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

  • J Med Chem. 2005 Aug 25;48(17):5504-8. doi: 10.1021/jm0502788.
Jeremy L Clark  1 ,  Laurent Hollecker ,  J Christian Mason ,  Lieven J Stuyver ,  Phillip M Tharnish ,  Stefania Lostia ,  Tamara R McBrayer ,  Raymond F Schinazi ,  Kyoichi A Watanabe ,  Michael J Otto ,  Phillip A Furman ,  Wojciech J Stec ,  Steven E Patterson ,  Krzysztof W Pankiewicz
Affiliations
  • 1. Pharmasset, Inc., 303-A College Road East, Princeton, New Jersey 08540, USA.
PMID: 16107149 DOI: 10.1021/jm0502788
Abstract

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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