4'-Substituted pyrimidine nucleosides lacking 5'-hydroxyl function as potential anti-HCV agents.
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.
Department of Laboratory Medicine and Pathology, 7-28 Heritage Medical Research Centre, University of Alberta, Edmonton, AB T6G 2S2, Canada.
Neeraj
N
Shakya
Department of Laboratory Medicine and Pathology, 7-28 Heritage Medical Research Centre, University of Alberta, Edmonton, AB T6G 2S2, Canada.
Satish
S
Vedi
Department of Laboratory Medicine and Pathology, 7-28 Heritage Medical Research Centre, University of Alberta, Edmonton, AB T6G 2S2, Canada.
Chao
C
Liang
Department of Laboratory Medicine and Pathology, 7-28 Heritage Medical Research Centre, University of Alberta, Edmonton, AB T6G 2S2, Canada.
Fang
F
Yang
Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
Babita
B
Agrawal
Department of Laboratory Medicine and Pathology, 7-28 Heritage Medical Research Centre, University of Alberta, Edmonton, AB T6G 2S2, Canada. Electronic address: rakesh.kumar@ualberta.ca.
Rakesh
R
Kumar
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D016174:Hepacivirus / Q000187:drug effects; D006801:Humans; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012254:Ribavirin / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D011741:Pyrimidine Nucleosides; D012254:Ribavirin
Antiviral; Hepatitis C virus; Nucleosides