Cyclic monophosphate prodrugs of base-modified 2′-C-methyl ribonucleosides as potent inhibitors of hepatitis C virus RNA replication

A new series of heterobase-modified 2′-C-methyl ribonucleosides was synthesized and tested as inhibitors of hepatitis C virus (HCV) RNA replication. The nucleosides showed a weak inhibitory activity in a HCV replicon system (EC50 = 92 μM) and did not exhibit any cytotoxicity (CC50 > 300 μM). Cyclic monophosphate (cMP) prodrugs of the same nucleosides were synthesized and also tested in the HCV replicon system. Prodrugs exhibited strong potency (EC50 = 0.008 μM) without significant cytotoxicity (CC50 > 50 μM).