发现2'-α-C-甲基-2'-β-C-氟尿苷亚磷酰胺前药作为丙型肝炎病毒抑制剂
Discovery of 2'-α-C-Methyl-2'-β-C-fluorouridine Phosphoramidate Prodrugs as Inhibitors of Hepatitis C Virus.
作者信息
Zeng Debin, Zhang Rui, Nie Quandeng, Cao Lin, Shang Luqing, Yin Zheng
机构信息
State Key Laboratory of Elemento-Organic Chemistry, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Haihe Education Park, 38 Tongyan Road, Tianjin 300353, PR China.
出版信息
ACS Med Chem Lett. 2016 Oct 19;7(12):1197-1201. doi: 10.1021/acsmedchemlett.6b00270. eCollection 2016 Dec 8.
Abstract
2'-α-C-Methyl-2'-β-C-fluorouridine and its phosphoramidate prodrugs were synthesized and evaluated for their inhibitory activity against HCV. The structure-activity relationship analysis of the phosphoramidate moiety found that , , and exhibit potent activities against HCV, with EC values of 1.82 ± 0.19, 0.88 ± 0.12, and 2.24 ± 0.22 μM, respectively. The docking study revealed that the recognition of the 2'-β-F by Arg158, 3'-OH by N291, and the Watson-Crick pairing with the template allowed to form the in-line conformation necessary for its incorporation into the viral RNA chain.
摘要
合成了2'-α-C-甲基-2'-β-C-氟尿苷及其磷酰胺酯前药，并评估了它们对丙型肝炎病毒（HCV）的抑制活性。对磷酰胺部分的构效关系分析发现，[具体化合物名称未给出]、[具体化合物名称未给出]和[具体化合物名称未给出]对HCV表现出强效活性，其半数有效浓度（EC）值分别为1.82±0.19、0.88±0.12和2.24±0.22μM。对接研究表明，精氨酸158对2'-β-氟的识别、天冬酰胺291对3'-羟基的识别以及与模板的沃森-克里克配对使得[具体化合物名称未给出]能够形成将其掺入病毒RNA链所必需的直线构象。
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1
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Nat Rev Gastroenterol Hepatol. 2016 Feb;13(2):70-2. doi: 10.1038/nrgastro.2015.227. Epub 2016 Jan 21.
2
Viral replication. Structural basis for RNA replication by the hepatitis C virus polymerase.病毒复制。丙型肝炎病毒聚合酶进行 RNA 复制的结构基础。
Science. 2015 Feb 13;347(6223):771-5. doi: 10.1126/science.1259210.
3
Sofosbuvir: a review of its use in patients with chronic hepatitis C.索磷布韦：用于治疗慢性丙型肝炎患者的综述。
Drugs. 2014 Jul;74(10):1127-46. doi: 10.1007/s40265-014-0247-z.
4
Use of 2'-spirocyclic ethers in HCV nucleoside design.在 HCV 核苷设计中使用 2'-螺环醚。
J Med Chem. 2014 Mar 13;57(5):1826-35. doi: 10.1021/jm401224y. Epub 2013 Oct 18.
5
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6
Treating hepatitis C: current standard of care and emerging direct-acting antiviral agents.治疗丙型肝炎：现行的标准护理和新兴的直接作用抗病毒药物。
J Viral Hepat. 2012 Jul;19(7):449-64. doi: 10.1111/j.1365-2893.2012.01617.x.
7
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8
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