Design, synthesis, and antiviral activity of 2'-deoxy-2'-fluoro-2'-C-methylcytidine, a potent inhibitor of hepatitis C virus replication.
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.
Clark
Jeremy L
JL
Pharmasset, Inc., 303-A College Road East, Princeton, New Jersey 08540, USA.
Hollecker
Laurent
L
Mason
J Christian
JC
Stuyver
Lieven J
LJ
Tharnish
Phillip M
PM
Lostia
Stefania
S
McBrayer
Tamara R
TR
Schinazi
Raymond F
RF
Watanabe
Kyoichi A
KA
Otto
Michael J
MJ
Furman
Phillip A
PA
Stec
Wojciech J
WJ
Patterson
Steven E
SE
Pankiewicz
Krzysztof W
KW
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
D000998:Antiviral Agents; C504520:2'-deoxy-2'-fluoro-2'-C-methylcytidine; D003841:Deoxycytidine