Synthesis and biological evaluation of novel benzo[c][1,2,5]thiadiazol-5-yl and thieno[3,2,-c]pyridine-2-yl imidazole derivatives as ALK5 inhibitors
Synthesis and biological evaluation of novel benzo[c][1,2,5]thiadiazol-5-yl and thieno[3,2,-c]pyridine-2-yl imidazole derivatives as ALK5 inhibitors
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新型苯并[c][1,2,5]噻二唑-5-基和噻吩并[3,2,-c]吡啶-2-基咪唑衍生物作为ALK5抑制剂的合成和生物学评价
DOI：
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发表时间：
2019
影响因子：
2.7
通讯作者：
Cheng Hua Jin
中科院分区：
文献类型：
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作者：
Zhen Guo;Xiaowei Song;Li-Min Zhao;Ming Guan Piao;Jishan Quan;Hu-Ri Piao;Cheng Hua Jin
转化生长因子（transforminggrowthfactor，TGF-β）是肿瘤生长和转移的关键因子，是肿瘤治疗的重要靶点。设计、合成了一系列苯并[c][1，2，5]噻二唑-5-基咪唑（14 a-g）和噻吩并[3，2-c]-吡啶-2-基咪唑（20 a-g），并评价了它们的激活素受体样激酶5（ALK 5）活性。在这些化合物中，14 c对ALK 5.激酶的活性最高（IC 50 =0.008 μM），分别是阳性对照化合物LY-2157299的16.1倍和1.8倍。(IC50=0.129 μM）和EW-7197（IC50=0.014 μM）。化合物14 g（350）显示出最高的ALK 5对p38α MAP激酶的选择性指数，其显著高于阳性对照化合物LY-2157299（4）和EW-7197（211）。用Western印迹分析和创伤愈合实验研究了化合物14 c对SPC-A1、HepG 2和HUVEC细胞中TGF-β诱导的Smad信号传导和细胞运动的抑制作用。ADMET预测分析表明，化合物14 c和14 g具有良好的药动学和类药行为。
Transforming growth factor (TGF-β), a key mediator of tumor growth and metastasis, has been recognized as an.important cancer drug target. A series of benzo[c][1,2,5]thiadiazol-5-yl imidazoles (14a–g) and thieno[3,2-c]-.pyridin-2-yl imidazoles (20a–g) were designed, synthesized, and evaluated for their activin receptor-like kinase.5 (ALK5) activities. Among these compounds, 14c showed the highest activity (IC50=0.008 μM) against ALK5.kinase, which was 16.1-fold and 1.8-fold higher than those of positive control compounds LY-2157299.(IC50=0.129 μM) and EW-7197 (IC50=0.014 μM), respectively. Compound 14g (350) showed the highest.selectivity index of ALK5 against p38α MAP kinase, which was significantly higher than that of positive control.compounds LY-2157299 (4) and EW-7197 (211). The inhibitory effects of compound 14c on TGF-β-induced.Smad signaling and cell motility were studied in SPC-A1, HepG2 and HUVEC cells using western blot analysis.and wound healing assay. ADMET prediction analysis showed that compounds 14c and 14g had good pharmacokinetics.and drug-likeness behaviors.