Design, synthesis, and antiviral activity of 2′-deoxy-2′-fluoro-2′-C-methylcytidine, a potent inhibitor of hepatitis C virus replication

The pyrimidine nucleoside beta-D-2'-deoxy-2'-fluoro-2'-C-methylcytidine (1) was designed as a hepatitis C virus RNA-dependent RNA polymerase (HCV RdRp) inhibitor. The title compound was obtained by a DAST fluorination of N-4-benzoyl-1-(2-methyl-3,5-di-O-benzoyl-beta-D-arabinofuranosyl]cytosine (6) to provide N-4-benzoyl-1-[2-fluoro-2-methyl-3,5-di-O-benzoyl-beta-D-ribofuranosyl]cytosine (7a). The protected 2'-C-methylcytidine (7c) was obtained as a byproduct from the DAST fluorination and allowed for the preparation of two biologically active compounds from a common precursor. Compound 1 and 2'-C-methylcytidine were assayed in a subgenomic HCV replicon assay system and found to be potent and selective inhibitors of HCV replication. Compound 1 shows increased inhibitory activity in the HCV replicon assay compared to 2'-C-methylcytidine and low cellular toxicity.