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Design, synthesis, and antiviral activity of 2'-deoxy-2'-fluoro-2'-C-methylcytidine, a potent inhibitor of hepatitis C virus replication. 2005
Jeremy L Clark, and
Laurent Hollecker, and
J Christian Mason, and
Lieven J Stuyver, and
Phillip M Tharnish, and
Stefania Lostia, and
Tamara R McBrayer, and
Raymond F Schinazi, and
Kyoichi A Watanabe, and
Michael J Otto, and
Phillip A Furman, and
Wojciech J Stec, and
Steven E Patterson, and
Krzysztof W Pankiewicz
Pharmasset, Inc., 303-A College Road East, Princeton, New Jersey 08540, USA.
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 to provide N(4)-benzoyl-1-[2-fluoro-2-methyl-3,5-di-O-benzoyl-beta-d-ribofuranosyl]cytosine. The protected 2'-C-methylcytidine 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.
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