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Synthesis and Biological Evaluations of 3-Benzothiazol-2-yl Coumarin Derivatives as MEK1 Inhibitors
Wang, Chao1; Xu, Fengrong1; Niu, Yan1; Wu, Yun1; Sun, Jing1; Peng, Yihong2; Liang, Lei1; Xu, Ping1
关键词Benzothiazolyl Coumarin Cyanation Dock Mek Inhibitor Unphosphorylated Mek1
刊名LETTERS IN DRUG DESIGN & DISCOVERY
2013-10-01
10期:8页:727-732
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Chemistry, Medicinal
资助者National Natural Science Foundation of China ; National Basic Research Program of China ; Specialized Research Fund for the Doctoral Program of Higher Education of China ; National Natural Science Foundation of China ; National Basic Research Program of China ; Specialized Research Fund for the Doctoral Program of Higher Education of China
研究领域[WOS]Pharmacology & Pharmacy
关键词[WOS]ALLOSTERIC MEK1 ; BRAF GENE ; CANCER ; PHARMACOKINETICS ; PHARMACODYNAMICS ; RO5068760 ; POTENT
英文摘要

In order to discover novel MEK inhibitors, a series of 3-(benzothiazol-2-yl) coumarin derivatives have been synthesized following our earlier study of 3-benzyl coumarin derivatives. The target compounds were obtained by condensation, cyanation, hydrolyzation and esterification starting from o-hydroxy benzaldehydes and benzothiazole-2-acetonitrile. The cyanation reaction could only occur when there were electron with drawing groups at C3 position of coumarin scaffold. All the synthesized compounds showed weak binding and inhibition potencies to phosphorylated MEK1 but obvious inhibitory effect to unphosphorylated MEK1, suggesting that compounds inhibition to MEK1 is mainly due to the inhibition of npMEK1 rather than pMEK1. The most potent compound 3 was with an inhibition rate of 60.7% at 1 mu M in the RAF-MEK cascading assay. Molecular docking studies revealed that the pocket occupation and structure hydrophobicity may be important for activity. These results can contribute to further optimization on coumarin scaffold and led to the design of novel coumarin derivatives as more potent MEK1 inhibitors.

语种英语
所属项目编号21172012 ; 2012CB518000 ; 20120001110010
资助者National Natural Science Foundation of China ; National Basic Research Program of China ; Specialized Research Fund for the Doctoral Program of Higher Education of China ; National Natural Science Foundation of China ; National Basic Research Program of China ; Specialized Research Fund for the Doctoral Program of Higher Education of China
WOS记录号WOS:000323215300008
引用统计
被引频次:3[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/51061
专题北京大学药学院_药物化学系
作者单位1.Peking Univ, State Key Lab Nat & Biomimet Drugs, Dept Med Chem, Sch Pharmaceut Sci,Hlth Sci Ctr, Beijing 100191, Peoples R China
2.Peking Univ, Sch Basic Med Sci, Dept Microbiol, Beijing 100191, Peoples R China
推荐引用方式
GB/T 7714
Wang, Chao,Xu, Fengrong,Niu, Yan,et al. Synthesis and Biological Evaluations of 3-Benzothiazol-2-yl Coumarin Derivatives as MEK1 Inhibitors[J]. LETTERS IN DRUG DESIGN & DISCOVERY,2013,10(8):727-732.
APA Wang, Chao.,Xu, Fengrong.,Niu, Yan.,Wu, Yun.,Sun, Jing.,...&Xu, Ping.(2013).Synthesis and Biological Evaluations of 3-Benzothiazol-2-yl Coumarin Derivatives as MEK1 Inhibitors.LETTERS IN DRUG DESIGN & DISCOVERY,10(8),727-732.
MLA Wang, Chao,et al."Synthesis and Biological Evaluations of 3-Benzothiazol-2-yl Coumarin Derivatives as MEK1 Inhibitors".LETTERS IN DRUG DESIGN & DISCOVERY 10.8(2013):727-732.
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