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

Jeremy L. Clark, 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

Research output: Contribution to journalArticlepeer-review

163 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)5504-5508
Number of pages5
JournalJournal of medicinal chemistry
Volume48
Issue number17
DOIs
StatePublished - Aug 25 2005

Fingerprint Dive into the research topics of 'Design, synthesis, and antiviral activity of 2′-deoxy-2′- fluoro-2′-C-methylcytidine, a potent inhibitor of hepatitis C virus replication'. Together they form a unique fingerprint.

Cite this