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Ligand Design in Medicinal Inorganic Chemistry

ISBN: 978-1-118-48852-2
472 pages
June 2014
Ligand Design in Medicinal Inorganic Chemistry (1118488520) cover image

Description

Increasing the potency of therapeutic compounds, while limiting side-effects, is a common goal in medicinal chemistry. Ligands that effectively bind metal ions and also include specific features to enhance targeting, reporting, and overall efficacy are driving innovation in areas of disease diagnosis and therapy.

Ligand Design in Medicinal Inorganic Chemistry presents the state-of-the-art in ligand design for medicinal inorganic chemistry applications. Each individual chapter describes and explores the application of compounds that either target a disease site, or are activated by a disease-specific biological process.

Ligand design is discussed in the following areas:

  • Platinum, Ruthenium, and Gold-containing anticancer agents
  • Emissive metal-based optical probes
  • Metal-based antimalarial agents
  • Metal overload disorders
  • Modulation of metal-protein interactions in neurodegenerative diseases
  • Photoactivatable metal complexes and their use in biology and medicine
  • Radiodiagnostic agents and Magnetic Resonance Imaging (MRI) agents
  • Carbohydrate-containing ligands and Schiff-base ligands in Medicinal Inorganic Chemistry
  • Metalloprotein inhibitors

Ligand Design in Medicinal Inorganic Chemistry provides graduate students, industrial chemists and academic researchers with a launching pad for new research in medicinal chemistry.

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Table of Contents

About the Editor xiii

List of Contributors xv

1 Introduction to Ligand Design in Medicinal Inorganic Chemistry 1
Michael R. Jones, Dustin Duncan, and Tim Storr

References 7

2 Platinum-Based Anticancer Agents 9
Alice V. Klein and Trevor W. Hambley

2.1 Introduction 9

2.2 The advent of platinum-based anticancer agents 9

2.3 Strategies for overcoming the limitations of cisplatin 11

2.4 The influence of ligands on the physicochemical properties of platinum anticancer complexes 11

2.4.1 Lipophilicity 11

2.4.2 Reactivity 13

2.4.3 Rate of reduction 14

2.5 Ligands for enhancing the anticancer activity of platinum complexes 15

2.5.1 Ligands for improving DNA affinity 15

2.5.2 Ligands for inhibiting enzymes 17

2.6 Ligands for enhancing the tumour selectivity of platinum complexes 20

2.6.1 Ligands for targeting transporters 21

2.6.2 Ligands for targeting receptors 22

2.6.3 Ligands for targeting the EPR effect 28

2.6.4 Ligands for targeting bone cancer 33

2.7 Ligands for photoactivatable platinum complexes 35

2.8 Conclusions 36

References 37

3 Coordination Chemistry and Ligand Design in the Development of Metal Based Radiopharmaceuticals 47
Eszter Boros, Bernadette V. Marquez, Oluwatayo F. Ikotun, Suzanne E. Lapi, and Cara L.

Ferreira

3.1 Introduction 47

3.1.1 Metals in nuclear medicine 48

3.1.2 The importance of coordination chemistry 49

3.1.3 Overview 50

3.2 General metal based radiopharmaceutical design 50

3.2.1 Choice of radionuclide 50

3.2.2 Production of the radiometal starting materials 51

3.2.3 Ligand and chelate design consideration 51

3.3 Survey of the coordination chemistry of radiometals applicable to nuclear medicine 53

3.3.1 Technetium 53

3.3.2 Rhenium 56

3.3.3 Gallium 57

3.3.4 Indium 60

3.3.5 Yttrium and lanthanides 61

3.3.6 Copper 62

3.3.7 Zirconium 65

3.3.8 Scandium 66

3.3.9 Cobalt 68

3.4 Conclusions 71

References 71

4 Ligand Design in d-Block Optical Imaging Agents and Sensors 81
Mike Coogan

4.1 Summary and scope 81

4.2 Introduction 82

4.2.1 Criteria for biological imaging optical probes 82

4.3 Overview of transition-metal optical probes in biomedicinal applications 83

4.3.1 Common families of transition metal probes 83

4.4 Ligand design for controlling photophysics 87

4.4.1 Photophysical processes in transition metal optical imaging agents and sensors 87

4.4.2 Photophysically active ligand families – tuning electronic levels 87

4.4.3 Ligands which control photophysics through indirect effects 90

4.4.4 Transition metal optical probes with carbonyl ligands 90

4.5 Ligand design for controlling stability 91

4.6 Ligand design for controlling transport and localisation 91

4.6.1 Passive diffusion 91

4.6.2 Active transport 92

4.7 Ligand design for controlling distribution 92

4.7.1 Mitochondrial-targeting probes 92

4.7.2 Nuclear-targeting probes 93

4.7.3 Bioconjugation 94

4.8 Selected examples of ligand design for important individual probes 101

4.8.1 A pH-sensitive ligand to control Ir luminescence 101

4.8.2 Dimeric NHC ligands for gold cyclophanes 102

4.9 Transition metal probes incorporating or capable of more than one imaging mode 103

4.9.1 Bimodal MRI/optical probes 103

4.9.2 Bimodal radio/optical probes 104

4.9.3 Bimodal IR/optical probes 106

4.10 Conclusions and prospects 106

Abbreviations 108

References 108

5 Luminescent Lanthanoid Probes 113
Edward S. O’Neill and Elizabeth J. New

5.1 Introduction 113

5.2 Luminescent probes 114

5.3 The lanthanoids – an overview 116

5.4 Photophysical properties of luminescent lanthanoid complexes 116

5.4.1 The need for a sensitiser 117

5.5 The suitability of lanthanoid complexes as luminescent probes 119

5.6 Modulating chemical properties by ligand design 120

5.6.1 Chemical stability 120

5.6.2 Photophysical properties 122

5.6.3 Analyte response 123

5.7 Modulating biological properties by ligand design 129

5.7.1 Cellular uptake 129

5.7.2 Localisation to desired region of the cell 131

5.7.3 Maintenance of cellular homeostasis 135

5.8 Concluding remarks 138

Acknowledgement 138

References 138

6 Metal Complexes of Carbohydrate-targeted Ligands in Medicinal Inorganic Chemistry 145
Yuji Mikata and Michael Gottschaldt

6.1 Introduction 145

6.2 Radioactive metal complexes bearing a carbohydrate moiety 147

6.3 MRI contrast agents utilizing metal complexes bearing carbohydrate moieties 150

6.4 Fluorescent complexes with carbohydrate-conjugated functions 153

6.5 Carbohydrate-attached photosensitizers for photodynamic therapy (PDT) 157

6.6 Carbohydrate-based metal complexes exhibiting anticancer activity 161

6.7 Carbohydrate-appended metallic nanoparticles, quantum dots, electrodes and surfaces 165

6.8 Concluding remarks 167

References 168

7 Design of Schiff Base-derived Ligands: Applications in Therapeutics and Medical Diagnosis 175
Rafael Pinto Vieira and Heloisa Beraldo

7.1 Introduction 175

7.2 Design of thiosemicarbazones and hydrazones as drug candidates for cancer chemotherapy 176

7.3 Design of bis(thiosemicarbazone) ligands 184

7.3.1 Bis(thiosemicarbazones) and their metal complexes as anticancer agents 184

7.3.2 Design of bis(thiosemicarbazones) as ligands for copper(II) complexes with potential applications in medical diagnosis 186

7.3.3 Design of functionalized bis(thiosemicarbazone) ligands to target selected biological processes 189

7.4 Design of Schiff base-derived ligands as anti-parasitic drug candidates: Applications in the therapeutics of chagas disease 193

7.5 Concluding remarks 197

References 197

8 Metal-based Antimalarial Agents 205
Maribel Navarro and Christophe Biot

8.1 Background 205

8.2 Standard antimalarial chemotherapy 208

8.2.1 Quinoline-based antimalarials 208

8.2.2 Quinoline-based antimalarials target 209

8.2.3 Other standard antimalarial therapies 210

8.3 Metal complexes in malaria 212

8.3.1 Chloroquine as an inter-ligand in the design of metal-based antimalarial agents 212

8.3.2 Chloroquine as an intra-ligand in the design of metal-based antimalarial agents 214

8.3.3 Trioxaquines as a ligand in the design of metal-based antimalarial agents 218

8.3.4 Other standard antimalarial drugs and diverse ligands used in the design of metal-based antimalarial agents 218

8.4 Conclusion 220

Acknowledgements 221

References 221

9 Therapeutic Gold Compounds 227
Susan J. Berners-Price and Peter J. Barnard

9.1 Introduction 227

9.2 Antiarthritic gold drugs 229

9.2.1 Gold (I) thiolates 229

9.2.2 Gold (I) phosphines 229

9.2.3 Design of specific enzyme inhibitors 230

9.3 Gold complexes as anticancer agents 231

9.3.1 Gold(I) compounds 231

9.3.2 Gold (III) compounds 241

9.4 Gold complexes as antiparasitic agents 244

9.4.1 Metal drug synergism 245

9.4.2 Emerging parasite drug targets for gold compounds 245

9.5 Concluding remarks: Design of gold complexes that target specific proteins 246

Acknowledgements 248

References 248

10 Ligand Design to Target and Modulate Metal–Protein Interactions in Neurodegenerative Diseases 257
Michael W. Beck, Amit S. Pithadia, Alaina S. DeToma, Kyle J. Korshavn, and Mi Hee Lim

10.1 Introduction 257

10.1.1 Metals in the brain 257

10.1.2 Aberrant metal–protein interactions 259

10.1.3 Oxidative stress 260

10.2 Neurodegenerative diseases 261

10.2.1 Alzheimer’s disease (AD) 261

10.2.2 Parkinson’s disease (PD) 261

10.2.3 Prion disease 261

10.2.4 Huntington’s disease (HD) 264

10.2.5 Amyotrophic lateral sclerosis (ALS) 264

10.3 Ligand design to target and modulate metal–protein interactions 265

10.3.1 Metal chelating compounds 267

10.3.2 Small molecules designed for metal–protein complexes 269

10.3.3 Other relevant compounds 272

10.3.4 Naturally occurring molecules 273

10.4 Conclusions 274

Abbreviations 275

References 276

11 Rational Design of Copper and Iron Chelators to Treat Wilson’s Disease and Hemochromatosis 287
Christelle Gateau, Elisabeth Mintz, and Pascale Delangle

11.1 Introduction 287

11.2 Chelating agents 288

11.2.1 Thermodynamic parameters 288

11.2.2 Principles of coordination chemistry applied to chelation therapy 289

11.2.3 Examples of classical chelating agents 290

11.3 Modern medicinal inorganic chemistry and chelation therapy 291

11.4 Iron overload 292

11.4.1 Iron distribution and homeostasis 292

11.4.2 Iron overload diseases 294

11.4.3 Fe3+ chelators 295

11.4.4 Current developments 296

11.5 Copper overload in Wilson’s disease 299

11.5.1 Copper metabolism 299

11.5.2 Copper homeostasis 300

11.5.3 Wilson’s disease 303

11.6 Current developments in copper overload treatments 304

11.6.1 From Cu homeostasis understanding to the rational design of drugs 304

11.6.2 Cu+ chelating units inspired from proteins involved in Cu homeostasis 305

11.6.3 Cu+ chelators inspired from metallochaperones 306

11.6.4 Cysteine-rich compounds inspired from metallothioneins 307

11.6.5 Liver-targeting: the ASGP-R 308

11.6.6 Two glycoconjugates that release high affinity Cu chelators in hepatocytes 308

11.7 Conclusion 311

Acknowledgments 312

References 312

12 MRI Contrast Agents 321
Célia S. Bonnet and Éva Tóth

12.1 Introduction to MRI contrast agents 321

12.2 Ligand optimization to increase relaxivity 323

12.2.1 Hydration number 324

12.2.2 Optimization of water exchange kinetics via rational ligand design 325

12.2.3 Optimization of the rotational dynamics via rational ligand design: Size and flexibility 329

12.3 Ligand design for CEST agents 332

12.3.1 Application of paramagnetic ions – PARACEST 333

12.4 Ligand design for responsive probes 333

12.4.1 Probes responsive to pH 334

12.4.2 Probes responsive to physiological cations 338

12.4.3 Probes responsive to enzymes 344

12.5 Conclusions 348

Abbreviations 348

References 348

13 Photoactivatable Metal Complexes and Their Use in Biology and Medicine 355
Tara R. deBoer-Maggard and Pradip K. Mascharak

13.1 Introduction 355

13.2 Cisplatin-inspired photoactivatable chemotherapeutics 358

13.3 Metal-based photosensitizers in photodynamic therapy 360

13.4 Photoinduced interactions of coordination complexes with DNA 362

13.4.1 Photocleavage of DNA with coordination complexes 362

13.4.2 Photoactivatable complexes as antisense agents 364

13.5 Photoactivatable metal complexes that release small bioactive molecules 367

13.6 Conclusion 371

References 372

14 Metalloprotein Inhibitors 375
David P. Martin, David T. Puerta, and Seth M. Cohen

14.1 Metal binding groups in metalloprotein inhibitor design 375

14.2 Thiols, carboxylates, phosphates, and hydroxamates 379

14.3 MBGs related to hydroxamic acids 382

14.4 MBGs related to carboxylic acids 387

14.5 MBGs related to thiols 391

14.6 Amine, alcohol, and carbonyl MBGs 393

14.7 Other MBGs 395

14.8 Conclusion 399

References 401

15 Ruthenium Anticancer Compounds with Biologically-derived Ligands 405
Changhua Mu and Charles J. Walsby

15.1 Introduction 405

15.1.1 Simple coordination complexes 406

15.1.2 Ruthenium(III) complexes with heterocyclic N-donor and/or DMSO ligands 406

15.1.3 Ruthenium(II) arene complexes 408

15.1.4 Polypyridyl complexes 410

15.1.5 Other ruthenium anticancer compounds 411

15.2 Amino acids and amino acid-containing ligands 411

15.3 Peptides and peptide-functionalized ligands 413

15.4 Coordinated proteins as ligands 416

15.5 Carbohydrate-based ligands 419

15.6 Purine, nucleoside, and oligonucleotide ligands 422

15.7 Other selected ruthenium complexes with biological ligands 424

15.7.1 steroids 424

15.7.2 Curcumin – an example of a natural product ligand 425

15.8 Conclusion 426

References 426

Index 439

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