The design, synthesis, and antiviral activity of 4'-azidocytidine analogues against hepatitis C virus replication: the discovery of 4'-azidoarabinocytidine.
4'-Azidocytidine 3 (R1479) has been previously discovered as a potent and selective inhibitor of HCV replication targeting the RNA-dependent RNA polymerase of hepatitis C virus, NS5B. Here we describe the synthesis and biological evaluation of several derivatives of 4'-azidocytidine by varying the substituents at the ribose 2' and 3'-positions. The most potent compound in this series is 4'-azidoarabinocytidine with an IC(50) of 0.17 microM in the genotype 1b subgenomic replicon system. The structure-activity relationships within this series of nucleoside analogues are discussed.
Smith
David B
DB
Roche Palo Alto LLC, Palo Alto, California 94304, USA.
Kalayanov
Genadiy
G
Sund
Christian
C
Winqvist
Anna
A
Pinho
Pedro
P
Maltseva
Tatiana
T
Morisson
Veronique
V
Leveque
Vincent
V
Rajyaguru
Sonal
S
Le Pogam
Sophie
S
Najera
Isabel
I
Benkestock
Kurt
K
Zhou
Xiao-Xiong
XX
Maag
Hans
H
Cammack
Nick
N
Martin
Joseph A
JA
Swallow
Steven
S
Johansson
Nils Gunnar
NG
Klumpp
Klaus
K
Smith
Mark
M
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D014779:Virus Replication / Q000187:drug effects*
C534614:4'-azidoarabinocytidine; D000998:Antiviral Agents; D003561:Cytarabine