ヌクレオシドのリチウム化反応から抗HIV-1リード化合物の創製へ
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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.<BR>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, <I>e.g.</I> isopropylidene group. Subsequent reaction with a variety of electrophiles furnishes 6-substituted derivatives, which are difficult to synthesize by any other methods.<BR>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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