Synthesis and anti-hepatitis C virus activity of 2'(beta)-hydroxyethyl and 4'(alpha)-hydroxymethyl carbodine analogues

Abstract

2'(beta)-Hydroxyethylated adenosine is a potent and selective inhibitor of hepatitis C virus (HCV) replication targeting the RNA-dependent RNA polymerase of HCV, NS5B. The synthesis and anti-HCV evaluation of carbodine analogues are described. The cyclopentene intermediate 10 was successfully made via sequential Johnson-Claisen orthoester rearrangement and ring-closing metathesis. Coupling of bases via a Pd(0) catalyst, selective dihydroxylation, and desilylation yielded the target carbodine analogues. Cytosine analogue 17 weakly inhibited the replication of the HCV replicon in Hua-7 cells by 50% at 21.1 muM.