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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. 2009
David B Smith, and
Genadiy Kalayanov, and
Christian Sund, and
Anna Winqvist, and
Tatiana Maltseva, and
Vincent J-P Leveque, and
Sonal Rajyaguru, and
Sophie Le Pogam, and
Isabel Najera, and
Kurt Benkestock, and
Xiao-Xiong Zhou, and
Ann C Kaiser, and
Hans Maag, and
Nick Cammack, and
Joseph A Martin, and
Steven Swallow, and
Nils Gunnar Johansson, and
Klaus Klumpp, and
Mark Smith
Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, California 94304, USA.
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 (EC(50) = 1.28 microM), 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 EC(50) 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).
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