Synthesis and Antiviral Activity of 2 '(beta)-Hydroxymethylated Carbodine Analogues Against Hepatitis C Virus

Abstract

2'(beta)-Hydoxymethylated adenosine is a potent and selective inhibitor of hepatitis C virus (HCV) replication. It targets the RNA-dependent RNA polymerase of HCV, NS5B. Synthesis and antiviral evaluation of carbocyclic versions,ire described. The cyclopentene intermediate (9 beta) was successfully synthesized through sequential Johnson-Claisen orthoester rearrangement and ring-closing metathesis (RCM). Coupling of bases via a Pd(0) catalyst, selective dihydroxylation. and desilylation yielded the target nucleoside analogues. The compounds 17 and 18 were assayed for their ability to Inhibit HCV RNA replication in a subgenomic replicon cell line and showed moderate antiviral activity with toxicity up to 20.0 and 24 7 mu g/mL, respectively.