查尔酮
化学
细胞凋亡
癌症
癌细胞
嘌呤
细胞生长
立体化学
选择性
细胞培养
IC50型
生物化学
癌症研究
酶
体外
生物
催化作用
遗传学
作者
Tao-Qian Zhao,Yuan-Di Zhao,Xin-Yang Liu,Zhonghua Li,Bo Wang,Xinhui Zhang,Yaquan Cao,Liying Ma,Hong‐Min Liu
标识
DOI:10.1016/j.ejmech.2018.10.058
摘要
To explore anti-gastric cancer agents with high efficacy and selectivity, we report the design, synthesis and optimization of a novel series of 3-(2,6,9-trisubstituted-9H-purine)-8-chalcone derivatives starting from the compound PCA-15 reported by us previously. Most of the target compounds demonstrated significant antiproliferative effects on MGC803 cancer cell line, and more potent than the positive control (PCA-15 and 5-Fu). Among them, compound 6o was identified to be the most active compound against MGC803 cell line with an IC50 value of 0.84 μM. Additionally, high selectivity was also observed between cancer and normal cells (23.35 μM against GES-1). Further mechanism studies confirmed that compound 6o could inhibit colony formation and migration, induce the apoptosis of MGC803 cells through both the mitochondrial-mediated intrinsic pathway and death receptor-mediated extrinsic pathway, which were evidenced by the up-regulation of Bax, cleaved-caspase 9/3/8, cleaved PARP and down-regulation of Bcl-2. Our systematic studies implied a new scaffold targeting gastric cancer cells for further development of small-molecule compounds with improved potency and selectivity.
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