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学科主题: 药学
题名:
Synthesis and Biological Evaluations of 3-Benzothiazol-2-yl Coumarin Derivatives as MEK1 Inhibitors
作者: 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
发表日期: 2013-10-01
卷: 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
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
项目资助者: National Natural Science Foundation of China ; National Basic Research Program of China ; Specialized Research Fund for the Doctoral Program of Higher Education of China
WOS记录号: WOS:000323215300008
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/51061
Appears in Collections:北京大学药学院_药物化学系_期刊论文

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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

Recommended Citation:
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.
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