title: Synthesis and in vitro anti-HCV activity of beta-D- and 1-2'-deoxy-2'-fluororibonucleosides.
abstract: 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.
authors.affiliation: Pharmasset, Inc., Tucker, GA, USA.
authors.forename: Junxing
authors.initials: J
authors.lastname: Shi
authors.forename: Jinfa
authors.initials: J
authors.lastname: Du
authors.forename: Tianwei
authors.initials: T
authors.lastname: Ma
authors.forename: Krzysztof W
authors.initials: KW
authors.lastname: Pankiewicz
authors.forename: Steven E
authors.initials: SE
authors.lastname: Patterson
authors.forename: Abdalla E A
authors.initials: AE
authors.lastname: Hassan
authors.forename: Phillip M
authors.initials: PM
authors.lastname: Tharnish
authors.forename: Tamaia R
authors.initials: TR
authors.lastname: McBrayer
authors.forename: Stefania
authors.initials: S
authors.lastname: Lostia
authors.forename: Lieven J
authors.initials: LJ
authors.lastname: Stuyver
authors.forename: Kyoichi A
authors.initials: KA
authors.lastname: Watanabe
authors.forename: Chung K
authors.initials: CK
authors.lastname: Chu
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Otto
mesh_terms: 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
chemical_list: 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