Topics in. Biological Inorganic Chemistry. Volume 2. Editorial Board: S. J. Lippard K. N. Raymond J. Reedijk P. J. Sadler. A. X. Trautwein R.

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1 Topics in Biological Inorganic Chemistry Volume 2 Editorial Board: I. Bertini M. J. Clarke C. D. Garner E. Kimura S. J. Lippard K. N. Raymond J. Reedijk P. J. Sadler. A. X. Trautwein R. Weiss

2 Springer Berlin Heidelberg New York Barcelona Hong Kong London Milan Paris Singapore Tokyo

3 Metallopharmaceuticals II Diagnosis and Therapy Editors: M.J. Clarke P.J. Sadler With contributions by M. W. Brechbiel, C. 1. Hill, J. F. Kronauge, K. Kumar, J. H. McNeill, C. Orvig, A. Packard, P. J. Sadler, R. Schinazi, C. F. Shaw III, H. Sun, J. T. Rhule, K. H. Thompson, M. F. Tweedle, Z. Zheng Springer

4 Volume Editors: Professor Michael J. Clarke Boston College Merkert Center Chestnut Hill, MA USA Professor Peter J. Sadler University of Edinburgh King's Buildings West Mains Road Edinburgh EH9 3JJ Scotland, GB ISSN ISBN -13: : / e-isbn-13: Library of Congress Cataloging-in-Publication Data Metallopharmaceuticals II ed.: M. J. Clarke; P. J. Sadler. - Berlin; Heidelberg; New York; Barcelona; Hong Kong; London; Milan; Paris; Singapore; Tokyo: Springer 2. Diagnosis and therapy/with contributions by M. W. Brechbiel (Topics in biological inorganic chemistry; Vol. 2) ISBN This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. Springer-Verlag Berlin Heidelberg 1999 Softcover reprint of the hardcover 15t edition 1999 The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of many information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Coverdesign: Friedheim Steinen-Broo, Pau/Spain; MEDIO, Berlin Typesetting: Scientific Publishing Services (P) Ltd, Madras SPIN: / printed on acid-free paper

5 Editorial Board of the Series Prof. Ivano Bertini University of Florence Via G. Capponi Florence Italy jbic@riscl.lrm.fi.cnr.it Prof. C. Dave Garner University of Manchester Oxford Road Manchester M13 9PL U.K. Dave.Garner@manchester.ac.uk Prof. Stephen J. Lippard Massachusetts Institute of Technology 77 Massachusetts Avenue Cambridge, Massachusetts USA lippard@lippard.mit.edu Prof. Jan Reedijk Leiden Institut of Chemistry Gorlaeus Lab. Leiden University P.O. Box 9502 NL-2300 RA Leiden The Netherlands Reedijk@chem.LeidenUniv.nl Prof. Alfred X. Trautwein Institut fur Physik Medizinische Universitat zu Liibeck Ratzeburger Allee 160 D Liibeck Germany trautwein@physik.mu-luebeck.de Prof. Michael J. Clarke Merkert Chemistry Center Boston College Chestnut Hill, MA USA clarke@bc.edu Prof. Eiichi Kimura Department of Medicinal Chemistry School of Medicine Hiroshima University Kasumi 1-2-3, Minami-ku Hiroshima 734 Japan ekimura@ipc.hiroshima-u.ac.jp Prof. Kenneth N. Raymond University of California Berkeley, CA USA raymond@garnet.berkeley.edu Prof. Peter J. Sadler University of Edinburg King's Buildings West Mains Road Edinburgh EH9 3JJ UK P.J.Sadler@ed.ac.uk Prof. Raymond Weiss Institut Le Bel, Lab. de Christallochimie et de Chimie Structurale 4, rue Blaise Pascal F Strasbourg Cedex France weiss@chimie.u-strabgjr

6 Preface Inorganic chemistry is beginning to have a major impact on medicine. It offers great potential for the design of novel therapeutic and diagnostic agents. Volume I in this series was concerned with anticancer drugs, especially the successful platinum complexes which target particular sites on DNA. In Volume 2, the wider scope of inorganic medicinal chemistry is illustrated. About one quarter of all magnetic resonance imaging (MRI) scans in the clinic now involve administration of a contrast agent. The challenges involved in optimising the electronic relaxation properties of paramagnetic contrast agents through chemical design, their formulation and dosing are described by Tweedle and Kumar. Progress is being made with agents that can also probe biochemical functions and be targeted to specific organs and tissues. Packard, Kronauge and Brechbiel describe recent advances in the targeting of radioactive compounds for diagnosis and therapy, which encompasses radio nuclide production and processing, organic chemistry and coordination chemistry for radiopharmaceutical synthesis, as well as associated biochemistry and molecular pharmacology. The outstanding success of man-made 99mTc, with its rich variableoxidation-state co-ordination chemistry, is evident. The versatile chemistry of antiviral polyoxometallates with their variable charge distribution, shape, acidity, hydrolytic stability and redox potentials is described by Rhule, Hill, Zheng and Schinazi. They also speculate that the primary mode of action of fullerenes involves inhibition of human immunodeficiency virus protease. Future progress with improving the water solubility of fullerenes is important. The potential of vanadium compounds as orally-administered insulin mime tics capable of lowering blood glucose and ameliorating other diabetic symptoms is described by Orvig, McNeill and Thompson. The main challenge is to control the toxicity of vanadium through the choice of oxidation state, types of chelated ligands, and amphiphilicity. A vanadium complex may well enter the clinic soon. The chemistry and biochemistry of bismuth, the heaviest non-radioactive element in the periodic table, is poorly understood despite its use in medicine for several centuries. Sun and Sadler describe recent advances in understanding the structures of bismuth antiulcer drugs and their target sites on proteins. Although gold drugs have been in widespread use for over 60 years for the treatment of rheumatoid arthritis (chrysotherapy), their chemistry and biochemistry are also poorly understood. Shaw describes how both injectable and oral gold drugs are biotransformed before they reach their biological target sites: they are prodrugs.

7 VIII Preface Could it be that the metabolite gold(i) dicyanide is an active species? This and some other gold complexes also exhibit antiviral activity. The realisation that gold(i) can be oxidised to gold(iii) in vivo, and that this has major effects on T-cell activation, is likely to lead to progress in understanding the toxic side-effects of gold drugs. Overall this volume will provide chemists, biochemists, molecular biologists and pharmacologists with new insights into the mechanism of action of metallodrugs and diagnostic agents, and inspiration for the design of novel ones. August 1999 Peter J. Sadler Michael J. Clarke

8 Contents Magnetic Resonance Imaging (MRI) Contrast Agents M.P. Tweedle, K. Kumar.... Metalloradiopharmaceuticals A.B. Packard, J.P. Kronauge, M. W. Brechbiel 45 Polyoxometalates and Fullerenes as Anti-HIV Agents J. T. Rhule, c.l. Hill, Z. Zheng, R. Schinazi Vanadium-Containing Insulin Drugs E.H. Thompson, J.H. McNeill, C. Orvig Bismuth Antiulcer Complexes H. Sun, P./. Sadler Chrysotherapy: Gold-Drug Metabolism and Immunochemistry c.p. Shaw III