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Tim Storr, Department of Chemistry, Simon Fraser University, Canada Professor Storr has over thirteen years' experience in the field of bioinorganic chemistry and he currently has active research programs in cancer imaging using metal-based agents, and also in the design of metal binding agents for metal overload applications. He teaches a graduate course in bioinorganic chemistry at Simon Fraser University. Professor Storr was a member of the organizing committee for the 2011 International Conference on Biological Inorganic Chemistry, and is currently organizing a ligand design symposium at the upcoming 2012 Canadian Chemistry Conference.
About the Editor xiii
List 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. 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 47Eszter 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 81Mike 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 113Edward 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 145Yuji 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 175Rafael 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 205Maribel 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 227Susan 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 257Michael 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 287Christelle 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 321Célia 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 355Tara 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 375David 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 405Changhua 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
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 therapeutic 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 the field of medicinal inorganic chemistry is not new, a better understanding of metal ion interactions in the body has enabled the development of many effective disease treatment strategies involving metal ions. The development of Cisplatin (cis-[Pt(NH3)2Cl2]) has played an instrumental role in bringing the field of medicinal inorganic chemistry into the mainstream [1]. Cisplatin and the second generation analog Carboplatin, shown in Figure 1.1, are the most commonly prescribed anticancer agents which greatly improve survival rates in ovarian, bladder, cervical, and testicular cancers [2].
Figure 1.1 Platinum-containing chemotherapeutic drug molecules ((a) Cisplatin and (b) the second generation analog Carboplatin). See Chapter 2 for more details
However, as recently written by Norman and Hambley, “with the notable exception of platinum anticancer drugs, metal-based therapeutics occupy a relatively minor place in the organic dominated history of drug development [3].” Therefore, there is a broad scope for innovation in the field of medicinal inorganic chemistry! An inherent advantage of metal complexes lies in the accessibility of multiple oxidation states, overall charge, and geometries. However, these properties can become a disadvantage if not controlled in the biological application. Predicting the behavior of metal-based medicinal agents in vivo is a major challenge facing medicinal inorganic chemists today. The history and basic concepts of medicinal inorganic chemistry have been comprehensively reviewed [4–11]. The main goal of this book is to highlight the role of ligand design in 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.
Metal ions have an essential role in the human body by providing charge balance, facilitating electron transport, and catalyzing enzymatic transformations. For each application, the metal cation and the atoms immediately 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 active site is maintained (Table 1.1).
Table 1.1 A brief introduction to essential metal ions in the body and their functions [15]
Continued research into the uptake, transport, and utilization of metal ions in the body has enabled the development of many disease treatment strategies targeting metals. For example, the role of ligand design in essential metal overload disorders such as Wilson's disease (Cu) and Hemochromatosis (Fe) is discussed by Delangle and co-workers in Chapter 11. In addition, the role of dysregulated metal ions in protein misfolding diseases of the brain, and the design of molecules targeting these processes, are discussed by Lim and co-workers in Chapter 10. Finally, the design of metal-binding molecules that inhibit the biological function of metalloproteins is discussed by Cohen and co-workers in Chapter 14 [16].
Natural systems provide much of the inspiration for the strategies employed by medicinal inorganic chemistry researchers. Thus, the design of active agents uses many of the same features present in biological systems to stabilize metal ions. The ligand(s) play a key role in determining the pharmacokinetic parameters 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, and thermodynamic stability, can be used in the design process [17, 18]. Ligands can be purposefully chosen to limit complex dissociation and metal-associated toxicity in vivo in the presence of endogenous metal-binding molecules such as citrate, phosphate, bicarbonate, and biomolecules such as glutathione, transferrin, and albumin. Additional factors that must be considered include: matching the oxidation state and coordination preferences of the metal ion, kinetics of complex formation, water solubility, overall charge, and the pathway of excretion from the body. Depending on the application, a larger degree of importance may be placed on specific design features of the medicinal agent. For magnetic resonance imaging (MRI) contrast agents discussed by Bonnet and Tóth in Chapter 12, the GdIII ion offers the best response and is incorporated into all but one of the commercially-approved agents. However, the high concentration used and known toxicity of the GdIII ion in the body necessitates the use of ligands that confer kinetic inertness and high thermodynamic stability 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 interactions 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 of both of these ligands have been approved for clinical use and are shown in Figure 1.2.
Figure 1.2 Examples of gadolinium complexes used in MRI imaging (a) Gd-DTPA and (b) Gd-DOTA. See Chapter 12 for further details
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 nitrogen mustard [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
Many of the same important design features for MRI contrast agents are applicable to metal-based radiopharmaceutical research as described by Ferreira and co-workers in Chapter 3. For metal-based radiopharmaceuticals, the low concentration of the radionuclide available in the ligand complexation step, as well as the short half-life of many radionuclides (e.g., 68Ga = 68 minutes), require careful consideration of the kinetics of complex formation. For the binding of metal ions in vivo, as described in Chapter 11 for metal overload disorders of Cu and Fe, ligand design needs to take into account the binding preferences of a specific oxidation state of the metal ion. As an example, in the Fe-overload disorder Hemochromatosis, the development of binding agents that stabilize the more kinetically-inert FeIII oxidation state are of interest. A high affinity for FeIII is necessary in order to compete with the iron transport protein, transferrin. An additional important design consideration is the FeIII/FeII redox potential of the resulting complex. A value below −300 mV (vs. the Normal Hydrogen Electrode (NHE)) is...
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