Synthesis and in vitro anti-HCV activity of β-D- and L-2′-deoxy-2′-fluororibonucleosides

Junxing Shi, Jinfa Du, Tianwei Ma, Krzysztof W. Pankiewicz, Steven E. Patterson, Abdalla E.A. Hassan, Phillip M. Tharnish, Tamara R. McBrayer, Stefania Lostia, Lieven J. Stuyver, Kyoichi A. Watanabe, Chung K. Chu, Raymond F. Schinazi, Michael J. Otto

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Based on the discovery of β-D-2′-deoxy-2′-fluorocytidine as a potent anti-hepatitis C virus (HCV) agent, a series of β-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 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 β-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 β-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 β-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.

Original languageEnglish (US)
Pages (from-to)875-879
Number of pages5
JournalNucleosides, Nucleotides and Nucleic Acids
Issue number5-7
StatePublished - Oct 20 2005

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