Ojima I. (ed.) Fluorine in Medicinal Chemistry and Chemical Biology

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Fluorine in Medicinal Chemistry and

Chemical Biology

Fluorine in Medicinal Chemistry and Chemical Biology Edited by Iwao Ojima

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

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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

F-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 CF

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

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,

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

and envision the new and exciting developments in the future. This book has a focus on

the unique and signiﬁ cant roles that ﬂ uorine plays in medicinal chemistry and chemical

biology, but also covers new and efﬁ cient synthetic methods for medicinal chemistry,

PET, and expanding applications of

F NMR spectroscopy to biomedical research.

The book starts with an introductory chapter, summarizing and discussing the unique

properties of ﬂ uorine and their relevance to medicinal chemistry and chemical biology.

Then, several hot topics in medicinal chemistry as well as discovery and development of

ﬂ uorine - containing drugs and drug candidates are described, including ﬂ uorinated pros-

tanoids (for glaucoma), ﬂ uorinated conformationally restricted glutamate analogues (for

CNS disorder), ﬂ uorinated MMP inhibitors (e.g. for cancer metastasis intervention),

ﬂ uoro - taxoids (for cancer), triﬂ uoro - artemisinin (for malaria), and ﬂ uorinated nucleosides

(for viral infections).

x Preface

Development of efﬁ cient synthetic methods is crucial for medicinal chemistry and

optimization of ﬂ uorine - containing drug candidates. Thus, the subsequent section presents

the recent advances in synthetic methodology for gem - diﬂ uoromethylene sugar nucleo-

sides, triﬂ uoroalanine oligopeptides, ﬂ uoroalkene dipeptide isosteres, ﬂ uorinated hetero-

cyclic systems, and oligo - gem - diﬂ uorocyclopropanes. In addition, an emerging “ ﬂ uorous

technology ” for the efﬁ cient synthesis and puriﬁ cation of biomolecules is discussed.

As mentioned above, there has been a remarkable advance in the biomedical applica-

tions of

F PET imaging. Thus, the next chapter deals with

F radiopharmaceuticals. On

the other hand, ﬂ uorinated amino acids and peptides have been playing a key role in

structural biology, chemical biology, and biological chemistry. Therefore, the subsequent

section presents the recent advances in this growing ﬁ eld of research, including the struc-

tural and chemical biology of ﬂ uorinated amino acids and peptides, protein design using

ﬂ uorinated amino acids, and ﬂ uorinated methionines as probes in biological chemistry.

F NMR spectroscopy, both in solution and in the solid state, has been expanding

its utility in chemical biology as well as diagnostic tools. Accordingly, the last two chapters

discuss the structure analysis of membrane - active peptides using ﬂ uorinated amino acids

by solid - state

F NMR and the applications of in vivo

F - magnetic resonance spectros-

copy to metabolism, biodistribution and neuropharmacology studies.

Although several recent reviews and books claim that a large number of ﬂ uorine -

containing drugs have been approved by the Federal Drug and Food Administration (FDA)

of the United States, there has not been an actual list of those drugs with structures.

Accordingly, I organized a team to go through the FDA records to collect all FDA -

approved ﬂ uorine - containing drugs, to date, for humans and for animals, and they have

produced a very useful list of those drugs, which is compiled in the Appendix.

I believe that this book is extremely informative for researchers who want to take

advantage of the use of ﬂ uorine in biomedical research such as rational drug design, theory

and synthesis, the use of ﬂ uorine labels for chemical and structural biology, metabolism

and biodistribution studies, protein engineering, clinical diagnosis, etc. This book will

serve as an excellent reference book for graduate students as well as scientists at all levels

in both academic and industrial laboratories.

I am grateful to Professor Takeo Taguchi, Tokyo University of Pharmacy and Life

Sciences for his valuable advice for the selection of world - leading contributors with

cutting - edge research projects, especially from Asia. I also acknowledge the very helpful

editorial assistance of Dr Qing Huang, Institute of Chemical Biology & Drug Discovery,

State University of New York at Stony Brook. I also would like to thank the Wiley – Black-

well editorial team, Richard Davies, Rebecca Stubbs, Sarah Hall, and Sarahjayne Sierra,

for their productive cooperation.

Iwao Ojima

Editor

Contributors

David Armstrong, Department of Chemistry, Durham University, Durham, UK

Jean - Pierre B é gu é , BIOCIS - CNRS, Centre d ’ Etudes Pharmaceutiques, Ch â tenay -

Malabry, France

Dani è le Bonnet - Delpon, BIOCIS - CNRS, Centre d ’ Etudes Pharmaceutiques, Ch â tenay -

Malabry, France

Gabriele Candiani, C.N.R. – Istituto di Chimica del Riconoscimento Molecolare, Milan,

Italy

Matthew W. Cartwright, Department of Chemistry, Durham University, Durham, UK

John A. Christopher, GlaxoSmithKline R & D, Stevenage, Hertfordshire, UK

Ginevra A. Clark, Department of Chemistry, Tufts University, Medford, Massachusetts,

USA

Manisha Das, Department of Chemistry, State University of New York at Stony Brook,

Stony Brook, New York, USA

John F. Honek, Department of Chemistry, University of Waterloo, Waterloo, Ontario,

Canada

Florent Huguenot, C.N.R. – Istituto di Chimica del Riconoscimento Molecolare, Milan,

Italy

Masahiro Ikejiri, Faculty of Pharmaceutical Sciences at Kagawa Campus Tokushima

Bunri University, Sanuki City, Kagawa, Japan

Toshiyuki Itoh, Department of Chemistry and Biotechnology, Tottori University, Tottori,

Japan