Synthesis, anti-HIV activity and molecular modeling studies of carbocyclic and 4'-thionucleosides
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This thesis describes the synthesis, biological evaluation and molecular modeling studies of carbocyclic and 4’-thionucleosides as potential antiviral agents. Chapter 1 reviews the activity, metabolism, toxicity and the development of resistance of antiviral nucleosides as well as their status in clinical trials. In Chapter 2, an efficient method for the synthesis of carbocyclic L-2’- deoxynucleosides using D-ribose is presented. The Mitsunobu reaction was used to condense various purine and pyrimidine bases with the carbocyclic sugar moiety. Chapter 3 describes a comparison study of solid phase synthesis versus solution phase synthesis of carbocyclic L-2’-deoxynucleosides. Solid phase synthesis gave better selectivity of N1-alkylated products versus O2-alkylated products in the synthesis of pyrimidine nucleosides, while only N9-alkylated products were obtained in both solid and solution phase synthesis of purine nucleosides. Chapter 4 details the synthesis and biological evaluation against HIV-1 in primary human lymphocytes of ß-L-2’,3’-didehydro-2’,3’-dideoxy-2’-fluoro-4’- thionucleosides (ß-L-2’-F-4’-S-d4Ns). The cytosine, 5-fluorocytosine and adenine derivatives showed potent anti-HIV activities (EC50 0.12, 0.15 and 1.74 µM, respectively) without significant cytotoxicity. The cytosine derivative (ß-L-2’-F-4’-S-d4C), however, showed cross-resistance to 3TC-resistant variant (HIV-1M184V). According to our molecular modeling studies, the steric hindrance between the sugar moiety of the unnatural L-nucleoside and the side chains of Val184 of M184V RT in 3TC-resistant mutant HIV strains destabilizes the RT-nucleoside triphosphate complex, which causes the cross-resistance to 3TC (M184V mutant). Chapter 5 describes the development of an efficient synthetic method for 3’-thio analogs of oxetanocin A. The thietane ring was synthesized using a carbohydrate template and the condensation between the sugar moiety and various heterocyclic bases was conducted using the Pummerer rearrangement reaction. Chapter 6 details the synthesis of various L-thietanose nucleosides with different sugar moieties to extend the usage of the synthetic method of the thietanse ring developed in our group. Chapter 7 desicribes molecular modeling studies showing that the 2’,3’-double bond of the sugar moiety of various 2’,3’-unsaturated nucleosides interacts with the aromatic moiety of Tyr115 of HIV-1 reverse transcriptase (RT) by hydrophobic p–p interaction. In 3TC-resistant mutant (M184V) RT, 2’-fluoro-2’,3’-unsaturated nucleosides with a bulky 4’-substituent experience significant steric hindrance with the side chain of Val184.