Design and synthesis of pyrrole-5-(2,6-dichlorobenzyl)sulfonylindolin-2-ones with C-3 ' side chains as potent Met kinase inhibitors

Liu Chia-Wei; Lai Chun-Liang; Lin Yu-Hsiang; Teng Li-Wei; Yang Sheng-chuan; Wei Win-Yin; Lin Shu Fu; Yang Ju-Ying; Huang Hung-Jyun; Wang Ru-Wen; Chiang Chao-Cheng; Lee Mei-Hui; Wang Yu-Chuan; Chuang Shih-Hsien; Chang Jia-Ming; Lee Ying-Shuan E.; Huang Jiann-Jyh

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Design and synthesis of pyrrole-5-(2,6-dichlorobenzyl)sulfonylindolin-2-ones with C-3 ' side chains as potent Met kinase inhibitors

机译：具有C-3'侧链作为有效Met激酶抑制剂的吡咯5-（2,6-二氯苄基）磺酰吲哚-2-酮的设计与合成

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Pyrrole-5-(2,6-dichlorobenzyl)sulfonylindolin-2-ones of scaffold 4 with various C-3' side chains were designed as potent Met kinase inhibitors. Structural optimization led to compounds 10, 20, and 22-24 which demonstrated subnanomolar IC50 values in the biochemical assay. The potent compound 20 inhibited Met with IC50 value of 0.37 nM and the proliferation of MKN45 cells with IC50 of 0.22 mu M. It suppressed Met autophosphorylation with the downstream signaling through Gab-1, PLC-gamma, FAK, Akt, STAT3, and ERK in cell. Complete inhibition of STAT3 and ERK phosphorylation was observed in MKN45 cells treated with 20 at the concentration of 100 nM. A computation simulation study was performed to reveal the interaction of 20 with Met.

机译：具有各种C-3'侧链的支架4的吡咯-5-（2,6-二氯苄基）磺酰吲哚-2-酮被设计为有效的Met激酶抑制剂。结构优化导致化合物10、20和22-24在生化分析中显示出亚纳摩尔的IC50值。强效化合物20抑制Met的IC50值为0.37 nM，抑制MKN45细胞的增殖，IC50值为0.22μM。它通过Gab-1，PLC-γ，FAK，Akt，STAT3和ERK抑制下游信号的Met自磷酸化作用。在单元格中。在浓度为100 nM的20 MKN45细胞中，观察到STAT3和ERK磷酸化的完全抑制。进行了计算仿真研究，以揭示20与Met的相互作用。

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《RSC Advances》 |2014年第103期|共9页
作者
Liu Chia-Wei; Lai Chun-Liang; Lin Yu-Hsiang; Teng Li-Wei; Yang Sheng-chuan; Wei Win-Yin; Lin Shu Fu; Yang Ju-Ying; Huang Hung-Jyun; Wang Ru-Wen; Chiang Chao-Cheng; Lee Mei-Hui; Wang Yu-Chuan; Chuang Shih-Hsien; Chang Jia-Ming; Lee Ying-Shuan E.; Huang Jiann-Jyh;
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1. Design and synthesis of pyrrole-5-(2,6-dichlorobenzyl)sulfonylindolin-2-ones with C-3 ' side chains as potent Met kinase inhibitors [J] . Liu Chia-Wei, Lai Chun-Liang, Lin Yu-Hsiang, RSC Advances . 2014,第103期

机译：具有C-3'侧链作为有效Met激酶抑制剂的吡咯5-（2,6-二氯苄基）磺酰吲哚-2-酮的设计与合成
2. Design, Synthesis and Biological Evaluation of 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-4-substituted-1H-indazoles as Potent Fibroblast Growth Factor Receptor Inhibitors [J] . Zhen Zhang, Dongmei Zhao, Yang Dai, Molecules . 2016,第10期

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3. Design, Synthesis and Biological Evaluation of 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-4-substituted-1H-indazoles as Potent Fibroblast Growth Factor Receptor Inhibitors [J] . Zhang Zhen, Zhao Dongmei, Dai Yang, Molecules . 2016,第10期

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Design and synthesis of pyrrole-5-(2,6-dichlorobenzyl)sulfonylindolin-2-ones with C-3 ' side chains as potent Met kinase inhibitors

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