title: Design, synthesis, and antiviral activity of 2'-deoxy-2'-fluoro-2'-C-methylcytidine, a potent inhibitor of hepatitis C virus replication.
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.
authors.affiliation: Pharmasset, Inc., 303-A College Road East, Princeton, New Jersey 08540, USA.
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Clark
authors.forename: Laurent
authors.initials: L
authors.lastname: Hollecker
authors.forename: J Christian
authors.initials: JC
authors.lastname: Mason
authors.forename: Lieven J
authors.initials: LJ
authors.lastname: Stuyver
authors.forename: Phillip M
authors.initials: PM
authors.lastname: Tharnish
authors.forename: Stefania
authors.initials: S
authors.lastname: Lostia
authors.forename: Tamara R
authors.initials: TR
authors.lastname: McBrayer
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
authors.forename: Kyoichi A
authors.initials: KA
authors.lastname: Watanabe
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Otto
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Furman
authors.forename: Wojciech J
authors.initials: WJ
authors.lastname: Stec
authors.forename: Steven E
authors.initials: SE
authors.lastname: Patterson
authors.forename: Krzysztof W
authors.initials: KW
authors.lastname: Pankiewicz
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; C504520:2'-deoxy-2'-fluoro-2'-C-methylcytidine; D003841:Deoxycytidine