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Research article2009Peer reviewed

The Design, Synthesis, and Antiviral Activity of Monofluoro and Difluoro Analogues of 4 '-Azidocytidine against Hepatitis C Virus Replication: The Discovery of 4 '-Azido-2 '-deoxy-2 '-fluorocytidine and 4 '-Azido-2 '-dideoxy-2 ',2 '-difluorocytidine

Smith, David B.; Kalayanov, Genadiy; Sund, Christian; Winqvist, Anna; Maltseva, Tatiana; Leveque, Vincent J. -P.; Rajyaguru, Sonal; Le Pogam, Sophie; Najera, Isabel; Benkestock, Kurt; Zhou, Xiao-Xiong; Kaiser, Ann C.; Maag, Hans; Cammack, Nick; Martin, Joseph A.; Swallow, Steven; Johansson, Nils Gunnar; Klumpp, Klaus; Smith, Mark

Abstract

The discovery of 4'-azidocytidine (3) (R1479) (J. Biol. Chem. 2006, 281, 3793; Bioorg. Med. Chem. Lett. 2007, 17, 2570) as a potent inhibitor of RNA synthesis by NS5B (EC50 = 1.28 mu M), the RNA polymerase encoded by hepatitis C virus (HCV), has led to the synthesis and biological evaluation of several monofluoro and difluoro derivatives of 4'-azidocytidine. The most potent compounds in this series were 4'-azido-2'-deoxy-2',2'-difluorocytidine and 4'-azido-2'-deoxy-2'-fluoroarabinocytidine with antiviral EC50 of 66 nM and 24 nM in the HCV replicon system, respectively. The structure-activity relationships within this series were discussed. which led to the discovery of these novel nucleoside analogues with the most potent compound, showing more than a 50-fold increase in antiviral potency as compared to 4'-azidocytidine (3).

Published in

Journal of Medicinal Chemistry
2009, Volume: 52, number: 9, pages: 2971-2978

    UKÄ Subject classification

    Medicinal Chemistry
    Organic Chemistry

    Publication identifier

    DOI: https://doi.org/10.1021/jm801595c

    Permanent link to this page (URI)

    https://res.slu.se/id/publ/108044