title: 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.
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 (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).
authors.affiliation: Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, California 94304, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Smith
authors.forename: Genadiy
authors.initials: G
authors.lastname: Kalayanov
authors.forename: Christian
authors.initials: C
authors.lastname: Sund
authors.forename: Anna
authors.initials: A
authors.lastname: Winqvist
authors.forename: Tatiana
authors.initials: T
authors.lastname: Maltseva
authors.forename: Vincent J-P
authors.initials: VJ
authors.lastname: Leveque
authors.forename: Sonal
authors.initials: S
authors.lastname: Rajyaguru
authors.forename: Sophie
authors.initials: S
authors.lastname: Le Pogam
authors.forename: Isabel
authors.initials: I
authors.lastname: Najera
authors.forename: Kurt
authors.initials: K
authors.lastname: Benkestock
authors.forename: Xiao-Xiong
authors.initials: XX
authors.lastname: Zhou
authors.forename: Ann C
authors.initials: AC
authors.lastname: Kaiser
authors.forename: Hans
authors.initials: H
authors.lastname: Maag
authors.forename: Nick
authors.initials: N
authors.lastname: Cammack
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Martin
authors.forename: Steven
authors.initials: S
authors.lastname: Swallow
authors.forename: Nils Gunnar
authors.initials: NG
authors.lastname: Johansson
authors.forename: Klaus
authors.initials: K
authors.lastname: Klumpp
authors.forename: Mark
authors.initials: M
authors.lastname: Smith