体内
癌症
化学
细胞凋亡
癌细胞
细胞周期
卡培他滨
药理学
细胞生长
细胞周期检查点
细胞毒性
体外
毒性
癌症研究
细胞培养
IC50型
生物化学
内科学
生物
医学
结直肠癌
有机化学
生物技术
遗传学
作者
Yiyue Feng,Yuanqing Lu,Junfang Li,Honghua Zhang,Lei Zhao,Han‐Zhong Feng,Xiaojie Deng,Dan Liú,Tao Shi,Weifan Jiang,Yong‐Xing He,Jian Zhang,Zhen Wang
标识
DOI:10.1016/j.ejmech.2021.113888
摘要
Although gastric cancer has become a major public health problem, oral agents applied in clinics for gastric cancer therapy are scarce. Therefore, to explore new oral chemical entities with high efficiency and low toxicity, 41 o-aminobenzamide derivatives based on the scaffolds of MS-275 and SAHA were designed, synthesized, and evaluated for their anti-gastric cancer abilities in vitro and in vivo. Structure-activity relationships were discussed, leading to the identification of compounds F8 (IC50 = 0.28 μM against HGC-27 cell) and T9 (IC50 = 1.84 μM against HGC-27 cell) with improved cytotoxicity, anti-gastric cancer proliferation potency, induction of cell apoptosis and cell cycle arrest ability, inhibition of cell migration and invasion. What is worth mentioning is that compound F8 was more efficient and less toxic than the positive drug capecitabine in vivo on the HGC-27-xenograft model. Meanwhile, compound F8 exhibited suitable pharmacokinetic properties and less acute toxicity (LD50 > 1000 mg/kg). Besides, western blotting analysis, IHC analysis, differentially expressed proteins analysis and ABPP experiment indicated that compound F8 could modulate molecular pathways involved in apoptosis and cell cycle progression. Consequently, compound F8 is a strong candidate for the development of human gastric cancer therapy.
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