Abstract
Lithiation of nucleosides has been shown to be a highly general method for chemical modification of the base moiety. A wide range of substitutions can be accomplished simply by using different electrophiles in the reaction with the respective lithiated species.In the case of uridine, the protecting group of the sugar hydroxyl groups appeared to be an important determinant of the efficiency and regiochemical outcome of the lithiation. Regiospecific abstraction of H-6 in uracil moiety with LDA takes place only when 2'- and 3'-hydroxyl groups are simultaneously protected with an alkylidene group, e.g. isopropylidene group. Subsequent reaction with a variety of electrophiles furnishes 6-substituted derivatives, which are difficult to synthesize by any other methods.As an application of the C-6 lithiation with LDA, a series of 6-iodo and 6-phenylthio acyclouridines were synthesized. Among these derivatives, 1- [(2-hydroxyethoxy) methyl] -6-phenylthiothymine (HEPT) was found to be a new lead for anti-HIV agents. The activity of HEPT is highly specific to HIV-1 : other viruses, including HIV-2, are totally non-susceptible to HEPT. Further synthetic study improved the activity to a greater extent. In terms of excellent activity, low toxicity, and effectiveness against AZT-resistant HIV-1, these HEPT analogues constitute promising candidates for AIDS chemotherapy.
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