Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-Université Montpellier 1-Université Montpellier 2, Place Eugène Bataillon, CC1704, 34095 Montpellier Cedex 5, France.
J Med Chem. 2010 Sep 23;53(18):6608-17. doi: 10.1021/jm100102v.
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'-H" series as potential chain terminators. We showed that their inhibition potency is strongly increased by the introduction of novel neutral and bis-negatively charged phosphoramidate side chains. Their inhibitory effect on HCV NS5B polymerase 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 polymerase activity. The most potent inhibitor, a 5'-phosphorylated dinucleotide bearing a bis-negatively charged amino side chain (7), exhibits an IC(50) value of 8 μM in vitro and EC(50) value of 2.6 μM 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.
先前有报道称，名为“GC 3'-OH”系列的膦酸酯二核苷酸，具有各种膦酸酯键，可作为丙型肝炎病毒（HCV）抑制剂。为了提高这些二核苷酸的疗效，我们合成了一种新型的“GC 3'-H”系列作为潜在的链终止子。我们发现通过引入新型中性和双负电荷的膦酸酯侧链，它们的抑制效力大大增强。我们在体外和含有 Huh-6 细胞的 HCV 亚基因组复制子中评估了它们对 HCV NS5B 聚合酶的抑制作用。正如预期的那样，3'-H 化合物比它们的 3'-OH 对应物更能抑制 HCV 聚合酶活性。最有效的抑制剂是一种带有双负电荷氨基侧链的 5'-磷酸二核苷酸（7），在体外的 IC50 值为 8 μM，在 HCV 亚基因组复制子系统中的 EC50 值为 2.6 μM。提出了一个分子结构模型，以解释 3'-H-胞嘧啶修饰带来的增益。
