Table of Contents

About The Editors v

Historical Development And Perspectives Of The Series vii

Preface To Volume 19 ix

Contributors To Volume 19 xix

Titles Of Volumes In The Metal Ions In Biological Systems Series xxiii

Contents Of Volumes In The Metal Ions In Life Sciences Series xxv

1 Metals In Medicine: The Therapeutic Use Of Metal Ions In The Clinic Peggy L. Carver 1

Abstract 2

1 Introduction 2

2 Metal-Related Diseases 4

3 Metals as Medicines 5

4 Metal Ion Toxicology 10

5 Concluding Remarks 11

Abbreviations 11

References 11

2 Small Molecules: The Past Or The Future In Drug Innovation? Anne Robert Françoise Benoit-Vical Yan Liu Bernard Meunier 17

Abstract 18

1 Introduction 18

2 Brief Historical Overview of Chemical Drug Development 19

3 Trioxaquines: Antimalarial Hybrid Molecules with a Dual Mode of Action 28

4 Regulation of Copper Homeostasis in Alzheimer's Disease 34

5 General Conclusions 42

Acknowledgments 42

Abbreviations and Definitions 42

References 42

3 Iron Chelation For Iron Overload In Thalassemia Guido Crisponi Valeria M. Nurchi Joanna I. Lachowicz 49

Abstract 50

1 Introduction 50

2 Overview on Thalassemias 51

3 Iron Chelation Therapy 55

4 Chelators in Use 58

5 Combination Therapy 74

6 New Chelators 75

7 Concluding Remarks 79

Acknowledgments 80

Abbreviations and Definitions 80

References 81

4 Ironing Out The Brain Roberta J. Ward Robert R. Crichton 87

Abstract 88

1 Iron Homeostasis in the Brain 88

2 Neurodegenerative Diseases, Disruption of Iron Homeostasis, and Iron Speciation 101

3 Iron and the Immune System 108

4 Iron Chelation Present and Future Directions 112

5 Concluding Remarks 114

Abbreviations 115

References 117

5 Infections Associated With Iron Administration Manfred Nairz Guenter Weiss 123

Abstract 124

1 Introduction 124

2 Iron, Immune Function, and Infection 129

3 Iron Administration and Infection 135

4 Concluding Remarks and Suggestions for Future Research 143

Acknowlegdments 143

Abbreviations 143

References 145

6 Iron Oxide Nanoparticle Formulations For Supplementation Amy Barton Pai 157

Abstract 158

1 Introduction 158

2 Structure and Biodistribution of Intravenous Iron Formulations 159

3 Therapeutic Efficacy in the Dialysis Population 164

4 Adverse Safety Signals 167

5 Concluding Remarks: Gaps in Regulatory Science for Intravenous Iron Formulations 174

Abbreviations 176

References 176

7 Building A Trojan Horse: Siderophore-Drug Conjugates For The Treatment Of Infectious Diseases Elzbieta Gumienna-Kontecka Peggy L. Carver 181

Abstract 182

1 Introduction 182

2 Overview of Siderophores 183

3 Siderophore Antimicrobial Conjugates 191

4 Use of Siderophore-Drug Conjugates to Alter the Spectrum of Activity of an Antimicrobial 197

5 Lessons Learned from the Development of Antibacterial Siderophore Drug Conjugates 198

6 Concluding Remarks 199

Acknowledgment 200

Abbreviations 200

References 200

8 Developing Vanadium As An Antidiabetic Or Anticancer Drug: A Clinical And Historical Perspective Debbie C. Crans LaRee Henry Gabriel Cardiff Barry I. Posner 203

Abstract 204

1 Introduction: Antidiabetic Vanadium-Containing Compounds 204

2 Biological Activities of Vanadium Compounds 209

3 Human Studies with Vanadium Compounds 214

4 Commercialization of Vanadium as Antidiabetic Agent 219

5 What is Next? 221

6 Conclusions and Outlook 224

Acknowledgment 225

Abbreviations 225

References 225

9 Chromium Supplementation In Human Health, Metabolic Syndrome, And Diabetes Wolfgang Maret 231

Abstract 232

1 The Nature of Essential Chemical Elements 232

2 Chromium in Mammalian Biology 235

3 Redox and Coordination Chemistry of Chromium Relevant to Biology 237

4 Chromium Metabolism 239

5 Low-Molecular-Weight Biological Chromium Complexes 240

6 Chromium Toxicity 241

7 Chromium in Diabetes and Metabolic Syndrome 243

8 Possible Resolution of Controversies in Chromium Biology 246

Acknowledgment 248

Abbreviations 248

References 248

10 Manganese: Its Role In Disease And Health Keith M. Erikson Michael Aschner 253

Abstract 254

1 Introduction 254

2 Manganese Essentiality 255

3 Factors Involved in Manganese Status 257

4 Manganese Neurotoxicity 260

5 Conclusions 262

Acknowledgment 262

Abbreviations 262

References 263

11 Cobalt-Schief Base Complexes: Preclinical Research And Potential Therapeutic Uses Elizabeth A. Bajema Kaleigh F. Roberts Thomas J. Meade 267

Abstract 268

1 Introduction 268

2 Antimicrobial Activity 269

3 Antiviral Activity 275

4 Anticancer Activity 276

5 Inhibiting Aggregation of Amyloid-β 284

6 Conclusions 293

Acknowledgments 294

Abbreviations and Definitions 294

References 295

12 Copper Depletion As A Therapeutic Strategy In Cancer Jay Lopez Divya Ramchandani Linda Vahdat 303

Abstract 304

1 Introduction 304

2 Metals 304

3 Copper Homeostasis in Pathophysiology 307

4 Copper in Cancer 309

5 Preclinical Studies 314

6 Clinical Trials of Copper Depletion in Cancer 318

7 Concluding Remarks and Future Directions 320

Acknowledgments 320

Abbreviations 321

References 322

13 Metal Compounds In The Development Of Antiparasitic Agents: Rational Design From Basic Chemistry To The Clinic Dinorah Cambino Lucía Otero 331

Abstract 332

1 Introduction 332

2 Rational Design of Prospective Agents 337

3 Identification and Validation of Parasite Targets 347

4 Metallomics in Parasites 349

5 Preclinical Studies 350

6 Concluding Remarks and Perspectives 352

Acknowledgments 353

Abbreviations 353

References 354

14 Chemical And Clinical Aspects Of Metal-Containing Antidotes For Poisoning By Cyanide Sigridur G. Suman Johanna M. Gretarsdottir 359

Abstract 360

1 Introduction 360

2 Naturally Occuring Cyanide 362

3 Poisoning by Cyanide 367

4 Metal-Containing Antidotes 372

5 Concluding Remarks 385

Acknowledgment 386

Abbreviations and Definitions 386

References 386

Subject Index 393