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Chapter 1 Is a Comprehensive Review Which Covers the Synthesis and Biological Activities of Important Carbocyclic Nucleosides

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Chapter 1 Is a Comprehensive Review Which Covers the Synthesis and Biological Activities of Important Carbocyclic Nucleosides SYNTHESIS OF CARBOCYCLIC NUCLEOSIDES AS POTENTIAL ANTIVIRAL AGENTS by JIANING WANG (Under the Direction of Chung K. Chu) ABSTRACT This dissertation describes the synthesis, biological evaluation and molecular modeling studies of carbocyclic nucleosides as potential antiviral agents. Chapter 1 is a comprehensive review which covers the synthesis and biological activities of important carbocyclic nucleosides. This review provides not only the basic information of carbocyclic nucleosides but also provides most recent advances in this field. Chapter 2 details the synthesis, anti-HIV-1 activity and mechanism of drug resistance of D- and L-2',3'-didehydro-2',3'-dideoxy-2'-fluoro-carbocyclic nucleosides. The L-form adenosine analog (L-2'F-C-d4A) exhibited the most potent anti-HIV-1 activity (EC50 0.77 μM) without cytotoxicity, while it is cross-resistant to the lamivudine-resistant variant (HIV-1M184V). Molecular modeling studies suggested that the steric hindrance between the sugar moiety of L- 2'F-C-d4A and the side chain of Val184 might destabilize the RT-nucleoside triphosphate complex, which causes the inactivity of L-2'F-C-d4A against M184V mutant. Chapter 3 deals with D- and L-2',3'-didehydro-2',3'-dideoxy-3'-fluoro-carbocyclic nucleosides, which are positional isomers of those described in Chapter 2. New schemes were developed to synthesize the 3'-F isomers, and D-3'F-C-d4G was found to be a very potent anti- HIV-1 compound (EC50 0.4 μM, EC90 2.8 μM), although it was inactive against M184V mutant. According to the molecular modeling studies, cross-resistance of D-3'-F-C-d4G to M184V mutant may be caused by the realignment of the primer and template in the HIV-RTM184V interaction, which destabilizes the RT-inhibitor triphosphate complex, resulting in a significant reduction in anti-HIV activity of the D-guanine derivative. Chapter 4 describes the anti-HCV drug discovery program and consists of four parts: (1) a mini-review of current status of anti-HCV nucleosides; (2) asymmetric synthesis of 2'- fluorine(s) substituted-2'-hydroxyl entecavir analogs as anti-HCV agents; (3) attempts at the synthesis of 2'-β-C-methyl-2'-hydroxyl entecavir analogs; (4) synthesis of 2'-O-methyl-2'- hydroxyl entecavir analogs as potential anti-HCV agents. Finally, a short summary of this dissertation is given in the chapter 5. INDEX WORDS: Antiviral activity, carbocyclic nucleosides, cross-resistance, human immunodeficiency virus (HIV), hepatitis C virus (HCV), entecavir analog SYNTHESIS OF CARBOCYCLIC NUCLEOSIDES AS POTENTIAL ANTIVIRAL AGENTS by JIANING WANG B.S. Beijing Medical University, People’s Republic of China, 1999 M.S. Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, People’s Republic of China, 2002 A Dissertation Submitted to the Graduate Faculty of The University of Georgia in Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY ATHENS, GEORGIA 2008 © 2008 Jianing Wang All Rights Reserved SYNTHESIS OF CARBOCYCLIC NUCLEOSIDES AS POTENTIAL ANTIVIRAL AGENTS by JIANING WANG Major Professor: Chung K. Chu Committee: J. Warren Beach Anthony C. Capomacchia Larry B. Hendry Electronic Version Approved: Maureen Grasso Dean of the Graduate School The University of Georgia August 2008 ACKNOWLEDGEMENTS First and foremost, I would like to express my sincere gratitude to my advisor, Dr. Chung K. Chu for his consistent guidance and support during the course of my Ph.D. program. His enthusiasm and foresight in the research have made a deep impression on me and will be the precious asset for my future career. I would also extend my appreciation to my committees who provided me valuable suggestions for my research and took great effort in helping me during my study: Drs. J. Warren Beach, Anthony C. Capomacchia and Larry B. Hendry. I wish to thank Professor Song Wu who encouraged me to start my Ph.D. study and helped me finish my master degree at the Institute of Materia Medica in Beijing. During this work, I have collaborated with many colleagues in the group and I wish to extend my warmest thanks to all those for sharing their experience and friendship: Dr. Peng Liu, Dr. Ashoke Sharon, Mr. Yunho Jin, Dr. Jagadeeshwar Rao, Dr. Srinivas Gadthula, Dr. Marco Radi, Dr. Zhanling Cheng and Dr. Yanyan Yang. My special gratitude goes to Ms. Helena Smith for her wonderful assistance and support. I owe a great deal of thanks to my wife, Jinghua Shi and my parents in China. Without their unconditional love and support, it would be impossible for me to finish my Ph.D. work in U.S.A. iv TABLE OF CONTENTS Page ACKNOWLEDGEMENTS........................................................................................................... iv LIST OF TABLES....................................................................................................................... viii LIST OF FIGURES .........................................................................................................................x LIST OF SCHEMES.................................................................................................................... xiv CHAPTER 1 INTRODUCTION AND LITERATURE REVIEW .....................................................1 INTRODUCTION.....................................................................................................2 FIVE-MEMBERED CARBOCYCLIC NUCLEOSIDES ........................................3 THREE-MEMBERED CARBOCYCLIC NUCLEOSIDES ..................................47 FOUR-MEMBERED CARBOCYCLIC NUCLEOSIDES.....................................52 SIX-MEMBERED CARBOCYCLIC NUCLEOSIDES.........................................55 CONCLUSION .......................................................................................................55 2 SYNTHESIS, ANTIVIRAL ACTIVITY, AND MECHANSIM OF DRUG RESISTANCE OF D- AND L-2',3'-DIDEHYDRO-2',3'-DIDEOXY-2'-FLUORO- CARBOCYCLIC NUCLEOSIDES.............................................................................57 ABSTRACT ............................................................................................................58 INTRODUCTION...................................................................................................59 RESULTS AND DISCUSSION .............................................................................61 EXPERIMENTAL SECTION ................................................................................76 v 3 D- AND L-2',3'-DIDEHYDRO-2',3'-DIDEOXY-3'-FLUORO-CARBOCYCLIC NUCLEOSIDES: SYNTHESIS, ANTI-HIV ACTIVITY AND MECHANISM OF RESISTANCE ...........................................................................................................103 ABSTRACT ..........................................................................................................104 INTRODUCTION.................................................................................................105 RESULTS AND DISCUSSION ...........................................................................106 EXPERIMENTAL SECTION ..............................................................................122 4 ASYMMETRIC SYNTHESIS OF NOVEL 2'-FLUORINE(S) SUBSTITUTED, 2'-β- C-METHYL-2'-HYDROXYL AND 2'-O-METHYL-2'-HYDROXYL ENTECAVIR ANALOGS AS POTENTIAL ANTI-HCV AGENTS ..............................................144 PART I: INTRODUCTION - BIOLOGICALLY ACTIVE ANTI-HCV NUCLEOSIDES....................................................................................................145 PART II: ASYMMETRIC SYNTHESIS OF NOVEL 2'-FLUORINE(S) SUBSTITUTED ENTECAVIR ANALOGS AS POTENTIAL ANTI-HCV AGENTS ...............................................................................................................158 PART III: ASYMMETRIC SYNTHESIS OF NOVEL 2'-β-C-METHYL-2'- HYDROXYL ENTECAVIR ANALOGS AS POTENTIAL ANTI-HCV AGENTS .............................................................................................................179 PART IV: ASYMMETRIC SYNTHESIS OF NOVEL 2'-O-METHYL-2'- HYDROXYL ENTECAVIR ANALOGS AS POTENTIAL ANTI-HCV AGENTS .............................................................................................................184 EXPERIMENTAL SECTION ..............................................................................186 5 CONCLUSION..........................................................................................................237 vi REFERENCES ............................................................................................................................241 vii LIST OF TABLES Page Table 1.1: Antiviral Activity of (-) & (+) 5'-Noraristeromycin. ....................................................12 Table 1.2: Antiviral activity of compounds 140 and 141 against HIV-wild type (xxBRU) and M184V mutant................................................................................................................29 Table 2.1: In vitro anti-HIV-1 activity and toxicity of D- and L- 2'-fluoro-2',3'-didehydro- carbocyclic nucleosides. .................................................................................................68 Table 2.2: Activity of selected nucleosides against lamivudine-resistant virus (HIV-1M184V) in human PBM cells............................................................................................................70 Table 2.3: In vitro anti-HIV activity of selected 2'F-C-d4Ns against HIV wild type (WT) virus and correlation with calculated energy of complex (2'F-C-d4N-TPs) / HIV-RT. ..........71 Table 2.4: In vitro anti-HIV activity
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