Nucleosides and Nucleotides as Antitumor and Antiviral Agents

338 Pages·1993·12.82 MB·English

by  Akira Matsuda

Nucleosides and Nucleotides
as Antitumor and Antiviral
Agents
Nucleosides and Nucleotides
as Antitumor and Antiviral
Agents
Edited by
Chung K. Chu
The University of Georgia
Athens. Georgia
and
David C. Baker
The University of Tennessee
Knoxville, Tennessee
Springer Science+Business Media, LLC
Llbrary of Congress Cataloglng-ln-Publlcatlon Data
Nucleosldes and nucleotldes as antltumor and antiviral agents / edlted
by Chung K. Chu and David C. Baker.
p. cm.
"Proceedlngs of an American Chemical Soclety Carbohydrate Dlvlslon
Symposlum on Nucleosldes as Antltumor and Antlvlral Agents: Tohru
Ueda Memorial Symposlum, held Aprll 7, 1992, In San Franclsco,
California". -- t.p. verso.
Includes bibllographlcal references and index.
ISBN 978-1-4613-6221-0 ISBN 978-1-4615-2824-1 (eBook)
DOI 10.1007/978-1-4615-2824-1
1. Antiviral agents--Testing--Congresses. 2. Antineoplastic
agents--Testing--Congresses. 3. Nucleosides--Derivatlves
-Therapeutlc use--Testing--Congresses. 4. Nucleotides--Derivatlves-
-Therapeutlc use--Testlng--Congresses. 1. Chu. Chung K.
II. Baker, DavId C., 1946- III. Symposium an Nucleosldes as
Antltumor and Antiviral Agents 11992 San Franciscol
RM411 . N79 1993
616.9·25061--dc20 93-13432
CIP
Proceedings of an American Chemical Society Carbohydrate Division Symposium on Nucleosides as
Antitumor and Antiviral Agents: Tohru Ueda Memorial Symposium, held Apri1 7, 1992, in San Francisco,
California
ISBN 978-1-4613-6221-0
C> 1993 Springer Science+Business Media New York
Originally published by Plenum Press, New York in 1993
Softcover reprint of the hardcover 1s t edition 1993
Ali rights reserved
No part of this book may be reproduced, stored in retrieval system, or transmitted in any format or by any
means, electronic, mechanical, pbotocopying, microfilming, recording, or otherwise, witbout written
permission from the Publisher
This book is dedicated to the memory of Professor Tohru Ueda (1931-1990)
PREFACE
Due to the worldwide epidemic of acquired immunodeficiency syndrome (AIDS), the
past ten years have witnessed a flurry of activity in the chemotherapy of viral diseases.
Unprecedented scientific efforts have been made by scientists and clinicians to combat
infections of human immunodeficiency virus (HIY), the causative agent. Looking back
over the past ten years, we have made remarkable progress toward the treatment of the viral
disease: isolation of HIV only two years after the identification of the disease, plus major
strides in the areas of the molecular biology and virology of the retrovirus, etc. More
remarkably, the discovery of the chemotherapeutic agent AZT (Retrovir) was made within
two years after the isolation and identification of the virus, followed by unprecedented drug
development efforts to culminate in the FDA approval of AZT in twenty-three months,
which was a record-breaking time for approval of any drug for a major disease.
The last six to seven years have particularly been an exciting and productive period for
nucleoside chemists. Since the activity of AZI' was established in 1985, nucleoside chemists
have had golden opportunities to discover additional anti-HIV nucleosipes, which are hoped
to be less toxic and more effective than AZT, and the opportunity continues. As we all are
aware, AZT possesses extremely potent anti-HIY activity, and no other nucleoside or non
nucleoside has surpassed the potency of AZT in vitro. Due to its bone-marrow toxicity,
however, its usefulness for AIDS patients as well as HIY-infected individuals is
unfortunately limited. Furthermore, the isolation of resistant strains from patients who have
been undergoing AZT chemotherapy for more than six months is an increasingly critical
problem in AIDS chemotherapy. More recently, AZT- resistant strains of HIY have been
isolated from patients who have never had AZT therapy. Due to the toxicity and viral
resistance against AZT, a number of drug firms have been making vigorous efforts to come
up with second-generation drugs for HIY infections. Consequently, two other nucleosides,
ddI (didanosine) and ddC (zalcitavine), have recently been approved by the FDA. Currently,
other nucleosides are also undergoing preclinical and clinical studies to determine their
usefulness as anti-HIY drugs, and we are confident that additional clinically useful
nucleosides will emerge from these efforts in the near future.
Of course, other classes of compounds, synthetic as well as natural products, have
been considered as anti-HIY agents. Although some of these classes of compounds, in
particular non-nucleoside reverse transcriptase (RT) inhibitors, exhibit potent anti-HIY
activity in .Yi1rQ, clinical trials suggest that the virus prematurely develops a resistance to
these compounds. Therefore, non-nucleoside RT inhibitors may not play an important role
in AIDS chemotherapy as single agents. As a result, nucleoside chemists can confidently
say that nucleosides are currently the only class of compounds playing a major role in AIDS
chemotherapy. Some diehard nucleoside chemists would further extend their statements that
nucleosides have always been the frontline armaments for human infectious diseases of viral
origin today and will be for years to come. Thus, it is critical to continue exploring the
chemistry and biology of nucleosides to prepare for future viral diseases yet to emerge.
Obviously, nucleosides are not only effective against viruses, but are also effective against
several other disease states such as cancer. This volume also deals with that subject matter,
as well as the related chemistry.
vii
This book is particularly significant in that this volume is dedicated to Professor Tohru
Ueda of Hokkaido University Faculty of Pharmaceutical Sciences. After dedicating over
forty years of his life for nucleoside chemistry, he passed away prematurely at the age of 58
due to lung cancer on September 19,1990. His outstanding contributions in nucleoside
chemistry will remain forever for us, as well as for the future generations that follow in his
footsteps. Finally, we would like to extend our appreciation to the Carbohydrate Division
of the American Chemical Society for providing us the opportunity to organize the Ueda
Memorial Symposium held in San Francisco, California on April 7, 1991, and for allowing
us to edit this volume of manuscripts which have been graciously supplied by friends and
former students of Professor Ueda. We truly appreciate the effort of these authors for
making this book possible. We would like to recognize Yoshitomi, Sankyo, Berlex
Biosciences, ISIS Pharmaceuticals, Gilead Sciences, and Syntex for their financial
contributions, without which the symposium would not have been possible. Special thanks
are also extended to our research groups who thoroughly reviewed each manuscript and to
our secretary, Sandra Fields, who assisted in its compilation.
C.K. Chu D. C. Baker
Department of Medicinal Chemistry Department of Chemistry
College of Pharmacy The University of Tennessee
The University of Georgia Knoxville, Tennessee
Athens, Georgia
viii
CONTENTS
Design of New Types of Antitumor Nucleosides: The Synthesis and Antitumor
Activity of 2'-Deoxy-(2'-C-Substituted)Cytidines. . . . . . . . . . . . . . . . . . 1
Akira Matsuda, Atsushi Azuma, Yuki Nakajima, Kenji Takenuki, Akihito
Dan, Tomoharu lino, Yuichi Yoshimura, Noriaki Minakawa, Motohiro
Tanaka, and Takuma Sasaki
Lithiation Chemistry of Uridine Derivatives: Access to a New Anti-HIV-1 Lead .... 23
Hiromichi Tanaka, Hiroyuki Hayakawa, and Tadashi Miyasaka
A Synthesis of 2'-Fluoro- and 3'-Fluoro-Substituted Purine Nucleosides
via A Direct Approach ................................... 55
KrzysztofW. Pankiewicz and Kyoichi A. Watanabe
Allenols Derived from Nucleic Acid Bases -A New Class of Anti-HIV
Agents: Chemistry and Biological Activity ..................... 73
Jiri Zemlicka
Structure-Activity Relationship among HIV Inhibitory 4'-Substituted
Nucleosides .......................................... 101
Ernest J. Prisbe, Hans Maag, Julien P.H. Verheyden, and
Robert M. Rydzewski
Adenosine-Derived 5'-a-Halo Thioether, Sulfoxide, Sulfone, and
(5'-Halo)Methylene Analogues:Inhibition of S-Adenosyl-L-
Homocysteine Hydrolase ................................. 115
Monis J. Robins, Stanislaw F. Wnuk, Khairuzzaman B. Mullah,
N. Kent Dalley, Ronald T. Borchardt, Younha Lee, and Chong-Sheng Yuan
Approaches to Novel Isomeric Nucleosides as Antiviral Agents 127
Vasu Nair
Carbocyclic 7-Deazaguanosine Nucleosides as Antiviral Agents 141
Stewart W. Schneller, Xing Chen, and Suhaib M. Siddiqi
L-Ascorbic and D-Isoascorbic Acids: Chiron Sources for 1' ,2'-SECO-
Nucleosidesltides, Phospho nates, and Other Molecules of
Biological Interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Elie Abushanab
Synthesis and Anticancer and Antiviral Activity of Certain Pyrimidine
Nucleoside Analogues .................................. 177
Tai-Shun Lin and Mao-Chin Liu
ix
Structure-Activity Correlations of 2',3'-Dideoxy- and 2',3'-Didehydro-
2',3'-Dideoxypyrimidine Nucleosides as Potential Anti-HIV Drugs. . . . . 203
Mohamed Nasr and Steven R. Turk
Stereocontrolled Routes for the Synthesis of Anti-HIV and Anti-HBV
Nucleosides ......................................... 219
J. Warren Beach, Lak S. Jeong, Hea O. Kim, S. Nampalli,
K. Shanmuganathan and Chung K. Chu
5-Substituted Arabinofuranosyluracil Nucleosides as Antiherpesvirus
Agents: From araT to BV-araU.............................. 245
Haruhiko Machida and Shinji Sakata
Conformational Studies and Anti-HIV Activity of Mono-and
Difluorodideoxy Nucleosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
Victor E. Marquez, Benjamin B. Lim, Jospeh J. Barchi, Jr.,
and Marc C. Nicklaus
Crystal Structures and Molecular Conformations of Anti-HIV Nucleosides. . . . . . 285
Patrick Van Roey and Chung K. Chu
Modified Oligoribonucleotides: Synthesis and Preliminary
Evaluation of a-RNA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
Franc;oise Debatt, Carole Chaix, Bemard Rayner and Jean-Louis Imbach
Towards Second-Generation Synthetic Backbones for Antisense
Oligonucleosides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
Yogesh S. Sanghvi and P. Dan Cook
Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
x
DESIGN OF NEW TYPES OF ANTITUMOR NUCLEOSIDES: THE
SYNTHESIS AND ANTITUMOR ACTIVITY OF 2'-DEOXY-(2'-C
SUBSTITUTED)CYTIDINESI,t
Akira Matsuda,*,a Atsushi Azuma,a Yuki Nakajima,a Kenji Takenuki,a
Akihito Dan,a Tomoharu Iino,a Yuichi Yoshimura,a Noriaki Minakawa,a
Motohiro Tanaka,b and Takuma Sasakib
apaculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060,
Japan
bCancer Research Institute, Kanazawa University, Kanazawa 920, Japan
INTRODUCTION
Interest in certain 2'-deoxyribofuranosylnucleosides and arabinofuranosylnucleosides
as potential anticancer chemotherapeutic agents was stimulated by the observation that l-~-D-
arabinofuranosylcytosine (ara-C, la) had antileukemic activity. Ara-C is one of the most
effective drugs for the treatment of adult acute myeloblastic leukemia.2,3 However, its
usefulness is limited by several drawbacks, including its short half-life in plasma, which is
due in part to the rapid deamination to chemotherapeutically inactive l-~-D-arabinofuranosyl-
uracil by the action of cytidine deaminase, development of drug resistance, and
ineffectiveness on solid tumors.4-7 Consequently, with the objective of overcoming these
problems, efforts have been made to develop a large number of prodrugs8 of ara-C or to
substitute certain functional groups other than the hydroxyl group at the 2'-position in place
of the hydrogen atom of 2'-deoxycytidine. By a latter approach, 2'-azido- and 2'-amino-2'
deoxy-~-D-arabinofuranosylcytosines (lb, c) have been synthesized from D-glucose9, 10 or
uridinell and were found to be potent inhibitors of mouse LI2lO leukemia cells in vitro as
well as in vivo. These nucleosides are resistant to deamination by human cytidine
deaminase.9,12 Among a series of 2'-deoxy-2'-halogeno-~-D-arabinofuranosylcytosines
(ld-g),13 2'-fluoro derivative Id showed a potent cell-growth inhibition of mouse L5178Y
hbis paper is dedicated to the memory of Professor Tohru Ueda, deceased September 19, 1990.
Nucleosides and Nucleotides as Antitumor and Antiviral Agents,
Edited by C.K. Chu and D.C. Baker, Plenum Press, New York, 1993