Synthesis and in vitro anti-HCV activity of beta-D- and 1-2'-deoxy-2'-fluororibonucleosides.
Based on the discovery of beta-D-2'-deoxy-2'-fluorocytidine as a potent anti-hepatitis C virus (HCV) agent, a series of beta-D- and L-2'-deoxy-2'-fluoroibonucleosides 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 introduction of the 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 compounds, namely beta-D-2'-deoxy-2',5-difluorocytidine (5), had anti-HCV activity in the subgenomic HCV replicon cell line, and inhibitory activity against ribosomal RNA. As beta-D-N4-hydroxycytidine (NHC) had previously shown potent anti-HCV activity, the two functionalities of the N4-hydroxyl and the 2'-fluoro were combined into one molecule, yielding beta-D-2'-deoxy-2'-fluoro-N4-hydroxycytidine (12). 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 reliably predict anti-HCV activity in vitro.
Shi
Junxing
J
Pharmasset, Inc., Tucker, GA, USA.
Du
Jinfa
J
Ma
Tianwei
T
Pankiewicz
Krzysztof W
KW
Patterson
Steven E
SE
Hassan
Abdalla E A
AE
Tharnish
Phillip M
PM
McBrayer
Tamaia R
TR
Lostia
Stefania
S
Stuyver
Lieven J
LJ
Watanabe
Kyoichi A
KA
Chu
Chung K
CK
Schinazi
Raymond F
RF
Otto
Michael J
MJ
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002417:Cattle; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D001908:Diarrhea Viruses, Bovine Viral / Q000378:metabolism; D015195:Drug Design; D005459:Fluorides / Q000494:pharmacology; D005461:Fluorine / Q000737:chemistry*; D016174:Hepacivirus / Q000378:metabolism*; D006801:Humans; D006858:Hydrofluoric Acid / Q000737:chemistry; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000821:virology; D008956:Models, Chemical; D008967:Molecular Biology / Q000379:methods; D017680:Potassium Compounds / Q000494:pharmacology; D011741:Pyrimidine Nucleosides / Q000737:chemistry; D012313:RNA / Q000737:chemistry; D012335:RNA, Ribosomal / Q000737:chemistry; D012263:Ribonucleosides / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism
D000998:Antiviral Agents; D017680:Potassium Compounds; D011741:Pyrimidine Nucleosides; D012335:RNA, Ribosomal; D012263:Ribonucleosides; D003841:Deoxycytidine; D005461:Fluorine; D012313:RNA; C033320:potassium fluoride; D005459:Fluorides; D006858:Hydrofluoric Acid