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Bioinorganic Medicinal Chemistry Edited by Enzo Alessio Related Titles Dunn, Peter / Wells, Andrew / Williams, Michael T. (eds.) Green Chemistry in the Pharmaceutical Industry 2010 ISBN: 978-3-527-32418-7 Mohr, Fabian (ed.) Gold Chemistry Applications and Future Directions in the Life Sciences 2009 ISBN: 978-3-527-32086-8 Thompson, K. Medicinal Inorganic Chemistry ISBN: 978-0-470-72544-3 Abraham, D. J. (ed.) Burger’s Medicinal Chemistry and Drug Discovery, Academic Version ISBN: 978-0-471-37027-7 Rehder, D. Bioinorganic Vanadium Chemistry 2008 ISBN: 978-0-470-06516-7 John Wiley & Sons, Inc. Wiley Handbook of Current and Emerging Drug Therapies Volumes 1-4 ISBN: 978-0-470-04098-0 Bioinorganic Medicinal Chemistry Edited by Enzo Alessio WILEY-VCH Verlag GmbH & Co. KGaA The Editor Prof. Dr. Enzo Alessio Universita` di Trieste Dipt. di Scienze Chimiche Via L.Giorgieri 1 34127 Trieste Italy & All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate. Library of Congress Card No.: applied for British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library. Bibliographic information published by the Deutsche Nationalbibliothek The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at http://dnb.d-nb.de & 2011 Wiley-VCH Verlag & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Composition MPS Limited, Chennai Printing and Bookbinding Cover Design Schulz Grafik-Design, FuXgo¨nheim Printed in the Federal Republic of Germany Printed on acid-free paper ISBN: 978-3-527-32631-0 Contents List of Contributors XV 1 Medicinal Inorganic Chemistry: State of the Art, New Trends, and a Vision of the Future 1 Nicola J. Farrer and Peter J. Sadler 1.1 Introduction 1 1.1.1 Metals in the Body: Essential Elements and Diseases of Metabolism 6 1.1.2 Metals as Therapeutic Agents 6 1.2 Antimicrobial Agents 8 1.3 Antiviral Agents 15 1.4 Systemic and Metabolic Diseases Including Inflammation 18 1.4.1 Diabetes and Obesity 18 1.4.2 Metal Homeostasis and Related Diseases 19 1.5 Metal Chelating Agents 19 1.6 Antiarthritic Drugs and Inflammation 21 1.7 Bipolar Disorder 22 1.8 Anticancer Agents 22 1.8.1 PtII Cytotoxic Agents 23 1.8.2 PtIV Prodrugs 24 1.8.3 Photoactivatable PtIV Complexes 25 1.8.4 Ruthenium 25 1.8.4.1 Interaction with Plasma Proteins 25 1.8.4.2 Ruthenium Arenes 26 1.8.5 Osmium 29 1.8.6 Titanium 29 1.8.7 Gold 31 1.8.8 Tin 32 1.8.9 Gallium 33 Bioinorganic Medicinal Chemistry. Edited by Enzo Alessio Copyright r 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32631-0 1.8.10 Arsenic 33 1.8.11 Copper 34 1.8.12 Zinc 34 1.8.13 Bismuth 34 1.8.14 Molybdenum 35 1.8.15 Photosensitizers: Porphyrins 35 1.9 Small Molecule Delivery and Control 35 1.9.1 Nitric Oxide (NO) 35 1.9.2 Carbon Monoxide (CO) 36 1.10 Diagnostic Agents 36 1.11 Veterinary Medicinal Inorganic Chemistry 37 1.12 Conclusions and Vision 37 2 Targeting Strategies for Metal-Based Therapeutics 49 Julia F. Norman and Trevor W. Hambley 2.1 Introduction 49 2.2 Physiological Targeting 49 2.2.1 Antitumor Drugs Targeting Tumor Hypoxia 50 2.2.2 Antitumor Drugs Targeting Vascular Structure 54 2.2.3 Antitumor Drugs Targeting Tumor pH 54 2.2.4 Light Activated Prodrugs 55 2.3 Molecular Targeting 57 2.3.1 Protein and Peptide Targeting 57 2.3.1.1 Protein Receptor Binding 57 2.3.2 Peptide Tethering 63 2.3.2.1 Directing Effects 64 2.3.3 Selective Activation 65 2.3.4 DNA Targeting 66 2.3.4.1 Duplex DNA Sequence Selectivity 66 2.3.4.2 Telomeric Targeting 68 2.4 Immunological Targeting 69 2.4.1 Antigen Targeting 70 2.4.2 Antibody Tethering 71 2.5 Concluding Remarks 73 3 Current Status and Mechanism of Action of Platinum-Based Anticancer Drugs 79 Shanta Dhar and Stephen J. Lippard 3.1 Introduction 79 3.1.1 Platinum Chemotherapy and Cancer 79 3.1.2 Palette of Current Platinum Chemotherapeutic Drugs 79 3.1.3 Early History of Cisplatin and Approved Platinum Drugs for the Clinic 82 3.2 Mechanism of Action of Cisplatin 82 3.2.1 Cisplatin Accumulation 82 3.2.2 Cisplatin Activation 82 VI | Contents 3.2.2.1 Binding to DNA Targets 83 3.2.2.2 Binding to Non-DNA Targets 84 3.2.3 Cellular Processing of Platinum-DNA Adducts 84 3.2.3.1 Cytotoxicity Associated with High Mobility Group (HMG) Proteins 85 3.2.3.2 Cytotoxicity Associated with Non-HMG Proteins 86 3.3 Limitations of Current Platinum-Based Compounds: New Strategies 87 3.4 Novel Concepts in the Development of Platinum Antitumor Drugs 87 3.4.1 Functionalized Single-Walled Carbon Nanotubes (SWNTs) as Vehicles for Delivery of Pt(IV)-Prodrugs 88 3.4.2 Targeted Nanoparticles for Delivery of Cisplatin for Prostate Cancer 89 3.4.3 Gold Nanoparticles as Delivery Vehicles for Platinum Compounds 90 3.4.4 Delivery of Pt(IV) Compounds Targeting Cancer Cell Metabolism 91 3.5 Concluding Remarks 93 4 New Trends and Future Developments of Platinum-Based Antitumor Drugs 97 Xiaoyong Wang and Zijian Guo 4.1 Introduction 97 4.2 Mechanisms of Action and Resistance 99 4.2.1 Mechanism of Action 99 4.2.2 Mechanism of Resistance 100 4.2.2.1 Decreased Drug Accumulation 100 4.2.2.2 Increased Detoxification 101 4.2.2.3 Enhanced Repair and Increased Tolerance to DNA Damage 101 4.2.2.4 Reduced Apoptotic Response and Activation of Survival Pathways 102 4.3 Monofunctional Platinum(II) Complexes 103 4.4 Trans-Platinum(II) Complexes 107 4.5 Multinuclear Platinum(II) Complexes 114 4.6 Platinum(IV) Complexes 124 4.7 Delivery of Platinum Drugs 130 4.8 Concluding Remarks and Future Perspectives 139 5 Ruthenium and Other Non-platinum Anticancer Compounds 151 Ioannis Bratsos, Teresa Gianferrara, Enzo Alessio, Christian G. Hartinger, Michael A. Jakupec, and Bernhard K. Keppler 5.1 Introduction 151 5.2 Ruthenium Anticancer Compounds 152 Contents | VII 5.2.1 Chemical Features of Ruthenium Compounds 152 5.2.2 Trans-[tetrachloridobis(1H-indazole)ruthenate(III)] Complexes and their Development 153 5.2.3 Ruthenium-dmso Compounds: The Development of NAMI-A 156 5.2.3.1 Chemical Features of NAMI-A 157 5.2.3.2 NAMI-A-Type Complexes 158 5.2.3.3 Mechanism of Action of NAMI-A 159 5.2.4 Half-Sandwich Ru-Organometallics 160 5.2.4.1 Piano-Stool Ru-Arene Compounds 160 5.2.4.2 RAPTA Compounds 162 5.2.4.3 Other Half-Sandwich Ru Compounds 163 5.3 From Gallium Nitrate to Oral Gallium Complexes 164 5.4 Titanium Anticancer Compounds 165 5.4.1 Budotitane: The First Transition Metal Complex in Clinical Trials in the Post-cisplatin Era 165 5.4.2 Titanocene Dichloride and Related Compounds 166 5.5 Ferrocene-Derived Anticancer Agents 166 5.6 The Main Group Organometallics Spirogermanium and Germanium-132 167 5.7 Arsenic in Cancer Chemotherapy 168 5.8 Overcoming the Resistance of Tumors to Anticancer Agents by Rare Earth Element Compounds 169 5.9 Conclusions 170 6 The Challenge of Establishing Reliable Screening Tests for Selecting Anticancer Metal Compounds 175 Angela Boccarelli, Alessandra Pannunzio, and Mauro Coluccia 6.1 Introduction 175 6.2 Tumor Cell Growth Inhibition and Cell Death Screening Assays 177 6.3 Metal-Based Anticancer Compounds and Gene Expression Microarray Technologies 181 6.3.1 Basal Transcription Profiling and Sensitivity/Resistance to Metal-Based Anticancer Drugs 183 6.3.2 Profiling Gene Expression Alterations in Response to Treatment with Metal-Based Anticancer Drugs 185 6.4 Metal-Based Anticancer Compounds and the Proteomic Approach 187 6.5 Concluding Remarks 190 6.5.1 Cytotoxic Metal-Based Anticancer Agents 190 6.5.2 Non-Cytotoxic Metal-Based Anticancer Agents 190 6.5.3 Tumor-Targeted Metal-Based Anticancer Agents 191 6.5.4 Towards a Global Mechanistic-Based Screening Approach 191 VIII | Contents 7 Gold-Based Therapeutic Agents: A New Perspective 197 Susan J. Berners-Price 7.1 Introduction 197 7.1.1 An Historical Perspective 197 7.1.2 Current Interest in Gold-Based Drugs 199 7.2 Biological Chemistry of Gold 200 7.2.1 Gold(I) Oxidation State 200 7.2.2 Gold(III) Oxidation State 202 7.3 Gold Antiarthritic Drugs 202 7.3.1 Structural Chemistry and Biotransformation Reactions 202 7.3.2 Mode of Action 204 7.4 Gold Complexes as Anticancer Agents 205 7.4.1 Gold(I) Compounds 205 7.4.1.1 Auranofin and Related Compounds 205 7.4.1.2 Tetrahedral Gold(I) Diphosphines and Related Compounds 206 7.4.1.3 Gold(I) N-Heterocyclic Carbene Compounds 209 7.4.2 Gold (III) Compounds 210 7.4.3 Mode of Action of Gold-Based Anticancer Drugs 212 7.5 Gold Complexes as Antiparasitic Agents 214 7.6 Concluding Remarks 215 8 MRI Contrast Agents: State of the Art and New Trends 223 Daniela Delli Castelli, Eliana Gianolio, and Silvio Aime 8.1 Introduction 223 8.2 T1 Agents 224 8.2.1 Theory of Paramagnetic Relaxation 224 8.2.2 Clinically Approved T1 Agents 227 8.2.2.1 Paramagnetic Gd(III)-Based Complexes 227 8.2.2.2 Mn(II)-Based Complexes 229 8.2.3 Preclinical Level 230 8.2.3.1 ECF Agents 230 8.2.3.2 Blood Pool Agents 231 8.2.3.3 Responsive T1 Agents 232 8.3 T2-Susceptibility Agents 234 8.3.1 Iron Oxide Particles 235 8.3.2 Paramagnetic Liposomes 235 8.4 CEST Agents 236 8.4.1 Theoretical Background 237 8.4.1.1 The Sensitivity Issue 239 8.4.2 Paramagnetic CEST Agents: PARACEST 241 8.4.2.1 Responsive PARACEST Agents 244 8.4.2.2 Cell Labeling 248 8.5 Concluding Remarks 249 Contents | IX