| |
[摘要]：Phosphoramidate dinucleosides named "GC 3'-OH" series, carrying various phosphoramidate linkages have been previously reported as hepatitis C virus (HCV) inhibitors. To enhance the efficacy of these dinucleotides, we synthesized a novel "GC 3'-OH series as potential chain terminators. We showed that their inhibition potency is strongly increased by the introduction of novel neutral and his-negatively charged phosphoramidate side chains. Their inhibitory effect on HCV NS5B polymerise was evaluated in vitro and in HCV subgenomic replicon containing Huh-6 cells. As expected, 3'-H compounds are more potent than their 3'-OH counterparts to inhibit HCV polymerise activity. The most potent inhibitor, a 5'-phosphorylated dinucleotide bearing a his-negatively charged amino side chain (7), exhibits an IC50 value of 8 mu M in vitro and EC50 value of 2.6 mu M in the HCV subgenomic replicon system. A molecular structure model is presented to propose an interpretation of the gain afforded by the of 3'-H-cytidine modification. |
|
