Chen Zhe, Cox Bryan D, Garnier-Amblard Ethel C, McBrayer Tamara R, Coats Steven J, Schinazi Raymond F, Amblard Franck
Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University, School of Medicine, Atlanta, GA 30322, United States.
Cocrystal Pharma, Inc., Tucker, GA 30084, United States.
Bioorg Med Chem Lett. 2017 Dec 1;27(23):5296-5299. doi: 10.1016/j.bmcl.2017.10.024. Epub 2017 Oct 12.
Several β-d-2'-deoxy-2'-substituted nucleoside analogs have displayed potent and selective anti-HCV activities and some of them have reached human clinical trials. In that regard, we report herein the synthesis of a series of 2'-deoxy,2'-dibromo substituted U, C, G and A nucleosides 10a-d and their corresponding phosphoramidate prodrugs 13a-d. The synthesized nucleosides 10a-d and prodrugs 13a-d were evaluated for their inhibitory activity against HCV as well as cellular toxicity. The results showed that the most potent compound was prodrug 13a, which exhibited micromolar inhibitory activity (EC = 1.5 ± 0.8 µM) with no observed toxicity. In addition, molecular modeling and free energy perturbation calculations for the 5'-triphosphate formed from 13a and related 2'-modified nucleotides are discussed.
几种β-d-2'-脱氧-2'-取代核苷类似物已显示出强效且选择性的抗丙型肝炎病毒（HCV）活性，其中一些已进入人体临床试验阶段。在此，我们报告了一系列2'-脱氧、2'-二溴取代的尿苷、胞苷、鸟苷和腺苷核苷10a-d及其相应的磷酰胺酯前药13a-d的合成。对合成的核苷10a-d和前药13a-d进行了抗HCV抑制活性以及细胞毒性评估。结果表明，最有效的化合物是前药13a，其表现出微摩尔级的抑制活性（EC = 1.5 ± 0.8 µM）且未观察到毒性。此外，还讨论了由前药13a和相关2'-修饰核苷酸形成的5'-三磷酸的分子建模和自由能扰动计算。
