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