4'-Substituted pyrimidine nucleosides lacking 5'-hydroxyl function as potential anti-HCV agents
- Bioorg Med Chem Lett. 2014 Mar 1;24(5):1407-9. doi: 10.1016/j.bmcl.2014.01.024.
- 1. Department of Laboratory Medicine and Pathology, 7-28 Heritage Medical Research Centre, University of Alberta, Edmonton, AB T6G 2S2, Canada.
- 2. Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
- 3. Department of Laboratory Medicine and Pathology, 7-28 Heritage Medical Research Centre, University of Alberta, Edmonton, AB T6G 2S2, Canada. Electronic address: [email protected].
Hepatitis C virus (HCV) Infection is one of the major health problems worldwide. If left untreated, it leads to liver cirrhosis, liver Cancer and death. Herein, we report synthesis and anti-HCV activity of a new class of pyrimidine nucleosides possessing a 4'-carboxymethyl (9-16, 21 and 23) or 4'-carboxamide function (17-19 and 24). Among these, 10-12 (EC50=33.1-42.4 μM), 14 and 21 (EC50=43.4-59.5 μM) exhibited potent activity in HCV-1a replicon cells without any toxicity to parent Huh-7 cells (CC50=>829-1055 μM). The anti-HCV activities demonstrated by this unusual class of compounds were superior to that of ribavirin (EC50=81.9 μM). Further, the most active analog, 12, was found to interact synergistically with ribavirin to inhibit HCV RNA replication.