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ID: ALA4177626
Journal: Bioorg Med Chem Lett
Title: Synthesis and anti-HCV activity of a series of β-d-2'-deoxy-2'-dibromo nucleosides and their corresponding phosphoramidate prodrugs.
Authors: Chen Z, Cox BD, Garnier-Amblard EC, McBrayer TR, Coats SJ, Schinazi RF, Amblard F.
Abstract: Several β-d-2'-deoxy-2'-substituted nucleoside analogs have displayed potent and selective anti-HCV activities and some of them have reached human clinical trials. In that regard, we report herein the synthesis of a series of 2'-deoxy,2'-dibromo substituted U, C, G and A nucleosides 10a-d and their corresponding phosphoramidate prodrugs 13a-d. The synthesized nucleosides 10a-d and prodrugs 13a-d were evaluated for their inhibitory activity against HCV as well as cellular toxicity. The results showed that the most potent compound was prodrug 13a, which exhibited micromolar inhibitory activity (EC50 = 1.5 ± 0.8 µM) with no observed toxicity. In addition, molecular modeling and free energy perturbation calculations for the 5'-triphosphate formed from 13a and related 2'-modified nucleotides are discussed.
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