Synthesis and biological evaluations of N′-substituted methylene-4-(quinoline-4-amino) benzoylhydrazides as potential anti-hepatoma agents
Synthesis and biological evaluations of N′-substituted methylene-4-(quinoline-4-amino) benzoylhydrazides as potential anti-hepatoma agents
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N'-取代的亚甲基-4-(喹啉-4-氨基)苯甲酰肼作为潜在抗肝癌药物的合成和生物学评价
DOI：
10.1016/j.bioorg.2020.103592
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发表时间：
2020-03-01
影响因子：
5.1
通讯作者：
Fang, Meijuan
中科院分区：
文献类型：
--
作者：
Li, Baicun;Zhu, Feifeng;Fang, Meijuan
为了开发新的喹啉类化合物用于治疗肝癌，我们合成了一系列N ′-取代亚甲基-4-（喹啉-4-氨基）苯甲酰肼类化合物，并评价了它们作为抗癌药物的生物活性。发现化合物5 h和5 j是针对HepG 2细胞系的有效抗增殖剂，其IC 50值分别为12.6 +/-0.1 μ M和27.3 +/-1.7 μ M。最有效的化合物5 h还表现出对SMMC-7721和Huh 7细胞的有效细胞毒性，IC 50值分别为9.6 +/- 0.7 μ M和6.3 +/- 0.2 μ M。令人鼓舞的是，5 h和5 j在正常细胞中表现出比肝癌细胞更低的细胞毒性。化合物5 h和5 j可下调c-Myc mRNA水平和c-Myc表达水平。同时，它们降低了抗凋亡蛋白Bcl-2的表达水平，增加了促凋亡蛋白Bax的表达水平，并与微管蛋白相关地切割PARP。因此，通过细胞集落形成、细胞周期分布以及细胞凋亡和迁移等多种实验来了解它们的抗肿瘤作用。结果表明，5 h和5 j对HepG 2细胞的生长具有抑制作用，其机制可能与抑制细胞存活、诱导细胞周期阻滞和细胞凋亡以及抑制细胞迁移有关。这些结果表明，5 h有可能作为潜在的先导化合物开发抗肝癌药物。
In the effort to develop novel quinoline derivatives for the treatment of liver cancer, we synthesized a series of N'-Substituted methylene-4-(quinoline-4-amino) benzoylhydrazides and evaluated their biological activities as anticancer agents. Compounds 5h and 5j were found to be the potent antiproliferative agents against HepG2 cell line with an IC50 value of 12.6 +/- 0.1 mu M and 27.3 +/- 1.7 mu M, respectively. The most effective compound 5h also exhibited potent cytotoxicity against SMMC-7721 and Huh7 cells with IC50, values of 9.6 +/- 0.7 mu M and 6.3 +/- 0.2 mu M, respectively. Inspiringly, both 5h and 5j exhibited lower cytotoxic property in normal cells than hepatic carcinoma cells. Compounds 5h and 5j could down-regulate mRNA level of c-Myc and expression level of c-Myc. Meanwhile, they decreased expression level of anti-apoptotic protein Bcl-2 and increased expression levels of pro-apoptotic protein Bax and cleaved PARP with reference to tubulin. So various assays including cell colony formation, cell cycle distribution, as well as cell apoptosis and migration were performed to understand their antitumor role. It was confirmed that 5h and 5j inhibited the growth of HepG2 cells due to their antisurvival effect, induction of cell cycle arrest and cell apoptosis, and inhibition of cell migration. These results demonstrated that 5h might be as potential lead compounds to develop anticancer agents for the treatment of hepatocellular carcinoma.