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Fluorine in Medicinal Chemistry and Chemical Biology Fluorine in Medicinal Chemistry and Chemical Biology Fluorine in Medicinal Chemistry and Chemical Biology Edited by Iwao Ojima © 2009 Blackwell Publishing, Ltd. ISBN: 978-1-405-16720-8 Fluorine in Medicinal Chemistry and Chemical Biology Edited by Iwao Ojima Institute of Chemical Biology & Drug Discovery, State University of New York at Stony Brook, New York, USA A John Wiley & Sons, Ltd., Publication This edition fi rst published 2009 © 2009 Blackwell Publishing Ltd Registered offi ce John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, United Kingdom For details of our global editorial offi ces, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com. The right of the author to be identifi ed as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. 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In view of ongoing research, equipment modifi cations, changes in governmental regulations, and the constant fl ow of information relating to the use of experimental reagents, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical, piece of equipment, reagent, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. Library of Congress Cataloging-in-Publication Data Fluorine in medicinal chemistry and chemical biology / Iwao Ojima (editor) p. cm. Includes bibliographical references and index. ISBN 978-1-4051-6720-8 (cloth : alk. paper) 1. Organofl uorine compounds. 2. Fluorination – Physiological effect. 3. Bioorganic chemistry. 4. Pharmaceutical chemistry. I. Ojima, Iwao. II. Taguchi, Takeo. QP535.F1F58 2009 615′.19–dc22 2008049835 A catalogue record for this book is available from the British Library. Set in 10 on 12 pt Times by SNP Best-set Typesetter Ltd., Hong Kong Printed and bound in Great Britain by CPI Antony Rowe, Ltd, Chippenham, Wiltshire Contents Preface page ix List of Contributors xi Abbreviations xv Introduction: Basic Aspects of Fluorine in Chemistry and Biology 1 1 Unique Properties of Fluorine and Their Relevance to Medicinal Chemistry and Chemical Biology 3 Takashi Yamazaki, Takeo Taguchi, and Iwao Ojima Medicinal Chemistry 47 2 Fluorinated Prostanoids: Development of Tafl uprost, a New Anti-glaucoma Agent 49 Yasushi Matsumura 3 Fluorinated Conformationally Restricted Glutamate Analogues for CNS Drug Discovery and Development 67 Atsuro Nakazato 4 Fluorinated Inhibitors of Matrix Metalloproteinases 99 Roberta Sinisi, Monika Jagodzinska, Gabriele Candiani, Florent Huguenot, Monica Sani, Alessandro Volonterio, Raffaella Maffezzoni, and Matteo Zanda 5 Fluoro-Taxoid Anticancer Agents 117 Antonella Pepe, Larisa Kuznetsova, Liang Sun, and Iwao Ojima 6 Antimalarial Fluoroartemisinins: Increased Metabolic and Chemical Stability 141 Jean-Pierre Bégué and Danièle Bonnet-Delpon 7 Synthesis and Biological Activity of Fluorinated Nucleosides 165 Tokumi Maruyama, Masahiro Ikejiri, Kunisuke Izawa, and Tomoyuki Onishi vi Contents Synthetic Methods for Medicinal Chemistry and Chemical Biology 199 8 Synthesis of gem-Difl uoromethylenated Nucleosides via gem-Difl uoromethylene-containing Building Blocks 201 Wei-Dong Meng and Feng-Ling Qing 9 Recent Advances in the Syntheses of Fluorinated Amino Acids 213 Kenji Uneyama 10 Fluorinated Moieties for Replacement of Amide and Peptide Bonds 257 Takeo Taguchi and Hikaru Yanai 11 Perfl uorinated Heteroaromatic Systems as Scaffolds for Drug Discovery 291 David Armstrong, Matthew W. Cartwright, Emma L. Parks, Graham Pattison, Graham Sandford, Rachel Slater, Ian Wilson John A. Christopher, David D. Miller, Paul W. Smith, and Antonio Vong 12 gem-Difl uorocyclopropanes as Key Building Blocks for Novel Biologically Active Molecules 313 Toshiyuki Itoh 13 Fluorous Mixture Synthesis (FMS) of Drug-like Molecules and Enantiomers, Stereoisomers, and Analogues of Natural Products 335 Wei Zhang 14 Fluorine-18 Radiopharmaceuticals 361 Michael R. Kilbourn and Xia Shao Applications of Fluorinated Amino Acids and Peptides to Chemical Biology and Pharmacology 389 15 Application of Artifi cial Model Systems to Study the Interactions of Fluorinated Amino Acids within the Native Environment of Coiled Coil Proteins 391 Mario Salwiczek, Toni Vagt, and Beate Koksch 16 Fluorinated Amino Acids and Biomolecules in Protein Design and Chemical Biology 411 He Meng, Ginevra A. Clark, and Krishna Kumar 17 Effects of Fluorination on the Bioorganic Properties of Methionine 447 John F. Honek 18 Structure Analysis of Membrane-Active Peptides Using 19F-labeled Amino Acids and Solid-State NMR 463 Parvesh Wadhwani and Erik Strandberg Contents vii 19 Study of Metabolism of Fluorine-containing Drugs Using In Vivo Magnetic Resonance Spectroscopy 495 Erika Schneider and Roger Lin Appendix 525 Approved Active Pharmaceutical Ingredients Containing Fluorine Elizabeth Pollina Cormier, Manisha Das, and Iwao Ojima 525 Section 1. Fluorine-containing Drugs for Human Use Approved by FDA in the United States 527 Section 2. Fluorine-containing Drugs for Veterinary Use Approved by FDA in the United States 585 Index 605 Preface This book presents the recent developments and future prospects of fl uorine in medicinal chemistry and chemical biology. The extraordinary potential of fl uorine - containing bio- logically relevant molecules in peptide/protein chemistry, medicinal chemistry, chemical biology, pharmacology, and drug discovery as well as diagnostic and therapeutic applica- tions, was recognized by researchers who are not in the traditional fl uorine chemistry fi eld, and thus the new wave of fl uorine chemistry has been rapidly expanding its biomedical frontiers. In 1996, I edited a book, Biomedical Frontiers of Fluorine Chemistry (American Chemical Society ’ s Symposium Series), together with Dr James R. McCarthy and Dr John T. Welch, covering the emerging new aspects of fl uorine chemistry at the biomedical interface. Since then, remarkable progress has been made. For example, in 2006, the best - selling and second - best - selling drugs in the world were Lipitor ® (atorvastatin calcium) (by Pfi zer/Astellas; $ 14.4 billion/year) and Advair ® (USA)/seretide ® (EU) (a mixture of fl uticasone propionate and salmeterol) (by GlaxoSmithKline; $ 6.1 billion/year), which contain one and three fl uorine atoms, respectively. Also, risperidone with a fl uorine atom, for schizophrenia (by Janssen; $ 4.2 billion/year) and lansoprazole, a proton pump inhibi- tor, with a CF3 moiety (by Takeda/Abbott; $ 3.4 billion/year) were ranked 10th and 17th, respectively. As such, it is not an exaggeration to say that, at present, every new drug dis- covery and development, without exception, explores fl uorine - containing drug candidates. Also, applications of 18 F PET (positron emission tomography), a powerful in vivo imaging technology in oncology, neurology, psychiatry, cardiology, and other medical specialties have already become an important part of medical care. In addition, 18 F PET has emerged as an important tool in drug development, especially for accurate measurements of phar- macokinetics and pharmacodynamics. Accordingly, I believe that it is the right time for us to review the recent advances
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