DESIGN AND SYNTHESIS OF NOVEL CARBOCYCLIC VERSIONS OF 2 '-SPIROCYCLOPROPYL RIBONUCLEOSIDES AS POTENT ANTI-HCV AGENTS

Abstract

The discovery of 2'-spirocyclopropyl-ribocytidine as a potent inhibitor of RNA synthesis by NS5B (IC(50) = 7.3 mu M), the RNA polymerase encoded by hepatitis C virus (HCV), has led to the synthesis and biological evaluation of carbocyclic versions of 2'-spiropropyl-nucleosides from cyclopentenol 6. Spirocyclopropylation of enone 7 was completed by using (2-chloroethyl)-dimethylsulfonium iodide and potassium t-butoxide to form the desired intermediate 9a. The synthesized nucleoside analogues, 18, 19, 26, and 27, were assayed for their ability to inhibit HCV RNA replication in a subgenomic replicon Huh7 cell line. The synthesized cytosine nucleoside 19 showed moderate anti-HCV activity (IC(50) = 14.4 mu M).