5'-O-masked 2'-deoxyadenosine analogues as lead compounds for hepatitis C virus (HCV) therapeutic agents.
On the basis of our previous study on antiviral agents against the severe acute respiratory syndrome (SARS) coronavirus, a series of nucleoside analogues whose 5'-hydroxyl groups are masked by various protective groups such as carboxylate, sulfonate, and ether were synthesized and evaluated to develop novel anti-hepatitis C virus (HCV) agents. Among these, several 5'-O-masked analogues of 6-chloropurine-2'-deoxyriboside (e.g., 5'-O-benzoyl, 5'-O-p-methoxybenzoyl, and 5'-O-benzyl analogues) were found to exhibit effective anti-HCV activity. In particular, the 5'-O-benzoyl analogue exhibited the highest potency with an EC(50) of 6.1 microM in a cell-based HCV replicon assay. Since the 5'-O-unmasked analogue (i.e., 6-chloropurine-2'-deoxyriboside) was not sufficiently potent (EC(50)=47.2 microM), masking of the 5'-hydroxyl group seems to be an effective method for the development of anti-HCV agents. Presently, we hypothesize two roles for the 5'-O-masked analogues: One is the role as an anti-HCV agent by itself, and the other is as a prodrug of its 5'-O-demasked (deprotected) derivative.
Ikejiri
Masahiro
M
Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193, Japan.
Ohshima
Takayuki
T
Kato
Keizo
K
Toyama
Masaaki
M
Murata
Takayuki
T
Shimotohno
Kunitada
K
Maruyama
Tokumi
T
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003839:Deoxyadenosines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D012367:RNA, Viral / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D003839:Deoxyadenosines; D012367:RNA, Viral; C058118:2'-deoxyadenosine