Table Of ContentAcyclic, Carbocyclic and L-Nucleosides
Acyclic, Carbocyclic and
Nucleosides
L-
L.A. Agrofoglio
Universite d'Orleans
Orleans
France
S.R. Challand
Beckenham
UK
SPRINGER SCIENCE+BUSINESS MEDIA, LLC
Library of Congress Catalog Card Number: 98-71636
Printed an acid-free paper
ISBN 978-94-010-3734-1 ISBN 978-94-007-0816-7 (eBook)
DOI 10.1007/978-94-007-0816-7
Ali rights reserved
© 1998 Springer Science+Business Media New York
Originally published by Kluwer Academic Publishers in 1998
Softcover reprint ofthe hardcover Ist edition 1998
No part of the material protected by this copyright notice may be reproduced or
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Contents
Preface ix
General introduction 1
References 15
1 The chemistry of acyclic nucleosides 18
l.l Introduction 18
1.2 Acyclovir and its derivatives 22
1.2.1 Synthesis of acyclovir 22
1.2.2 Purine modified acyclovir analogues 26
1.2.3 Pyrimidine analogues of acyclovir 38
1.2.4 Carba-analogues of acyclovir and related compounds 42
1.2.5 Prodrugs and other derivatives of acyclovir 46
1.3 Ganciclovir (DHPG) and its derivatives 55
1.3.1 Synthesis of ganciclovir (DHPG) 55
1.3.2 Purine modified ganciclovir analogues 57
1.3.3 Pyrimidine analogues of ganciclovir 65
1.3.4 Acyclic sugar modified analogues of ganciclovir 68
1.3.5 Prodrugs of ganciclovir and penciclovir 80
1.4 Acyclic nucleoside phosphonate analogues 87
1.4.1 Synthesis of HPMP derivatives 89
1.4.2 Synthesis of PME derivatives 95
1.5 Seconucleosides and their derivatives 103
1.5.1 2' ,3' -Seconucleosides 104
1.5.2 I' ,2' -Seconucleosides 106
1.5.3 3' ,4' -Seconucleosides 111
1.6 Miscellaneous acyclic nucleosides 114
1.6.1 HEPT and its analogues 114
1.6.2 Cytallene and adenallene 116
1.6.3 Other acyclic nucleosides 122
References 128
2 Biological activity of acyclic nucleosides 136
2.1 Introduction 136
2.2 Acyclovir and its prodrugs 137
2.3 Ganciclovir and its prodrugs 143
2.4 Penciclovir and famciclovir 149
2.5 Phosphonylmethoxyalkylpurines 153
2.5.1 PMEA and PMEG 155
2.5.2 HPMPA and HPMPC 162
2.6 HEPT 165
2.7 Allenes 167
2.8 Conclusion 168
References 168
VI CONTENTS
3 The chemistry of carbocyclic nucleosides 174
3.1 Introduction 174
3.2 Coupling procedures for introducing the heterocycle moiety 176
3.2.1 Direct introduction of the heterocycle 176
3.2.2 Construction of purine and pyrimidine carbocyclics via precursors 182
3.3 Synthesis offunctionalized cyclopentylamines with ribo-, arabino-, or
xylo-configurations 184
3.3.1 Carbocyclic analogues ofribofuranosyl nucleosides: aristeromycin 184
3.3.2 Carbocyclic analogues of deoxyribofuranosyl nucleosides 194
3.3.3 Carbocyclic analogues of arabi no and xylofuranosyl nucleosides 199
3.3.4 Carbovir 201
3.3.5 The neplanocins 204
3.4 Fluorinated carbocyclic nucleoside analogues 207
3.4.1 Summary of general methods for introducing fluorine atoms into
carbocyclic sugars 208
3.4.2 Synthesis of C-6' -fluorinated carbocyclic nucleosides 213
3.4.3 Synthesis ofC-2'-fluorinated carbocyclic nucleosides 215
3.4.4 Synthesis ofC-3'-fluorinated carbocyclic nucleosides 217
3.4.5 Synthesis of gem-difluorinated carbocyclic nucleosides 218
3.5 Carbocycles substituted by other functional groups 218
3.5.1 Azido and amino carbocyclic nucleoside analogues 218
3.5.2 6'-p-Hydroxyribonucleosides 219
3.5.3 Carbocyclic nucleosides lacking the 5'-methylene group 221
3.5.4 6'-p-Hydroxymethyl carbovir 223
3.5.5 Carbocyclic nucleosides with a bicyclic ring sugar 224
3.5.6 Carbocyclic nucleosides homologated at the 3'-position 228
3.6 Cyclobutyl analogues ofnucleosides 230
3.6.1 From cyclobutene-epoxides 231
3.6.2 From cyclobutanones 232
3.6.3 Synthesis of fluorinated cyclobutyl nucleosides 237
3.6.4 Synthesis from pinenes 239
3.6.5 Miscellaneous four-ring carbocyclic nucleosides 239
3.7 Synthesis of cyclopropyl analogues of nucleosides 242
3.8 Cyclohexyl nucleosides 247
References 249
4 Biological activity of carbocyclic nucleosides 256
4.1 Introduction 256
4.2 Inhibitors of AdoHcy hydrolase (SA H) 256
4.2.1 Neplanocin A and its derivatives 256
4.2.2 Aristeromycin and other inhibitors of SAH 261
4.3 Inhibitors of viral DNA replication 263
4.3.1 Carbocyclic 2' -deoxyguanosine (2' -COG) 263
4.3.2 Carbocyclic arabinofuranosyl nucleosides 265
4.3.3 Carbocyclic analogues of 2' -deoxyuridine 267
4.3.4 Cyclobutyl analogues of nucleosides 268
4.3.5 Carbocyclic nucleosides with fixed sugar conformations 271
4.4 Reverse transcriptase inhibitors; carbovir and its prodrugs 274
4.5 Cyclopropyl-or cyclohexyl-analogues of nucleosides 280
4.6 Conclusion 280
References 281
5 The chemistry of L-nucleosides 285
5.1 Introduction 285
CONTENTS Vll
5.2 Synthesis of L-nucJeosides 287
5.2.1 Synthesis of {P/IX)-L-dideoxynucJeosides (L-d2N and L-d4N) 287
5.2.2 Synthesis of fluorinated L-nucleosides 298
5.2.3 Synthesis of p-L-oxathiolanyl-and P-L-dioxolanyl nucJeosides 301
5.2.4 Synthesis of miscellaneous p-L-nucJeosides 309
5.3 Synthesis of iso-L-nucJeosides 316
5.4 Summary 319
References 319
6 Anti-viral activities of L-nucleosides 323
6. I Introduction 323
6.2 Anti-viral activity of P-L-ddNs 324
6.2.1 P-L-ddC and P-L-FddC 324
6.2.2 Other P-L-ddNs 325
6.3 Activities of P-L-oxothiolanyl and dioxolanyl nucJeosides 328
6.3.1 L-Oxothiolanyl nucJeosides 328
6.3.2 L-Dioxolanyl nucleosides 330
6.4 Activity of P-L-fluorinated nucJeosides 331
6.5 Activity of miscellaneous p-L-nucJeosides 332
6.5.1 2' -Deoxy and 2'-deoxythia-L-nucJeosides 332
6.5.2 Miscellaneous 332
6.6 Conclusion 333
References 333
Appendix A Nomenclature of nucleosides 336
Appendix B Abbreviations in widespread use 340
Appendix C Glossary of terms used 344
Appendix D Acknowledgements 358
Index 377
Preface
The study of nucleosides and their phosphorylated derivatives as biologic
ally active molecules has been a fundamental pursuit since the 1940s
and 50s. It was then that the nature of nucleic acids in cells was
established, ultimately resulting in the identification of the double helix
structure of DNA and the explanation of the genetic code. As the
metabolic processes by which these materials were manipulated in vivo
became understood, so the investigation of close analogues of the
components of nucleic acids grew, with the expectation that they might
interfere in some way with the natural pathways and perhaps have utility
as drugs. Early work focused on traditional nucleoside analogues in which
the base was linked to one or other of the naturally occurring sugars. Some
of these were indeed shown to possess anti-metabolic properties but it
became apparent that their usefulness was severely limited by instability
and poor selectivity. Since the discovery of the first successful anti-viral
drug, acyclovir, in 1974, interest has diversified towards compounds in
which the sugar component of the nucleoside has departed significantly
from the natural form. Some of this activity has resulted in structures
containing unusual substituents, for example the azido group of AZT, used
for treating HIV infections, but there have been many more studies in
which the sugar has been substantially altered into a carbocyclic ring of
varying size, or an open chain. More recently it has been appreciated that
enantiomers of natural sugars (the L-series) may possess unprecedented
patterns of selectivity, at least as far as viruses such as HIV and Hepatitis
B are concerned, both of which are important targets for anti-viral
chemotherapy.
The key to finding useful anti-viral agents is to attain high selectivity
of action, for which the compounds need to be sufficiently similar to the
natural materials that they can be recognized by viral enzymes but
sufficiently different that they will not interfere with the essential enzymes
of the host cell. The general principles behind the design of nucleosides
with carbocyclic, acyclic and unnaturally configured sugars are similar in
conception, but the ways of making these compounds are in many cases
not trivial and a wide variety of synthetic strategies have been adopted.
Our objective in this book is to draw together in one work all of this
material in a form which is easily consulted and at the same time guides
the reader into the research literature on the subject. The coverage is
x PREFACE
primarily from the point of view of the medicinal chemist, but outline
guidance on the main trends in biological activity is provided as well.
Inevitably the main focus of biological interest is on anti-viral agents
because this is where there has been the greatest success and consequently
the most detailed biochemical and biological study, but this is not to say
that nucleosides have no potential for use in other areas. A great number
of nucleosides have in the past been investigated as anti-tumour agents,
though few have come into regular use and much of the thinking in the
anti-cancer field has now shifted to ways of controlling cell growth
through oncogenes and other regulatory factors. Sporadic reports on the
anti-microbial activity of nucleosides have also appeared from time to
time, but nevertheless at the time of writing it is with anti-viral
chemotherapy that most medicinal chemists would associate nucleoside
analogues.
Among the people we would like to thank for assistance in the
preparation of this manuscript are Professor Charles Rees for originally
suggesting the idea, Navin Sullivan for help with the initial planning, the
Agence Nationale de Recherches sur Ie SIDA (ANRS) for financial
support, and the ICOA for logistical support throughout. Special gratitude
is due to Dr Mi-Gyoung Agrofoglio-Lee for her critical remarks, her
patience in 'holding the fort' while the manuscript was in preparation, her
efficient help in proofreading and in the preparation of the diagrams. We
would also like to thank Julia Challand for moral support and Paul Sayer
and the former staff at Chapman & Hall.
L.A. Agrofoglio
S.R. Challand
Orleans, July, 1998
General introduction
Interest in chemical entities capable of blocking or modifying cell
metabolism ultimately goes back to the discovery of the structure of DNA
in the 1950s. The understanding of the biochemical processes by which
DNA controls cell viability in vivo rapidly led to the idea that compounds
could be designed and synthesized which might interfere with one or more
of these processes. Several classes of drug have since been discovered
which depend for their effect on some kind of modification of the proper
functioning of nucleic acids. Intercalators and alkylating agents were
among the earliest therapeutic agents which were recognized as behaving
in this way and were widely used as treatments for bacterial infections and
some forms of cancer. It was a small but significant step forward to arrive
at the notion that analogues of the four natural nucleoside components
of DNA might have similar effects. The result was multifarious pro
grammes of research aimed at synthesizing such compounds and
investigating their effects on biological and biochemical systems.
Several times since the 1950s the threat of human disease provided great
stimulus to this effort, particularly through programmes initiated in the
early 1970s to combat cancer and, more recently, viral infections. The
most recent example was the impetus provided by the appearance of HIV
and AIDS in the early 1980s and the incidental realization that hepatitis B,
which resembles HIV in some respects, might be treated by similar or
closely related drugs.
One of the earliest nucleoside analogues to achieve some degree of success
was p-o-5-iodo-2'-deoxyuridine (IUdR, Idoxuridine) which was described
by Prusoff et al. [1] in the early 1960s. The compound found some use in the
topical treatment of herpes virus infections but did not advance into
widespread use because its selectivity of action was poor and it gave rise to
intolerable side-effects when used systemically. Since then the search for
novel nucleosides with anti-viral or anti-tumour properties has been diligent
and diverse, driven by the desire to attain the goal of potent activity but
without the associated toxicity. Some of the results of this research are
represented in Figure 0.1, where compounds with anti-viral and anti-cancer
applications are illustrated. For example, I-p-o-arabinofuranosylcytosine
(ara-C) (1) and 5-ftuoro-2'-deoxyuridine (2) display anti-cancer activities
[2-6]; 2' -ftuoro-5-iodo-l-p-o-arabinofuranosyl cytosine (FIAC) (3), 2'
ftuoro-5-methyl-l-p-o-arabinofuranosyluracil (FMA U) (4), and 2' -ftuoro-
OH OH
2
ara-C
5-FU
anti-tumour activity
OH OH
3 4 5
FIAC FMAU FIAU
anti-HSV activity
HN)M'
0 0
Jd)
H6c~
~I
HO\:)
Hold
H°tJ
N,
6 7 8
AZT ddC ddl
anti-HI V activity
Figure 0.1
