Design, Synthesis, and Antiviral Activity of 2'-Deoxy-2'-fluoro-2'-C-methylcytidine, a Potent Inhibitor of Hepatitis C Virus Replication

JL Clark, L Hollecker, JC Mason… - Journal of medicinal …, 2005 - ACS Publications
JL Clark, L Hollecker, JC Mason, LJ Stuyver, PM Tharnish, S Lostia, TR McBrayer…
Journal of medicinal chemistry, 2005ACS Publications
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-β-d-arabinofuranosyl] cytosine (6) to provide N 4-benzoyl-1-[2-fluoro-2-methyl-3, 5-
di-O-benzoyl-β-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 …
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 N4-benzoyl-1-(2-methyl-3,5-di-O-benzoyl-β-d-arabinofuranosyl]cytosine (6) to provide N4-benzoyl-1-[2-fluoro-2-methyl-3,5-di-O-benzoyl-β-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.
ACS Publications