Abstract
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 μM 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.
Keywords: Benzothiazolyl, Coumarin, Cyanation, Dock, MEK inhibitor, Unphosphorylated MEK1.
Letters in Drug Design & Discovery
Title:Synthesis and Biological Evaluations of 3-Benzothiazol-2-yl Coumarin Derivatives as MEK1 Inhibitors
Volume: 10 Issue: 8
Author(s): Chao Wang, Fengrong Xu, Yan Niu, Yun Wu, Jing Sun, Yihong Peng, Lei Liang and Ping Xu
Affiliation:
Keywords: Benzothiazolyl, Coumarin, Cyanation, Dock, MEK inhibitor, Unphosphorylated MEK1.
Abstract: 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 μM 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.
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Cite this article as:
Wang Chao, Xu Fengrong, Niu Yan, Wu Yun, Sun Jing, Peng Yihong, Liang Lei and Xu Ping, Synthesis and Biological Evaluations of 3-Benzothiazol-2-yl Coumarin Derivatives as MEK1 Inhibitors, Letters in Drug Design & Discovery 2013; 10 (8) . https://dx.doi.org/10.2174/15701808113109990012
DOI https://dx.doi.org/10.2174/15701808113109990012 |
Print ISSN 1570-1808 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-628X |
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