Synthesis and anti-viral activity of a series of D- and l-2′-deoxy-2′-fluororibonucleosides in the subgenomic HCV replicon system

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

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45 Scopus citations

Abstract

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 N4-hydroxycytidine (NHC) had previously shown potent anti-HCV activity, we combined the two functionalities of the N4-hydroxyl and the 2′-fluoro into one molecule, resulting (2′R)-D-2′-deoxy- 2′-fluoro-N4-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.

Original languageEnglish (US)
Pages (from-to)1641-1652
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume13
Issue number5
DOIs
StatePublished - Mar 1 2005

Bibliographical note

Funding Information:
HCV replicon RNA-containing Huh 7 cells were provided by Apath, LLC, St. Louis, MO. C.K.C. and R.F.S. are supported in part by NIH grant RO1-AI-32351. C.K.C. is supported in part by NIH grant 1-RO1-AI-25899. R.F.S. is supported by NIH grant 2P30-AI-50409, and the Department of Veterans Affairs. R.F.S. and C.K.C. are the founders and consultants of Pharmasset Ltd, and did not receive any funding from the company for these studies.

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

Keywords

  • 2′- Fluororibosides
  • 2′-Deoxy-2′-fluororibonucleosides
  • BVDV
  • Fluorination
  • HCV

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