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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.
Auteur
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.
Contenu
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'Nei...