Synthesis and evaluation of the HIF-1α inhibitory activity of 3(5)-substituted-4-(quinolin-4-yl)- and 4-(2-phenylpyridin-4-yl)pyrazoles as inhibitors of ALK5.
Synthesis and evaluation of the HIF-1α inhibitory activity of 3(5)-substituted-4-(quinolin-4-yl)- and 4-(2-phenylpyridin-4-yl)pyrazoles as inhibitors of ALK5.
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DOI：
10.1016/j.bmcl.2019.126822
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发表时间：
2019-11
影响因子：
2.7
通讯作者：
Yan-Wei Li;Xiang-Yu Li;Shanji Li;Li-Min Zhao;Juan Ma;H. Piao;Zhe Jiang;C. Jin;Xuejun Jin
中科院分区：
文献类型：
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作者：
Yan-Wei Li;Xiang-Yu Li;Shanji Li;Li-Min Zhao;Juan Ma;H. Piao;Zhe Jiang;C. Jin;Xuejun Jin
缺氧诱导因子-1 α（hypoxia-inducible factor-1 α，HIF-1α）在肿瘤细胞凋亡、转移和增殖中起重要作用，是肿瘤治疗的重要靶点。合成了6个系列的3（5）-（6-甲基吡啶-2-基）-4-（喹啉-4-基）吡唑（11 a-d，12 a-d，和18 a-d）和3（5）-（6-甲基吡啶-2-基）-4-（2-苯基吡啶-4-基）吡唑（19 a-d，20 a-d，和21 a-d），并在酶和细胞水平上评价了它们对激活素受体样激酶5（ALK 5）和HIF-1α的抑制活性。研究了先导化合物20 d（J-1012）对HCT 116细胞中HIF-1α激活的影响，J-1012可剂量依赖性地降低缺氧或肿瘤坏死因子（TNF）诱导的HIF-1α蛋白积聚。分析表明J-1012抑制HIF-1α蛋白的合成，而不影响HIF-1α蛋白的降解。J-1012通过抑制HIF-1α的活化，抑制HCT 116细胞的转移和增殖，促进细胞凋亡。这些结果提示J-1012可能是一种潜在的抗结肠癌药物。
The transcription factor hypoxia-inducible factor-1α (HIF-1α) plays an important role in apoptosis, metastasis, and proliferation and is recognized as an important potential therapeutic target for cancer. Six series of 3(5)-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)pyrazoles (11a–d,12a–d, and18a–d) and 3(5)-(6-methylpyridin-2-yl)-4-(2-phenyl-pyridin-4-yl)pyrazoles (19a–d,20a–d, and21a–d) were synthesized and evaluated for activin receptor-like kinase 5 (ALK5) and HIF-1α inhibitory activity at the enzyme and cell levels. The effect of the lead compound20d(J-1012) on HIF-1α activation in HCT116 cells was investigated.J-1012markedly decreased the hypoxia-induced or TNF-induced accumulation of HIF-1α protein dose-dependently. Analysis revealed thatJ-1012inhibited HIF-1α protein synthesis, without affecting the degradation of HIF-1α protein. Furthermore, by inhibiting the activation of HIF-1α,J-1012suppressed the metastasis and proliferation and promoted apoptosis of HCT116 cells. These results suggest thatJ-1012may be a potential therapeutic agent against human colon cancer.