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Discovery of 2'-?-C-Methyl-2'-?-C-fluorouridine Phosphoramidate Prodrugs as Inhibitors of Hepatitis C Virus.

ABSTRACT: 2'-?-C-Methyl-2'-?-C-fluorouridine and its phosphoramidate prodrugs were synthesized and evaluated for their inhibitory activity against HCV. The structure-activity relationship analysis of the phosphoramidate moiety found that 17m, 17q, and 17r exhibit potent activities against HCV, with EC50 values of 1.82 ± 0.19, 0.88 ± 0.12, and 2.24 ± 0.22 ?M, respectively. The docking study revealed that the recognition of the 2'-?-F by Arg158, 3'-OH by N291, and the Watson-Crick pairing with the template allowed 23 to form the in-line conformation necessary for its incorporation into the viral RNA chain.

SUBMITTER: Zeng D

PROVIDER: S-EPMC5150674 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Discovery of 2'-α-C-Methyl-2'-β-C-fluorouridine Phosphoramidate Prodrugs as Inhibitors of Hepatitis C Virus.

Zeng Debin D Zhang Rui R Nie Quandeng Q Cao Lin L Shang Luqing L Yin Zheng Z

ACS medicinal chemistry letters 20161019 12

2'-α-C-Methyl-2'-β-C-fluorouridine and its phosphoramidate prodrugs were synthesized and evaluated for their inhibitory activity against HCV. The structure-activity relationship analysis of the phosphoramidate moiety found that 17m, 17q, and 17r exhibit potent activities against HCV, with EC50 values of 1.82 ± 0.19, 0.88 ± 0.12, and 2.24 ± 0.22 μM, respectively. The docking study revealed that the recognition of the 2'-β-F by Arg158, 3'-OH by N291, and the Watson- ...[more]

PMID: 27994763

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