Synthesis of carbocyclic nucleosides as potential antiviral agents

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 ¼M) 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 ¼M, EC90 2.8 ¼M), 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'- -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.