Synthesis and anti-viral activity of a series of d- and l-2'-deoxy-2'-fluororibonucleosides in the subgenomic HCV replicon system.
Based on the discovery of (2'R)-d-2'-deoxy-2'-fluorocytidine as a potent anti-hepatitis C virus (HCV) agent, a series of d- and l-2'-deoxy-2'-fluororibonucleosides with modifications at 5- and/or 4-positions were synthesized and evaluated for their in vitro activity against HCV and bovine viral diarrhea virus (BVDV). The key step in the synthesis, the introduction of 2'-fluoro group, was achieved by either fluorination of 2,2'-anhydronucleosides with hydrogen fluoride-pyridine or potassium fluoride, or a fluorination of arabinonucleosides with DAST. Among the 27 analogues synthesized, only the 5-fluoro compound, namely (2'R)-d-2'-deoxy-2',5-difluorocytidine (13), demonstrated potent anti-HCV activity and toxicity to ribosomal RNA. The replacement of the 4-amino group with a thiol group resulted in the loss of activity, while the 4-methylthio substituted analogue (25) exhibited inhibition of ribosomal RNA. As N(4)-hydroxycytidine (NHC) had previously shown potent anti-HCV activity, we combined the two functionalities of the N(4)-hydroxyl and the 2'-fluoro into one molecule, resulting (2'R)-d-2'-deoxy-2'-fluoro-N(4)-hydroxycytidine (23). However, this nucleoside showed neither anti-HCV activity nor toxicity. All the l-forms of the analogues were devoid of anti-HCV activity. None of the compounds showed anti-BVDV activity, suggesting that the BVDV system cannot always predict anti-HCV activity.
Shi
Junxing
J
Pharmasset, Inc., 1860 Montreal Rd., Tucker, GA 30084, USA. jshi@pharmasset.com
Du
Jinfa
J
Ma
Tianwei
T
Pankiewicz
Krzysztof W
KW
Patterson
Steven E
SE
Tharnish
Phillip M
PM
McBrayer
Tamara R
TR
Stuyver
Lieven J
LJ
Otto
Michael J
MJ
Chu
Chung K
CK
Schinazi
Raymond F
RF
Watanabe
Kyoichi A
KA
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002417:Cattle; D003853:Deoxyribonucleosides / Q000138:chemical synthesis* / Q000494:pharmacology*; D016679:Genome, Viral; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D009682:Magnetic Resonance Spectroscopy; D012093:Replicon; D016339:Spectrometry, Mass, Fast Atom Bombardment
D000998:Antiviral Agents; D003853:Deoxyribonucleosides