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Synthesis and biological evaluations of N'-substituted methylene-4-(quinoline-4-amino) benzoylhydrazides as potential anti-hepatoma agents.
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2020-01-20 , DOI: 10.1016/j.bioorg.2020.103592
Baicun Li 1 , Feifeng Zhu 2 , Fengming He 2 , Qingqing Huang 2 , Xiaoguang Liu 2 , Tong Wu 2 , Taige Zhao 2 , Yingkun Qiu 2 , Zhen Wu 2 , Yuhua Xue 2 , Meijuan Fang 2
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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 μM and 27.3 ± 1.7 μM, respectively. The most effective compound 5h also exhibited potent cytotoxicity against SMMC-7721 and Huh7 cells with IC50 values of 9.6 ± 0.7 μM and 6.3 ± 0.2 μM, 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 anti-survival 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.

中文翻译:

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及生物学评价。

为了开发用于治疗肝癌的新型喹啉衍生物,我们合成了一系列N'-取代的亚甲基-4-(喹啉-4-氨基)苯甲酰肼,并评估了其作为抗癌剂的生物学活性。发现化合物5h和5j是针对HepG2细胞系的有效抗增殖剂,IC50值分别为12.6±0.1μM和27.3±1.7μM。最有效的化合物5h还显示出对SMMC-7721和Huh7细胞的有效细胞毒性,IC50值分别为9.6±0.7μM和6.3±0.2μM。令人鼓舞的是,5h和5j在正常细胞中均显示出比肝癌细胞低的细胞毒性。化合物5h和5j可以下调c-Myc的mRNA水平和c-Myc的表达水平。与此同时,与微管蛋白相比,它们降低了抗凋亡蛋白Bcl-2的表达水平,并增加了促凋亡蛋白Bax和裂解的PARP的表达水平。因此进行了包括细胞集落形成,细胞周期分布以及细胞凋亡和迁移在内的各种测定,以了解它们的抗肿瘤作用。证实了5h和5j由于其抗存活作用,诱导细胞周期停滞和细胞凋亡以及抑制细胞迁移而抑制了HepG2细胞的生长。这些结果证明5h可能作为开发抗癌药治疗肝细胞癌的潜在先导化合物。进行细胞凋亡和迁移以了解其抗肿瘤作用。证实了5h和5j由于其抗存活作用,诱导细胞周期停滞和细胞凋亡以及抑制细胞迁移而抑制了HepG2细胞的生长。这些结果表明5h可能作为开发抗癌剂治疗肝细胞癌的潜在先导化合物。进行细胞凋亡和迁移以了解其抗肿瘤作用。证实了5h和5j由于其抗存活作用,诱导细胞周期停滞和细胞凋亡以及抑制细胞迁移而抑制了HepG2细胞的生长。这些结果表明5h可能作为开发抗癌剂治疗肝细胞癌的潜在先导化合物。
更新日期:2020-01-21
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