| HIV, the causative agent of the deadly disease known as AIDS, has received enormous attention in the past several years. A number of dideoxynucleosides have been discovered to be potent against HIV reverse transcriptase, one of the key enzymes involved in the viral replication cycle. Several of them have been licensed as drugs for the treatment of HIV infection. However, all of them have inherent drawbacks such as cytotoxicity and viral resistance.; Reported in the thesis are the results of a search for more potent compounds with lower toxicity against HIV reverse transcriptase. The thesis includes three parts. In the first part, effects of hypermodifications in the nucleobase moiety of dideoxynucleosides on antiviral profile were studied. Analogues bearing a ring extended nucleobase moiety of two active compounds, both normal dideoxyadenosine and 2{dollar}spprime{dollar}-isomeric dideoxyadenosine, were synthesized. Hydrolytic stability studies for these compounds indicated that transposition of the nucleobase moiety from the normal 1{dollar}spprime{dollar}-position to the 2{dollar}spprime{dollar}-position resulted in the extreme stability of the isomeric compound even under severe conditions. This compound was also found to be a poor substrate for the mammalian enzyme, adenosine deaminase, whereas its normal counterpart was a moderately good substrate for the same enzyme. Although the novel dideoxynucleosides exhibited low antiviral activity against HIV, they served as probes for the binding site of HIV reverse transcriptase, and revealed that HIV reverse transcriptase does not tolerate a dimensionally enlarged nucleobase.; In the second part, a class of new compounds bearing the functionalities of both nucleoside and nonnucleoside inhibitors of HIV reverse transcriptase were synthesized by methodologies involving selective reduction of bis-tosylate and nucleophilic displacement of an appropriate sugar by highly fused heterocyclic compounds. However, these new compounds did not show notable antiviral activity against HIV.; Finally, a class of novel dideoxynucleosides containing a (3,3,0) fused bicyclic sugar moiety were studied as potential antiviral agents. This class of bicyclic nucleosides are structurally related to natural griseolic acids. Total synthesis of the bicyclic dideoxynucleosides were realized concisely and stereospecifically by starting from a bicyclic sugar precursor. Absolute stereochemistry was established by 1D and 2D NMR experiments. |
