新型2',3'-二脱氧-2'-α-氟-2'-β-甲基鸟苷磷酰胺酯前药的合成及其抗丙型肝炎病毒活性
Synthesis and Anti-HCV Activity of a Novel 2',3'-Dideoxy-2'-α-fluoro-2'-β--methyl Guanosine Phosphoramidate Prodrug.
作者信息
Yu Wenquan, Li Ertong, Lv Zhigang, Liu Ke, Guo Xiaohe, Liu Yuan, Chang Junbiao
机构信息
College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan 450001, P. R. China.
High & New Technology Research Center of Henan Academy of Sciences, Zhengzhou, Henan 450002, P. R. China.
出版信息
ACS Med Chem Lett. 2017 May 1;8(6):682-684. doi: 10.1021/acsmedchemlett.7b00174. eCollection 2017 Jun 8.
Abstract
A novel 2',3'-dideoxy-2'-α-fluoro-2'-β--methyl-6-methoxy guanosine () and its phosphoramidate prodrug () have been designed and synthesized. Their biological activity was evaluated in both cytotoxicity and cell-based HCV replicon assays. Neither compounds exhibited cytotoxicity up to the highest concentration tested (100 μM) in the Huh-7 cell line. The prodrug () displayed nanomolar level antiviral activity (EC = 0.39-1.1 μM) against the HCV genotype (GT) 1a, 1b, 2a, and 1b S282T replicons.
摘要
一种新型的2',3'-二脱氧-2'-α-氟-2'-β-甲基-6-甲氧基鸟苷（）及其磷酰胺酯前药（）已被设计并合成。在细胞毒性和基于细胞的丙型肝炎病毒（HCV）复制子测定中评估了它们的生物活性。在Huh-7细胞系中，直至测试的最高浓度（100μM），两种化合物均未表现出细胞毒性。前药（）对HCV基因型（GT）1a、1b、2a和1b S282T复制子显示出纳摩尔水平的抗病毒活性（EC = 0.39 - 1.1μM）。
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本文引用的文献
1
Nucleoside Phosphate and Phosphonate Prodrug Clinical Candidates.核苷磷酸酯和膦酸酯前药临床候选药物。
J Med Chem. 2016 Dec 8;59(23):10400-10410. doi: 10.1021/acs.jmedchem.6b00523. Epub 2016 Sep 8.
2
Recent advances on the synthesis of hepatitis C virus NS5B RNA-dependent RNA-polymerase inhibitors.新型丙型肝炎病毒 NS5B RNA 依赖的 RNA 聚合酶抑制剂的合成进展。
Eur J Med Chem. 2015 Sep 18;102:188-214. doi: 10.1016/j.ejmech.2015.07.046. Epub 2015 Jul 31.
3
Discovery of HCV NS5B thumb site I inhibitors: core-refining from benzimidazole to indole scaffold.丙型肝炎病毒NS5B拇指位点I抑制剂的发现：从苯并咪唑到吲哚支架的核心优化
Eur J Med Chem. 2015 Apr 13;94:218-28. doi: 10.1016/j.ejmech.2015.03.012. Epub 2015 Mar 6.
4
Synthesis of nucleoside phosphate and phosphonate prodrugs.核苷磷酸酯和膦酸酯前药的合成。
Chem Rev. 2014 Sep 24;114(18):9154-218. doi: 10.1021/cr5002035. Epub 2014 Aug 21.
5
Global epidemiology and genotype distribution of the hepatitis C virus infection.全球丙型肝炎病毒感染的流行病学和基因型分布。
J Hepatol. 2014 Nov;61(1 Suppl):S45-57. doi: 10.1016/j.jhep.2014.07.027. Epub 2014 Jul 30.
6
Discovery of PSI-353661, a Novel Purine Nucleotide Prodrug for the Treatment of HCV Infection.PSI-353661的发现，一种用于治疗丙型肝炎病毒感染的新型嘌呤核苷酸前药。
ACS Med Chem Lett. 2010 Dec 17;2(2):130-5. doi: 10.1021/ml100209f. eCollection 2011 Feb 10.
7
Polymerases of hepatitis C viruses and flaviviruses: structural and mechanistic insights and drug development.丙型肝炎病毒和黄病毒的聚合酶：结构与机制的见解和药物研发。
Antiviral Res. 2014 May;105:8-16. doi: 10.1016/j.antiviral.2014.02.006. Epub 2014 Feb 19.
8
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J Med Chem. 2014 Mar 13;57(5):1836-44. doi: 10.1021/jm4015422. Epub 2014 Jan 6.
9
Nucleotide prodrugs for the treatment of HCV infection.用于治疗丙型肝炎病毒感染的核苷酸前药。
Adv Pharmacol. 2013;67:39-73. doi: 10.1016/B978-0-12-405880-4.00002-0.
10
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