A Divergent Approach for the Synthesis of D- and L-4 '-Ethynyl Dioxolane Nucleosides with Potent Anti-HIV Activity

초록

Novel 4'-C-ethynyl isomeric dioxolane nucleoside analogues (beta-D, alpha-D, beta-L, and alpha-L, respectively) are successfully synthesized via a divergent strategy from the common starting material, (Z)-but-2-ene-1,4-diol, and are characterized and evaluated for their anti-HIV-1 and anti-HIV-2 activities. The beta-D and beta-L products display potent in vitro activities against HIV-1 (IIIB) with EC50 values of 0.75 and 0.87 mu M, respectively, and against HIV-2 (ROD) with EC50 values of 0.75 and 0.35 mu M, respectively, being better in comparison with 3TC [EC50, 5.27 mu M (HIV1) and 1.30 mu M (HIV-2)]. The beta-D and beta-L nucleosides also potently inhibit different drug-resistant strains of the HIV-1 virus (L100I, K103N, Y181C, and V106A). The selectivity indices and cytotoxic profiles of the beta-D and beta-L nucleosides are much better than those of the standard drugs AZT and d4T.

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