Ligand Design in Medicinal Inorganic Chemistry

Ligand Design in Medicinal InorganicChemistry

Edited by

TIM STORRDepartment of Chemistry, Simon Fraser University, Burnaby, BC V5A-1S6, Canada

This edition first published 2014© 2014 John Wiley & Sons, Ltd

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Library of Congress Cataloging-in-Publication Data

Ligand design in medicinal inorganic chemistry / editor, Tim Storr.pages cm

Includes bibliographical references and index.ISBN 978-1-118-48852-2 (cloth)

1. DNA-drug interactions. 2. Ligand binding (Biochemistry) 3. Drugs–Design. 4. Pharmaceutical chemistry. I. Storr, Tim, editor of compilation.QP624.75.D77L54 2014612′.01524 – dc23

2013049102

A catalogue record for this book is available from the British Library.

ISBN: 9781118488522

Typeset in 10/12pt TimesLTStd by Laserwords Private Limited, Chennai, India

1 2014

Contents

About the Editor xiiiList of Contributors xv

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

References 7

2 Platinum-Based Anticancer Agents 9Alice V. Klein and Trevor W. Hambley2.1 Introduction 92.2 The advent of platinum-based anticancer agents 92.3 Strategies for overcoming the limitations of cisplatin 112.4 The influence of ligands on the physicochemical properties of platinum

anticancer complexes 112.4.1 Lipophilicity 112.4.2 Reactivity 132.4.3 Rate of reduction 14

2.5 Ligands for enhancing the anticancer activity of platinum complexes 152.5.1 Ligands for improving DNA affinity 152.5.2 Ligands for inhibiting enzymes 17

2.6 Ligands for enhancing the tumour selectivity of platinum complexes 202.6.1 Ligands for targeting transporters 212.6.2 Ligands for targeting receptors 222.6.3 Ligands for targeting the EPR effect 282.6.4 Ligands for targeting bone cancer 33

2.7 Ligands for photoactivatable platinum complexes 352.8 Conclusions 36

References 37

3 Coordination Chemistry and Ligand Design in the Development of Metal BasedRadiopharmaceuticals 47Eszter Boros, Bernadette V. Marquez, Oluwatayo F. Ikotun, Suzanne E. Lapi, and Cara L.Ferreira3.1 Introduction 47

3.1.1 Metals in nuclear medicine 483.1.2 The importance of coordination chemistry 493.1.3 Overview 50

vi Contents

3.2 General metal based radiopharmaceutical design 503.2.1 Choice of radionuclide 503.2.2 Production of the radiometal starting materials 513.2.3 Ligand and chelate design consideration 51

3.3 Survey of the coordination chemistry of radiometals applicable to nuclear medicine 533.3.1 Technetium 533.3.2 Rhenium 563.3.3 Gallium 573.3.4 Indium 603.3.5 Yttrium and lanthanides 613.3.6 Copper 623.3.7 Zirconium 653.3.8 Scandium 663.3.9 Cobalt 68

3.4 Conclusions 71References 71

4 Ligand Design in d-Block Optical Imaging Agents and Sensors 81Mike Coogan4.1 Summary and scope 814.2 Introduction 82

4.2.1 Criteria for biological imaging optical probes 824.3 Overview of transition-metal optical probes in biomedicinal applications 83

4.3.1 Common families of transition metal probes 834.4 Ligand design for controlling photophysics 87

4.4.1 Photophysical processes in transition metal optical imaging agents and sensors 874.4.2 Photophysically active ligand families – tuning electronic levels 874.4.3 Ligands which control photophysics through indirect effects 904.4.4 Transition metal optical probes with carbonyl ligands 90

4.5 Ligand design for controlling stability 914.6 Ligand design for controlling transport and localisation 91

4.6.1 Passive diffusion 914.6.2 Active transport 92

4.7 Ligand design for controlling distribution 924.7.1 Mitochondrial-targeting probes 924.7.2 Nuclear-targeting probes 934.7.3 Bioconjugation 94

4.8 Selected examples of ligand design for important individual probes 1014.8.1 A pH-sensitive ligand to control Ir luminescence 1014.8.2 Dimeric NHC ligands for gold cyclophanes 102

4.9 Transition metal probes incorporating or capable of more than one imaging mode 1034.9.1 Bimodal MRI/optical probes 1034.9.2 Bimodal radio/optical probes 1044.9.3 Bimodal IR/optical probes 106

4.10 Conclusions and prospects 106Abbreviations 108References 108

Contents vii

5 Luminescent Lanthanoid Probes 113Edward S. O’Neill and Elizabeth J. New5.1 Introduction 1135.2 Luminescent probes 1145.3 The lanthanoids – an overview 1165.4 Photophysical properties of luminescent lanthanoid complexes 116

5.4.1 The need for a sensitiser 1175.5 The suitability of lanthanoid complexes as luminescent probes 1195.6 Modulating chemical properties by ligand design 120

5.6.1 Chemical stability 1205.6.2 Photophysical properties 1225.6.3 Analyte response 123

5.7 Modulating biological properties by ligand design 1295.7.1 Cellular uptake 1295.7.2 Localisation to desired region of the cell 1315.7.3 Maintenance of cellular homeostasis 135

5.8 Concluding remarks 138Acknowledgement 138References 138

6 Metal Complexes of Carbohydrate-targeted Ligands in Medicinal InorganicChemistry 145Yuji Mikata and Michael Gottschaldt6.1 Introduction 1456.2 Radioactive metal complexes bearing a carbohydrate moiety 1476.3 MRI contrast agents utilizing metal complexes bearing carbohydrate moieties 1506.4 Fluorescent complexes with carbohydrate-conjugated functions 1536.5 Carbohydrate-attached photosensitizers for photodynamic therapy (PDT) 1576.6 Carbohydrate-based metal complexes exhibiting anticancer activity 1616.7 Carbohydrate-appended metallic nanoparticles, quantum dots, electrodes and surfaces 1656.8 Concluding remarks 167

References 168

7 Design of Schiff Base-derived Ligands: Applications in Therapeutics and MedicalDiagnosis 175Rafael Pinto Vieira and Heloisa Beraldo7.1 Introduction 1757.2 Design of thiosemicarbazones and hydrazones as drug candidates for cancer

chemotherapy 1767.3 Design of bis(thiosemicarbazone) ligands 184

7.3.1 Bis(thiosemicarbazones) and their metal complexes as anticancer agents 1847.3.2 Design of bis(thiosemicarbazones) as ligands for copper(II) complexes with

potential applications in medical diagnosis 1867.3.3 Design of functionalized bis(thiosemicarbazone) ligands to target selected bio-

logical processes 1897.4 Design of Schiff base-derived ligands as anti-parasitic drug candidates: Applications in

the therapeutics of chagas disease 193

viii Contents

7.5 Concluding remarks 197References 197

8 Metal-based Antimalarial Agents 205Maribel Navarro and Christophe Biot8.1 Background 2058.2 Standard antimalarial chemotherapy 208

8.2.1 Quinoline-based antimalarials 2088.2.2 Quinoline-based antimalarials target 2098.2.3 Other standard antimalarial therapies 210

8.3 Metal complexes in malaria 2128.3.1 Chloroquine as an inter-ligand in the design of metal-based antimalarial agents 2128.3.2 Chloroquine as an intra-ligand in the design of metal-based antimalarial agents 2148.3.3 Trioxaquines as a ligand in the design of metal-based antimalarial agents 2188.3.4 Other standard antimalarial drugs and diverse ligands used in the design

of metal-based antimalarial agents 2188.4 Conclusion 220

Acknowledgements 221References 221

9 Therapeutic Gold Compounds 227Susan J. Berners-Price and Peter J. Barnard9.1 Introduction 2279.2 Antiarthritic gold drugs 229

9.2.1 Gold (I) thiolates 2299.2.2 Gold (I) phosphines 2299.2.3 Design of specific enzyme inhibitors 230

9.3 Gold complexes as anticancer agents 2319.3.1 Gold(I) compounds 2319.3.2 Gold (III) compounds 241

9.4 Gold complexes as antiparasitic agents 2449.4.1 Metal drug synergism 2459.4.2 Emerging parasite drug targets for gold compounds 245

9.5 Concluding remarks: Design of gold complexes that target specific proteins 246Acknowledgements 248References 248

10 Ligand Design to Target and Modulate Metal–Protein Interactions in NeurodegenerativeDiseases 257Michael W. Beck, Amit S. Pithadia, Alaina S. DeToma, Kyle J. Korshavn, and Mi Hee Lim10.1 Introduction 257

10.1.1 Metals in the brain 25710.1.2 Aberrant metal–protein interactions 25910.1.3 Oxidative stress 260

10.2 Neurodegenerative diseases 26110.2.1 Alzheimer’s disease (AD) 26110.2.2 Parkinson’s disease (PD) 261

Contents ix

10.2.3 Prion disease 26110.2.4 Huntington’s disease (HD) 26410.2.5 Amyotrophic lateral sclerosis (ALS) 264

10.3 Ligand design to target and modulate metal–protein interactions 26510.3.1 Metal chelating compounds 26710.3.2 Small molecules designed for metal–protein complexes 26910.3.3 Other relevant compounds 27210.3.4 Naturally occurring molecules 273

10.4 Conclusions 274Abbreviations 275References 276

11 Rational Design of Copper and Iron Chelators to Treat Wilson’s Disease andHemochromatosis 287Christelle Gateau, Elisabeth Mintz, and Pascale Delangle11.1 Introduction 28711.2 Chelating agents 288

11.2.1 Thermodynamic parameters 28811.2.2 Principles of coordination chemistry applied to chelation therapy 28911.2.3 Examples of classical chelating agents 290

11.3 Modern medicinal inorganic chemistry and chelation therapy 29111.4 Iron overload 292

11.4.1 Iron distribution and homeostasis 29211.4.2 Iron overload diseases 29411.4.3 Fe3+ chelators 29511.4.4 Current developments 296

11.5 Copper overload in Wilson’s disease 29911.5.1 Copper metabolism 29911.5.2 Copper homeostasis 30011.5.3 Wilson’s disease 303

11.6 Current developments in copper overload treatments 30411.6.1 From Cu homeostasis understanding to the rational design of drugs 30411.6.2 Cu+ chelating units inspired from proteins involved in Cu homeostasis 30511.6.3 Cu+ chelators inspired from metallochaperones 30611.6.4 Cysteine-rich compounds inspired from metallothioneins 30711.6.5 Liver-targeting: the ASGP-R 30811.6.6 Two glycoconjugates that release high affinity Cu chelators in hepatocytes 308

11.7 Conclusion 311Acknowledgments 312References 312

12 MRI Contrast Agents 321Célia S. Bonnet and Éva Tóth12.1 Introduction to MRI contrast agents 32112.2 Ligand optimization to increase relaxivity 323

12.2.1 Hydration number 32412.2.2 Optimization of water exchange kinetics via rational ligand design 325

x Contents

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

12.3 Ligand design for CEST agents 33212.3.1 Application of paramagnetic ions – PARACEST 333

12.4 Ligand design for responsive probes 33312.4.1 Probes responsive to pH 33412.4.2 Probes responsive to physiological cations 33812.4.3 Probes responsive to enzymes 344

12.5 Conclusions 348Abbreviations 348References 348

13 Photoactivatable Metal Complexes and Their Use in Biology and Medicine 355Tara R. deBoer-Maggard and Pradip K. Mascharak13.1 Introduction 35513.2 Cisplatin-inspired photoactivatable chemotherapeutics 35813.3 Metal-based photosensitizers in photodynamic therapy 36013.4 Photoinduced interactions of coordination complexes with DNA 362

13.4.1 Photocleavage of DNA with coordination complexes 36213.4.2 Photoactivatable complexes as antisense agents 364

13.5 Photoactivatable metal complexes that release small bioactive molecules 36713.6 Conclusion 371

References 372

14 Metalloprotein Inhibitors 375David P. Martin, David T. Puerta, and Seth M. Cohen14.1 Metal binding groups in metalloprotein inhibitor design 37514.2 Thiols, carboxylates, phosphates, and hydroxamates 37914.3 MBGs related to hydroxamic acids 38214.4 MBGs related to carboxylic acids 38714.5 MBGs related to thiols 39114.6 Amine, alcohol, and carbonyl MBGs 39314.7 Other MBGs 39514.8 Conclusion 399

References 401

15 Ruthenium Anticancer Compounds with Biologically-derived Ligands 405Changhua Mu and Charles J. Walsby15.1 Introduction 405

15.1.1 Simple coordination complexes 40615.1.2 Ruthenium(III) complexes with heterocyclic N-donor and/or DMSO ligands 40615.1.3 Ruthenium(II) arene complexes 40815.1.4 Polypyridyl complexes 41015.1.5 Other ruthenium anticancer compounds 411

15.2 Amino acids and amino acid-containing ligands 41115.3 Peptides and peptide-functionalized ligands 41315.4 Coordinated proteins as ligands 416

Contents xi

15.5 Carbohydrate-based ligands 41915.6 Purine, nucleoside, and oligonucleotide ligands 42215.7 Other selected ruthenium complexes with biological ligands 424

15.7.1 steroids 42415.7.2 Curcumin – an example of a natural product ligand 425

15.8 Conclusion 426References 426

Index 439

About the Editor

Tim Storr obtained his B.Sc. from the University of Victoria, Canada, and his Ph.D. in Medicinal InorganicChemistry from the University of British Columbia, Canada, in 2005 working with Professor Chris Orvig.He then pursued postdoctoral studies with Professor T. Daniel P. Stack at Stanford University studying metal-loenzyme mimics. In 2008 he joined the faculty at Simon Fraser University, Canada, as an assistant professorwhere his bioinorganic chemistry research programme targets the development of new chemical tools todiagnose and treat disease. His research is funded by the Natural Sciences and Engineering Research Counciland the Michael Smith Foundation for Health Research. Current research interests include metal overloaddisorders, Alzheimer’s disease, cancer, diagnostic imaging, site-selective therapies, and catalysis.

List of Contributors

Peter J. BarnardDepartment of Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne Vic-toria, 3086, Australia

Michael W. BeckDepartment of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan48109, USA

Heloisa BeraldoDepartamento de Química, Universidade Federal de Minas Gerais, Av. Presidente Antonio Carlos 6627,Belo Horizonte, MG, 31270-901, Brazil

Susan J. Berners-PriceInstitute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast Queensland, 4222, Australia

Christophe BiotUMR CNRS 8576, Unité de Glycobiologie Structurale et Fonctionnelle, Université Lille 1, 59650Villeneuve d’Ascq, France

Célia S. BonnetCentre de Biophysique Moléculaire, UPR 4301 CNRS, Rue Charles Sadron, Université d’Orléans, Orléans,45071, France

Eszter BorosA.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School,149 13th St, Charlestown, MA, USA, 02129

Seth M. CohenDepartment of Chemistry and Biochemistry, 9500 Gilman Drive, University of California, San Diego, CA,92093, USA

Mike CooganDepartment of Chemistry, Faraday Building, Lancaster University, Bailrigg, Lancaster, LA1 4YB, UK

Tara R. deBoer-MaggardDepartment of Chemistry and Biochemistry, University of California, 1156, High Street, Santa Cruz, CA,95064, USA

Pascale DelangleUMR-E3, Laboratoire Reconnaissance ionique et Chimie de Coordination, Université Joseph Fourier –Grenoble 1/CEA/Institut Nanoscience et Cryogénie/SCIB, 17 rue des martyrs, 38054, Grenoble, France

Alaina S. DeTomaDepartment of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan,48109, USA

xvi List of Contributors

Dustin DuncanDepartment of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC, V5A-1S6,Canada

Cara L. FerreiraNordion, 4004 Wesbrook Mall, Vancouver, BC, Canada, V6T 2A3

Christelle GateauUMR-E3, Laboratoire Reconnaissance ionique et Chimie de Coordination, Université Joseph Fourier –Grenoble 1/CEA/Institut Nanoscience et Cryogénie/SCIB, 17 rue des martyrs, 38054, Grenoble, France

Michael GottschaldtLaboratory for Organic and Macromolecular Chemistry, Friedrich-Schiller-University Jena, Humboldt-strasse 10, 07743, Jena, GermanyJena Center for Soft Matter (JCSM), Friedrich-Schiller-University Jena, Philosophenweg 7, 07743, Jena,Germany

Trevor W. HambleySchool of Chemistry, University of Sydney, City Road, Darlington, NSW 2008, Australia

Oluwatayo F. IkotunDepartment of Radiology, Washington University, 510 S. Kingshighway Blvd, St Louis, MO, USA, 63110

Michael R. JonesDepartment of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC, V5A-1S6,Canada

Alice V. KleinSchool of Chemistry, University of Sydney, NSW 2006, Australia

Kyle J. KorshavnDepartment of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan,48109, USA

Suzanne E. LapiDepartment of Radiology, Washington University, 510 S. Kingshighway Blvd, St Louis, MO, USA, 63110

Mi Hee LimDepartment of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan,48109, USALife Sciences Institute, University of Michigan, 210 Washtenaw Ave., Ann Arbor, Michigan, 48109, USADepartment of Chemistry, Ulsan National Institute of Science and Technology (UNIST), 50 UNIST-gil,Eonyan-eup, Ulju-gun, Ulsan, 698-798, Korea

Bernadette V. MarquezDepartment of Radiology, Washington University, 510 S. Kingshighway Blvd, St Louis, MO, USA, 63110

David P. MartinDepartment of Chemistry and Biochemistry, 9500 Gilman Drive, University of California, San Diego, CA,92093, USA

Pradip K. MascharakDepartment of Chemistry and Biochemistry, University of California, 1156, High Street, Santa Cruz, CA,95064, USA

List of Contributors xvii

Yuji MikataKYOUSEI Science Center, Nara Women’s University, Kitauoya-Higashi-machi, Nara 630-8506, Japan

Elisabeth MintzUMR 5249, Laboratoire Chimie et Biologie des Méteaux, Université Joseph Fourier – Grenoble 1/CNRS/CEA/Institut de Recherches en Sciences et Technologies pour le Vivant/LCBM, 17 rue des martyrs, 38054,Grenoble, France

Changhua MuDepartment of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, British ColumbiaV5A 1S6, Canada

Maribel NavarroChemistry and Analytical Sciences, School of Veterinary and Life Sciences, Murdoch University, Perth,Western Australia 6150, Australia

Elizabeth J. NewSchool of Chemistry, The University of Sydney, Sydney, NSW, 2006, Australia

Edward S. O’NeillSchool of Chemistry, The University of Sydney, Sydney, NSW, 2006, Australia

Amit S. PithadiaDepartment of Chemistry, University of Michigan, 930 North. University Avenue, Ann Arbor, Michigan,48109, USA

David T. PuertaDepartment of Chemistry and Biochemistry, 9500 Gilman Drive, University of California, San Diego, CA,92093, USA

Tim StorrDepartment of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC, V5A-1S6,Canada

Éva TóthCentre de Biophysique Moléculaire, UPR 4301 CNRS, Rue Charles Sadron, Université d’Orléans, Orléans,45071, France

Rafael Pinto VieiraDepartment of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC, V5A-1S6,CanadaDepartamento de Química, Universidade Federal de Minas Gerais, Av. Presidente Antonio Carlos 6627,Belo Horizonte, MG, 31270-901, Brazil

Charles J. WalsbyDepartment of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, British ColumbiaV5A 1S6, Canada

1Introduction to Ligand Design in Medicinal

Inorganic Chemistry

Michael R. Jones, Dustin Duncan, and Tim Storr

Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC, V5A-1S6, Canada

Medicinal inorganic chemistry continues to provide significant innovation in both diagnostic and therapeu-tic medicine. The field can be divided into two main categories: drugs that target metal ions in some form,and metal-based drugs in which the central metal ion is essential for the clinical application. Although thefield of medicinal inorganic chemistry is not new, a better understanding of metal ion interactions in the bodyhas enabled the development of many effective disease treatment strategies involving metal ions. The devel-opment of Cisplatin (cis-[Pt(NH3)2Cl2]) has played an instrumental role in bringing the field of medicinalinorganic chemistry into the mainstream [1]. Cisplatin and the second generation analog Carboplatin, shownin Figure 1.1, are the most commonly prescribed anticancer agents which greatly improve survival rates inovarian, bladder, cervical, and testicular cancers [2].

However, as recently written by Norman and Hambley, “with the notable exception of platinum anticancerdrugs, metal-based therapeutics occupy a relatively minor place in the organic dominated history of drugdevelopment [3].” Therefore, there is a broad scope for innovation in the field of medicinal inorganic chem-istry! An inherent advantage of metal complexes lies in the accessibility of multiple oxidation states, overallcharge, and geometries. However, these properties can become a disadvantage if not controlled in the biolog-ical application. Predicting the behavior of metal-based medicinal agents in vivo is a major challenge facingmedicinal inorganic chemists today. The history and basic concepts of medicinal inorganic chemistry havebeen comprehensively reviewed [4–11]. The main goal of this book is to highlight the role of ligand designin the rapidly expanding field of medicinal inorganic chemistry [12–14]. Through a series of 14 chapters,expert researchers describe the importance of ligand design in medicinal inorganic chemistry.

Ligand Design in Medicinal Inorganic Chemistry, First Edition. Edited by Tim Storr.© 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

2 Ligand Design in Medicinal Inorganic Chemistry

PtCl

Cl NH3

NH3

PtO

O NH3

NH3

O

O

(a) (b)

Figure 1.1 Platinum-containing chemotherapeutic drug molecules ((a) Cisplatin and (b) the second generationanalog Carboplatin). See Chapter 2 for more details

Metal ions have an essential role in the human body by providing charge balance, facilitating electrontransport, and catalyzing enzymatic transformations. For each application, the metal cation and the atomsimmediately surrounding the metal cation (i.e., coordination sphere) can be tuned specifically. The type,number, and geometry of the ligands, commonly in the form of amino acid side-chains, ensure that the activesite is maintained (Table 1.1).

Continued research into the uptake, transport, and utilization of metal ions in the body has enabled thedevelopment of many disease treatment strategies targeting metals. For example, the role of ligand design inessential metal overload disorders such as Wilson’s disease (Cu) and Hemochromatosis (Fe) is discussed byDelangle and co-workers in Chapter 11. In addition, the role of dysregulated metal ions in protein misfold-ing diseases of the brain, and the design of molecules targeting these processes, are discussed by Lim andco-workers in Chapter 10. Finally, the design of metal-binding molecules that inhibit the biological functionof metalloproteins is discussed by Cohen and co-workers in Chapter 14 [16].

Table 1.1 A brief introduction to essential metal ions in the body and their functions [15]

Metal ions Coordination number, geometry, ligand preferences Function

Na+ 6, octahedral, carboxylate/ether/hydroxyl Charge balance, osmotic pressure,and nerve activity

Mg2+ 6, octahedral, carboxylate/phosphate Structural role in hydrolases,isomerases, and phosphate transfer

K+ 6–8, flexible, carboxylate/ether/hydroxyl Charge balance, osmotic pressure,and nerve activity

Ca2+ 6–8, flexible, carbonyl/carboxylate/phosphate Structural, charge balance, reactioninitiator, and phosphate transfer

Cr3+ 6, octahedral, oxygen-donors Essential to carbohydrate/lipidmetabolism

Mn2+/3+ 6, tetragonal/octahedral,carboxylate/hydroxide/imidazole/phosphate

Structural role in oxidases

Fe2+/3+ 4 or 6, tetrahedral or octahedral, carboxylate/oxide/phenolate/thiolate/imidazole/pyrrole

Electron transfer in oxidases andoxygen binding/transport

Co+/2+/3+ 4 or 6, tetrahedral or octahedral,carboxylate/imidazole/thioether/thiolate

Alkyl group transfer (B12), oxidases

Cu+/2+ 3–5, trigonal planar, tetrahedral, square planar,square pyramid, carboxylate/imidazole/thioether/thiolate

Electron transfer, oxidases, andhydroxylases

Zn2+ 4 or 5, tetrahedral or square pyramid,carbonyl/carboxylate/imidazole/thiolate

Structure in zinc fingers, generegulation, anhydrases,dehydrogenases, and peptidases

Introduction to Ligand Design in Medicinal Inorganic Chemistry 3

Natural systems provide much of the inspiration for the strategies employed by medicinal inorganic chem-istry researchers. Thus, the design of active agents uses many of the same features present in biologicalsystems to stabilize metal ions. The ligand(s) play a key role in determining the pharmacokinetic parame-ters of the metal-containing drug molecule allowing for tuning of a compound for the specific application.Basic inorganic chemistry concepts such as Hard Soft Acid Base (HSAB) Theory, kinetic inertness, andthermodynamic stability, can be used in the design process [17, 18]. Ligands can be purposefully chosen tolimit complex dissociation and metal-associated toxicity in vivo in the presence of endogenous metal-bindingmolecules such as citrate, phosphate, bicarbonate, and biomolecules such as glutathione, transferrin, andalbumin. Additional factors that must be considered include: matching the oxidation state and coordinationpreferences of the metal ion, kinetics of complex formation, water solubility, overall charge, and the pathwayof excretion from the body. Depending on the application, a larger degree of importance may be placed onspecific design features of the medicinal agent. For magnetic resonance imaging (MRI) contrast agents dis-cussed by Bonnet and Tóth in Chapter 12, the GdIII ion offers the best response and is incorporated into allbut one of the commercially-approved agents. However, the high concentration used and known toxicity ofthe GdIII ion in the body necessitates the use of ligands that confer kinetic inertness and high thermodynamicstability to the complex. High thermodynamic stability of GdIII complexes, along with other lanthanides,is achieved with multidentate poly(amino)polycarboxylate ligands which form strong electrostatic interac-tions with the hard cation. Example ligands include the linear diethylenetriaminepentaacetic acid (DTPA)and macrocyclic 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). The GdIII complexes ofboth of these ligands have been approved for clinical use and are shown in Figure 1.2.

Many of the same important design features for MRI contrast agents are applicable to metal-based radio-pharmaceutical research as described by Ferreira and co-workers in Chapter 3. For metal-based radiopharma-ceuticals, the low concentration of the radionuclide available in the ligand complexation step, as well as theshort half-life of many radionuclides (e.g., 68Ga= 68 minutes), require careful consideration of the kineticsof complex formation. For the binding of metal ions in vivo, as described in Chapter 11 for metal overloaddisorders of Cu and Fe, ligand design needs to take into account the binding preferences of a specific oxida-tion state of the metal ion. As an example, in the Fe-overload disorder Hemochromatosis, the developmentof binding agents that stabilize the more kinetically-inert FeIII oxidation state are of interest. A high affinityfor FeIII is necessary in order to compete with the iron transport protein, transferrin. An additional importantdesign consideration is the FeIII/FeII redox potential of the resulting complex. A value below−300 mV (vs. theNormal Hydrogen Electrode (NHE)) is hypothesized to prevent redox-cycling in the presence of biologicalreducing agents, such as ascorbate and glutathione, and the possibility of generating reactive oxygen species(ROS) in vivo [19, 20]. However, the design of metal complexes that undergo redox processes under con-trolled conditions in the body has proven to be an effective targeting method in cancer diagnosis and therapy.Under certain conditions, the reducing environment of hypoxic tumor tissues [21] can be exploited for the

O

NN

NO O

O OO

OOO

Gd

OH2

2−

N N

NN

O

O

Gd

O

O

O O

OH2

−

(a) (b)O O

O

Figure 1.2 Examples of gadolinium complexes used in MRI imaging (a) Gd-DTPA and (b) Gd-DOTA. See Chapter12 for further details

4 Ligand Design in Medicinal Inorganic Chemistry

RuCl

Cl Cl

Cl

N

S

HN

OCH3

CH3

−

NH

HN

+ CoO

OH2N

N

O

O

ClCl

+

(a) (b) (c) (d)

Pt

O

O

O

O

Cl NH2

Cl NH3

NH

S S

NNNN

NH

64Cu

Figure 1.3 Redox-activated metal complexes. Reduction in vivo results in a more kinetically-labile metal center:(a) RuIII complex NAMI-A [19, 27]. One hypothesized mechanism of action involves reduction to RuII. (b) PtIV

complex Satraplatin [28]. Activation occurs upon reduction to PtII. (c) A CoIII complex containing a nitrogenmustard [24]. Reduction to CoII leads to ligand exchange and activation of the nitrogen mustard. (d) 64CuIIATSM[29]. Reduction to 64CuI leads to ligand exchange and intracellular trapping of the metal ion

selective activation of metal-based diagnostics and therapeutics [22]. Examples include Ru-based anticanceragents (Chapter 15), PtIV complexes (Chapter 2), CoIII compounds [23, 24], and the radiopharmaceutical64Cu-diacetyl-bis-N4-methylthiosemicarbazone (64CuATSM) (Chapters 3 and 7). The anticancer activity ofthe ferrocene-containing ferrocifens [25], and antimalarial activity of ferrocene-containing agents discussedin Chapter 8 [26], may in part be due to redox activation of the ferrocene unit and generation of ROS.

In addition to providing a stable complex, ligands can impart additional properties to metal ions. Forexample, ligand photosensitization of metal complexes can provide an emissive response useful for imagingand/or drug activation. Ligands are essential to the development of emissive metal complexes for biologi-cal applications. There has been significant interest in the development of both transition metal- (Chapter4) and lanthanide- (Chapter 5) containing optical probes. In Chapters 4 and 5, the important design fea-tures of metal-based optical probes are described in detail. Optical probes, in general, permit the in vitrovisualization of biological processes at the subcellular level, and have recently been reported for in vivo diag-nostic applications [30, 31]. Properties such as biological stability, large Stokes shift (difference in energybetween excitation and emission wavelengths), and long luminescence lifetimes of metal-based probes pro-vide an improvement over organic fluorophores. In almost all cases, metal-containing optical probes dependon photophysical processes involving the ligand, and the majority of ligands used are conjugated heterocyclesincluding bipyridine, phenanthroline, and phenylpyridines. These same planar aromatic heterocyclic ligandscan also display DNA-intercalating ability, thereby providing a targeting feature to certain optical probes[32]. As discussed by Coogan in Chapter 4, transition metal optical probes containing d6 complexes (ReI,RuII, and IrIII) are the most commonly studied (Figure 1.4), and more recently d8 and d10 platinum and goldcomplexes have been reported. The combination of optical imaging and cytotoxicity in one agent is brieflydescribed for both Pt (Chapter 2) and Au (Chapter 9) complexes. Lanthanide probes employ much of the samedesign features as MRI agents (thermodynamic stability and kinetic inertness), and in contrast to the transi-tion metal optical probes, the emission is primarily metal-based (4f electrons), thus leading to sharp line-likeemission spectra. The low extinction coefficients of lanthanide ions (f-f transitions are Laporte forbidden)necessitates the use of a sensitizing moiety, an organic absorber which can transfer energy to the lanthanideexcited state. In the majority of cases, the sensitizer is either directly bound to the lanthanide ion, or attachedto a chelating ligand that is bound to the lanthanide ion (Figure 1.4). As described by O’Neill and New inChapter 5, the long luminescence lifetimes, and information rich spectra of lanthanide complexes, providemany opportunities in optical imaging research. Ligand photosensitization of metal complexes can be used ina number of pharmaceutical applications, where following excitation, the energy transfer can initiate ligand

Introduction to Ligand Design in Medicinal Inorganic Chemistry 5

N

N

N

N

H

O

NH

CO2Et

O

HN

Eu

H2O

Ph

Ph

N S

O

N

O

N

N N

NMn

NO

ReOC

OCCO

Cl N

N

(a) (b) (c)

EtO2C

Figure 1.4 Examples of photoactivated metal complexes: (a) An emissive ReI tricarbonyl complex [33]. (b) Anemissive EuIII complex containing a sensitizer (in bold) for in vitro imaging [34]. (c) A Mn complex that releasesNO under photoexcitation [35]

dissociation leading to the release of bioactive agents. Energy transfer can also occur to exogenous moleculessuch as O2 which is the mechanism of activation in photodynamic therapy. In Chapter 13, Mascharak andco-workers describe the design features of metal complexes that are activated by light. Through ligand design,they show that photoactivation is controlled by the power, wavelength, and exposure time of the light. Specificexamples include photoactivated toxicity and the release of small-molecule signaling agents such as NO andCO (Figure 1.4).

The targeting of a diagnostic and/or therapeutic agent in the body is essential to an accurate diagnosis aswell as for limiting the off-target toxicity of the administered drug in therapeutic applications. In the caseof Cisplatin, uptake is not specific to cancer cells and thus off-target toxicity is a major limiting factor, withless than 1% of the injected drug reaching its tumor DNA target [36]. Despite this drawback, Cisplatin isstill an effective front-line treatment. A major research focus for medicinal chemists today is to improve thetargeting of the medicinal agent and a large number of innovative ideas are presented in this book. We willonly highlight a few specific examples here. Information on the uptake, transport, localization, and eventualexcretion of a drug molecule is instrumental in the design of more effective agents. An interesting example isthe longstanding (several thousand years!) application of Au in medicine. The emergence of specific thiol andselenol protein drug targets such as thioredoxin reductase, and the use of ligands to control cellular uptakeand reactivity of the Au metal center, are excellently described by Berners-Price and Barnard in Chapter 9. InChapter 7, Vieira and Beraldo detail the design of Schiff base-derived ligands in a number of disease appli-cations. Many of the chapters describe the attachment of a biological targeting vector to a metal complex.Biological targeting vectors include, but are not limited to: carbohydrates, amino acids, peptides, antibodies,and active drug molecules. The distance between the targeting vector and the metal complex is an importantdesign consideration. Mikata and Gottschaldt review the use of carbohydrate targeting ligands in Chapter 6.Appending a carbohydrate moiety to a metal complex has the ability to reduce toxicity, and improve solubilityand molecular targeting of the metal-based drug via use of carbohydrate active transport pathways. In Chapter8, Navarro and Biot describe the attachment of the known antimalarial Chloroquine (CQ), either pendent ordirectly bound to a metal complex, which affords a series of new leads that overcome the CQ-resistance ofthe malaria parasite (Figure 1.5). A major mechanism of drug transport in the blood is via binding to thehydrophobic pockets of the protein human serum albumin (HSA). Targeted HSA binding greatly enhancescontrast for the commercially available blood pool imaging agent MS-325 (Chapter 12); a pendent lipophilicphosphine moiety is attached to the GdIII complex which interacts with HSA and slows the rotational correla-tion time (τR) of the complex (Figure 1.5). The development of a series of Ru anticancer agents that employligands designed to interact with HSA and improve targeting are described by Mu and Walsby in Chapter 15.

6 Ligand Design in Medicinal Inorganic Chemistry

NCl

Au

HNN

PPh3

+

(a) (b)

O

NN

N

OO

OO

O

O

OO

Gd

OH2

2−

O POH

O O

O

Figure 1.5 Metal-based agents with attached targeting molecules: (a) A Au complex [37] connected to themalaria drug chloroquine (in bold). (b) The MRI agent MS-325 with attached HSA targeting unit (in bold) [38]

Metal complexes attached to peptide targeting vectors are of great interest in medicinal inorganic chem-istry and the identification of new disease targets will lead to continual development in this area. A numberof radiodiagnostic agents containing tumor-specific peptides attached to radiometal chelates are discussedby Ferreira and co-workers in Chapter 3. High target to background ratios provide non-invasive images oftumors and metastatic tissue, and also present the possibility of attaching therapeutic isotopes (e.g., 90Y and153Sm) for treatment. Similar peptide targeting strategies are discussed for Pt (Chapter 2) and Au (Chapter 9)anticancer agents to take advantage of specific active transport pathways. The use of radiolabeled antibodiesfor tumor imaging and therapy is of significant interest. The extended plasma half-life of antibodies requiresa long-lived isotope to obtain useful diagnostic images. The application of 89Zr (Chapter 3), and the useof desferrioxamine (DFO) as the metal chelate (a biological siderophore shown in Figure 1.6), in combina-tion with antibodies such as Bevacizumab demonstrates the influence of medicinal inorganic chemistry inmodern diagnostic imaging. Finally, the recent development of a CuI pro-ligand that is selectively activatedin liver hepatocytes shows considerable promise as a Wilson’s disease treatment (Chapter 11) [39]. Thesecompounds are decorated with carbohydrate residues that are recognized by the asialoglycoprotein receptor(ASGP-R), and once internalized, cleavage of disulfide bonds in the reducing intracellular medium releasesthe active chelator. Pro-chelator molecules also show considerable promise in binding dysregulated metals inneurodegenerative disease (Chapter 10) [40, 41].

The field of medicinal inorganic chemistry offers an important opportunity to expand our ability to diagnoseand treat disease. Throughout this book, the authors have described the importance of ligand design in tai-loring the properties of drug candidates to the specific application. Each individual chapter shares significant

H2N NNH

OH

O

O

N

HNN

OH

O

O

OH

O

Figure 1.6 Desferrioxamine (DFO) is a bacterial siderophore produced by the actinobacteria Streptomyces pilo-sus. DFO is used to treat acute iron poisoning (Chapter 11), and is also used as a radiometal chelate (Chapter 3)

Introduction to Ligand Design in Medicinal Inorganic Chemistry 7

insight into how ligand design is increasing our understanding of pathophysiology of disease, and providing amechanism to increase the efficacy of drug molecules. We hope you enjoy each chapter as much as we have,and apply the concepts and insights within to your own research in medicinal inorganic chemistry.

References

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2. Harper, B.W., Krause-Heuer, A.M., Grant, M.P. et al. (2010) Advances in platinum chemotherapeutics. Chem. Eur.J., 16 (24), 7064–7077.

3. Norman, J.F. and Hambley, T.W. (2011) Targeting strategies for metal-based therapeutics, in Bioinorganic MedicinalChemistry (ed E. Alessio), Wiley-VCH Verlag GmbH, Weinheim, pp. 58–87.

4. Metzler-Nolte, N. and Alberto, R. (2010) Medicinal Inorganic Chemistry: Concepts, Applications, and Perspectives,Wiley-VCH Verlag GmbH, Weinheim.

5. Alessio, E. (2011) Bioinorganic Medicinal Chemistry, Wiley-VCH Verlag GmbH & Co KGaA, Weinheim.6. Dabrowiak, J.C. (2009) Metals in Medicine, John Wiley & Sons, Ltd, Chichester.7. Farrer, N.J. and Sadler, P.J. (2011) Medicinal inorganic chemistry: state of the art, new trends, and a vision of the

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Chemical Society, Washington, DC.9. Thompson, K.H. (2011) Medicinal inorganic chemistry: an introduction, in Encyclopedia of Inorganic and Bioinor-

ganic Chemistry, John Wiley & Sons, Ltd, Chichester, DOI: 10.1002/9781119951438.eibc0362.10. Thompson, K.H. and Orvig, C. (2003) Boon and bane of metal ions in medicine. Science, 300 (5621), 936–939.11. Jaouen, G.M.N. (2010) Medicinal Organometallic Chemistry, Springer, Heidelberg.12. Chiang, L., Jones, M.R., Ferreira, C.L. and Storr, T. (2012) Multifunctional ligands in medicinal inorganic chemistry-

current trends and future directions. Curr. Top. Med. Chem., 12 (3), 122–144.13. Storr, T., Thompson, K.H. and Orvig, C. (2006) Design of targeting ligands in medicinal inorganic chemistry. Chem.

Soc. Rev., 35 (6), 534–544.14. Thompson, K.H. (2011) Medicinal inorganic chemistry: ligand design objectives and principles, in Encyclopedia

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15. Roat-Malone, R. (2007) Bioinorganic Chemistry: A Short Course, Wiley-Interscience.16. Meggers, E. (2011) From conventional to unusual enzyme inhibitor scaffolds: the quest for target specificity. Angew.

Chem. Int. Ed., 50 (11), 2442–2448.17. Wolfgang, K. and Schwederski, B. (2013) Bioinorganic Chemistry – Inorganic Elements in the Chemistry of Life:

An Introduction and Guide, John Wiley & Sons, Ltd, Chichester.18. Housecrofte, C.S. and Sharpe, A.G. (2012) Inorganic Chemistry, 4th edn, Prentice Hall.19. Mestroni, G., Alessio, E., Sava, G. et al. (1994) Water-soluble ruthenium(III)-dimethyl sulfoxide complexes: chem-

ical behaviour and pharmaceutical properties. Metal-Based Drugs, 1 (1), 41–63.20. Pierre, J.L. and Fontecave, M. (1999) Iron and activated oxygen species in biology: the basic chemistry. Biometals,

12 (3), 195–199.21. Hanahan, D. and Weinberg, R.A. (2011) Hallmarks of cancer: the next generation. Cell, 144 (5), 646–674.22. Graf, N. and Lippard, S.J. (2012) Redox activation of metal-based prodrugs as a strategy for drug delivery. Adv. Drug

Delivery Rev., 64 (11), 993–1004.23. Chang, J.Y.C., Lu, G.L., Stevenson, R.J. et al. (2013) Cross-bridged cyclen or cyclam Co(III) complexes containing

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8 Ligand Design in Medicinal Inorganic Chemistry

26. Dubar, F., Slomianny, C., Khalife, J. et al. (2013) The ferroquine antimalarial conundrum: redox activation andreinvasion inhibition. Angew. Chem. Int. Ed., 52 (30), 7690–7693.

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34. Pal, R., Parker, D. and Costello, L.C. (2009) A europium luminescence assay of lactate and citrate in biological fluids.Org. Biomol. Chem., 7 (8), 1525–1528.

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37. Navarro, M., Perez, H. and SanchezDelgado, R.A. (1997) Toward a novel metal-based chemotherapy againsttropical diseases. 3. Synthesis and antimalarial activity in vitro and in vivo of the new gold-chloroquine complexAu(PPh3)(CQ) PF6. J. Med. Chem., 40 (12), 1937–1939.

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2Platinum-Based Anticancer Agents

Alice V. Klein and Trevor W. Hambley

School of Chemistry, University of Sydney, NSW 2006, Australia

2.1 Introduction

The ligands of platinum anticancer complexes influence everything from the type of pharmaceuticalformulation required, to the pharmacokinetics and the mode of cytotoxicity. The ligands determine theaqueous solubility of platinum complexes, which in turn determines the route of drug administration; forinstance, oral versus intravenous. Once the platinum complex enters the circulation, its reactivity dictatesthe number of unwanted side-reactions with blood proteins, while the size, charge, lipophilicity and shapeof the ligands influence the distribution of the complex throughout the body and the rate at which it isexcreted. High molecular weight ligands are useful for trapping platinum complexes in tumour tissue; aphenomenon known as the enhanced permeability and retention (EPR) effect [1, 2], while charged ligandscan be employed to enhance tumour penetration [3, 4]. Lipophilic ligands are useful for increasing cellularuptake [5, 6], while the shape of the ligands can be tailored to improve DNA affinity, facilitate binding withreceptors on the surface of tumour cells, and inhibit enzymes involved in cancer progression. The ligandsalso determine the type of DNA-adduct that is formed, as well as the mode of cell-death that ensues. As aresult, careful consideration must be exercised in the choice of ligands, in order to optimise the anticancerproperties of novel platinum complexes.

2.2 The advent of platinum-based anticancer agents

The era of platinum-based chemotherapy dawned in the 1960s, following Barnett Rosenberg’s serendipitousdiscovery of the antiproliferative effects of cisplatin (1) [7]. Cisplatin was granted FDA approval in 1978,with its success paving the way for the regulatory approval of the second- and third-generation platinum

Ligand Design in Medicinal Inorganic Chemistry, First Edition. Edited by Tim Storr.© 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

10 Ligand Design in Medicinal Inorganic Chemistry

Pt

H2N O

NH2

O

O

O

Pt

O

O

O

O

H3N

H3N

Pt

H3N Cl

H3N Cl

(1) (2) (3)

Figure 2.1 Platinum anticancer complexes that have been granted FDA approval. Cisplatin (1), carboplatin (2)and oxaliplatin (3)

anticancer agents, carboplatin (2) and oxaliplatin (3) [8, 9] (Figure 2.1). Platinum drugs play a central rolein cancer treatment and are used today in almost half of all chemotherapeutic regimes, often in combinationwith other anticancer agents [8, 10]

Since the discovery of the anticancer properties of cisplatin, a vast amount of research has been directedtowards understanding its mode of action. To reach its biological target, DNA, cisplatin must travel throughthe bloodstream, in which the relatively high chloride concentration (∼100 mM) largely prevents aquationof the chlorido ligands [8, 9, 11, 12], although binding to blood proteins including human serum albuminand haemoglobin is known to occur [13–15]. Upon arrival at the tumour site, cellular uptake of cisplatinis achieved either by passive diffusion down a concentration gradient [11, 12], or by facilitated transportmechanisms, for instance, via the copper transporter-1 (CTR1) [16–19] or the organic cation transporters(OCTs) [20–22]. Once the drug enters cells, the lowered chloride ion concentration (3–20 mM) allows acti-vation of the platinum complex by aquation of one or both of the chlorido ligands [11, 12]. In its activatedform, cisplatin can bind to DNA, usually by forming crosslinks with adjacent purines on the same DNAstrand, though crosslinks can also form between guanines separated by another base or between oppositestrands [9, 23, 24]. These platinum-DNA adducts cause distortions in the DNA structure, including unwind-ing and bending, which can trigger apoptotic cell death [9, 24, 25]. Alternatively, the drug may react withintracellular components including glutathione, metallothionein, membrane phospholipids and cytoskeletalmicrofilaments [9, 11, 26]. Cisplatin can also be removed from tumour cells by the copper efflux trans-porters ATP7A and ATP7B and the GS-X efflux pumps, a family of organic anion transporters which areable to export platinum-glutathione adducts out of cells [17, 27–30]. The extracellular and intracellularpromiscuity of cisplatin results in less than 1% of intravenously administered drug reaching its tumour DNAtarget [10].

Cisplatin has been used to treat many tumour types, including ovarian, bladder, head and neck, cervicaland non-small-cell lung cancer, and is particularly useful for treating testicular cancer, for which it boasts anoverall cure rate exceeding 90% [10, 25, 31]. There are, however, several limitations related to its clinical use.The leading drawback of the drug is its severe dose-limiting side-effects, which arise from its indiscriminateuptake by all rapidly dividing cells (including tumour cells but also, for instance, bone marrow cells), and thepressure on the kidneys to excrete the drug from the body [8]. Side-effects include nephrotoxicity, emetogen-esis, neurotoxicity, myelosuppression and otoxicity [8, 10, 25]. Furthermore, numerous cancer types are ableto develop resistance to cisplatin, by means of enhanced DNA adduct repair and tolerance, reduced cellularuptake and increased efflux, downregulation of cell-death pathways, and inactivation by proteins and thiols[8, 9, 11, 25]. Finally, cisplatin has been found to suffer from poor tumour penetration, with evidence sug-gesting that clinically effective doses of the drug are only delivered to tumour cells situated closest to bloodvessels [32, 33].