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 μM. It suppressed Met autophosphorylation with the downstream signaling through Gab-1, PLC-γ, 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.

中文翻译：

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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†

具有不同C-3'侧链的支架4的吡咯–5-（2,6-二氯苄基）磺酰lindolin-2-ones被设计为有效的Met激酶抑制剂。结构优化导致了化合物10，20，和22-24这表明亚纳摩尔IC _50个在生物化学测定值。有效的化合物20抑制Met的IC ₅₀值为0.37 nM，抑制MKN45细胞的增殖，IC ₅₀值为0.22μM。它通过细胞中的Gab-1，PLC-γ，FAK，Akt，STAT3和ERK抑制下游信号的Met自磷酸化作用。在用20处理的MKN45细胞中观察到STAT3和ERK磷酸化的完全抑制浓度为100 nM。进行了计算仿真研究，以揭示20与Met的相互作用。