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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. Understanding of the biochemical processes involved in cell metabolism rapidly led to the idea that compounds could be designed which might interfere with these processes, and thus could be used in the treatment of the diseases caused by viral infection. Since then, several classes of drugs have been discovered which depend for their effect on modification of the proper functioning of nucleic acids and, with the introduction of acyclovir for the treatment of Herpes infections, nucleoside analogues have become the cornerstone of antiviral chemotherapy.
The success of the early nucleoside agents, the toxicity and metabolic instability of many nucleoside analogues, and the effects of viral pathogens on public health are driving the design, synthesis and evaluation of new nucleoside analogues, with much attention turning to nucleosides containing `non natural' sugar analogues. This book focuses on the development of these agents, and draws together all the available material in an easily consulted form, which at the same time guides the reader into the research literature on the subject. Written primarily for the medicinal chemist, coverage includes both synthetic strategies and outline guidance on the main trends in biological activity. Particular attention is drawn to the comparison of synthetic routes to compounds with their natural analogues. Finally, the important antiviral activities of the compounds are treated, including anti-retrovirus, anti-hepadnavirus and anti-herpes virus properties.
Written mainly for medicinal chemists in the pharmaceutical industry and synthetic organic chemists in academe, this book will also be attractive to researchers in institutions focusing on cellular metabolism. Advanced students of organic chemistry will find the clear discussion of the synthetic strategies adopted in the development of these compounds a useful introduction to this exciting and challenging area.

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. Understanding of the biochemical processes involved in cell metabolism rapidly led to the idea that compounds could be designed which might interfere with these processes, and thus could be used in the treatment of the diseases caused by viral infection. Since then, several classes of drugs have been discovered which depend for their effect on modification of the proper functioning of nucleic acids and, with the introduction of acyclovir for the treatment of Herpes infections, nucleoside analogues have become the cornerstone of antiviral chemotherapy.
The success of the early nucleoside agents, the toxicity and metabolic instability of many nucleoside analogues, and the effects of viral pathogens on public health are driving the design, synthesis and evaluation of new nucleoside analogues, with much attention turning to nucleosides containing `non natural' sugar analogues. This book focuses on the development of these agents, and draws together all the available material in an easily consulted form, which at the same time guides the reader into the research literature on the subject. Written primarily for the medicinal chemist, coverage includes both synthetic strategies and outline guidance on the main trends in biological activity. Particular attention is drawn to the comparison of synthetic routes to compounds with their natural analogues. Finally, the important antiviral activities of the compounds are treated, including anti-retrovirus, anti-hepadnavirus and anti-herpes virus properties.
Written mainly for medicinal chemists in the pharmaceutical industry and synthetic organic chemists in academe, this book will also be attractive to researchers in institutions focusing on cellular metabolism. Advanced students of organic chemistry will find the clear discussion of the synthetic strategies adopted in the development of these compounds a useful introduction to this exciting and challenging area.

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CONTENTS

Preface = ⅸ

General introduction = 1

 References = 15

1 The chemistry of acyclic nucleosides = 18

 1.1 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 Carba­analogues 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 $$1′$$, $$2′$$­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

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 of functionalized cyclopentylamines with ribo­, arabino­, or xylo­configurations = 184

  3.3.1 Carbocyclic analogues of ribofuranosyl nucleosides : aristeromycin = 184

  3.3.2 Carbocyclic analogues of deoxyribofuranosyl nucleosides = 194

  3.3.3 Carbocyclic analogues of arabino 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 of C­$$2′$$­fluorinatcd carbocyclic nucleosides = 215

  3.4.4 Synthesis of C­$$3′$$­fluorinated carbocyclic nucleosides = 217

  3.4.5 Synthesis of gem­difluorinated 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 $$6′$$­β­Hydroxyribonucleosides = 219

  3.5.3 Carbocyclic nucleosides lacking the $$5′$$­methylene group = 221

  3.5.4 $$6′$$­β­Hydroxymethyl 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 of nucleosides = 230

  3.6.1 From cyclobutene­epoxides = 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 four­ring 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 （SAH） = 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 （$$2′$$­CDG） = 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 L­nucleosides = 285

 5.1 Introduction = 285

 5.2 Synthesis of L­nucleosides = 287

  5.2.1 Synthesis of （β／α）­L­dideoxynucleosides （L­d2N and L­d4N） = 287

  5 2.2 Synthesis of fluorinated L­nucleosides = 298

  5.2.3 Synthesis of β­L­oxathiolanyl­ and β­L­dioxolanyl nucleosides = 301

  5.2.4 Synthesis of miscellaneous β­L­nucleosides = 309

 5.3 Synthesis off iso­L­nucleosides = 316

 5.4 Summary = 319

 References = 319

6 Anti­viral activities of L­nucleosides = 323

 6.1 Introduction = 323

 6.2 Anti­viral activity of β­L­ddNs = 324

  6.2.1 β­L­ddC and β­L­FddC = 324

  6.2.2 Other β­L­ddNs = 325

 6.3 Activities of β­L­oxothiolanyl and dioxolanyl nucleosides = 328

  6.3.1 L­Oxothiolanyl nucleosides = 328

  6.3.2 L­Dioxolanyl nucleosides = 330

 6.4 Activity of β­L­fluorinated nucleosides = 331

 6.5 Activity of miscellaneous β­L­nucleosides = 332

  6.5.1 $$2′$$­Deoxy and $$2′$$­deoxythia­L­nucleosides = 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