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Synthesis and anti-HCV activity of a series of ?-d-2'-deoxy-2'-dibromo nucleosides and their corresponding phosphoramidate prodrugs.

ABSTRACT: Several ?-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.

SUBMITTER: Chen Z

PROVIDER: S-EPMC5693771 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Synthesis and anti-HCV activity of a series of β-d-2'-deoxy-2'-dibromo nucleosides and their corresponding phosphoramidate prodrugs.

Chen Zhe Z Cox Bryan D BD Garnier-Amblard Ethel C EC McBrayer Tamara R TR Coats Steven J SJ Schinazi Raymond F RF Amblard Franck F

Bioorganic & medicinal chemistry letters 20171012 23

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 sh ...[more]

PMID: 29066308

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