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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

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journal contribution
posted on 14.05.2009, 00:00 by David B. Smith, Genadiy Kalayanov, Christian Sund, Anna Winqvist, Tatiana Maltseva, Vincent J.-P. Leveque, Sonal Rajyaguru, Sophie Le Pogam, Isabel Najera, Kurt Benkestock, Xiao-Xiong Zhou, Ann C. Kaiser, Hans Maag, Nick Cammack, Joseph A. Martin, Steven Swallow, Nils Gunnar Johansson, Klaus Klumpp, Mark Smith
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 μM), 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).