications and Uses of As2O3 308

16.7 Summary and Conclusions 308 Acknowledgements 309 References 309

17 34Se The Use of Selenium-Based

Drugs in Medicine 313

Michael Carland and Tahli Fenner

17.1 Introduction to Selenium and its Biochemistry 313

17.2 Diseases Associated with Selenium Deficiency 315

17.2.1 Asthma 316

17.2.2 Keshan disease 316

17.2.3 Human immunodeficiency virus (HIV) 317

17.3 Therapeutic Uses of Supranutritional Doses of Selenium 317

17.3.1 Arsenism 317

17.3.2 Cancer prevention 318

17.4 Synthetic Selenium-Containing Therapeutics 321

17.4.1 Anti-oxidants and anti-inflammatory agents 321

17.4.2 Anti-cancer 324

17.4.3 Anti-hypertensives 327

17.4.4 Anti-virals and anti-bacterials 327

17.5 Conclusion 328

References 328

18 43Tc Technetium in Medicine 333

Oyebola O. Sogbein and John F. Valliant

18.1 Overview 333

18.2 Technetium: Historical Accounts and Properties Relevant to Nuclear Medicine 334

18.3 Technetium Radiopharmaceuticals 336

18.3.1 Tc-essential compounds 336

18.3.2 Tc-tagged compounds 338

18.4 Peptide-Targeted Radiopharmaceuticals 343

18.5 Current Areas of Research 344

18.5.1 Bioorganometallic chemistry 344

18.5.2 Tc and solid supports 345

18.5.3 Technetium-94m 349

18.6 Outlook 350 References 352

19 44Ru Perspectives of Ruthenium Complexes in Cancer Therapy 359

Olivier Lentzen, Cécile Moucheron and Andrée Kirsch-De Mesmaeker

19.1 Introduction 359

19.2 Ruthenium Complexes that Mimic Platinum

Drugs 360

19.2.1 Chloro-ammino derivatives 361

19.2.2 Dimethyl-sulfoxide complexes 362

19.2.3 Complexes with mixed chloride and heterocyclic ligands 364

19.3 Design of New Anti-cancer Compounds based on the Photoreactivity of Polyazaaromatic Ruthenium(II) Complexes 365

19.3.1 Energy transfer processes leading to photo-cleavages 367

19.3.2 Photoelectron transfer processes leading to

DNA cleavages 368

19.3.3 Photoelectron transfer processes leading to photoadduct formation 371

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