2,4-Disubstituted quinazolines targeting breast cancer cells via EGFR-PI3K

被引：24

作者：

Li, Er-dong ^{[1
,2
]}

Lin, Qiao ^{[1
,2
]}

Meng, Ya-qi ^{[1
,2
]}

Zhang, Lu-ye ^{[1
,2
]}

Song, Pan-pan ^{[1
,2
]}

Li, Na ^{[1
,2
]}

Xin, Jing-chao ^{[1
,2
]}

Yang, Peng ^{[1
,2
]}

Bao, Chong-nan ^{[1
,2
]}

Zhang, Dan-qing ^{[1
,2
]}

Zhang, Yang ^{[1
,2
]}

Wang, Ji-kuan ^{[1
,2
]}

Zhang, Qiu-rong ^{[1
,2
]}

Liu, Hong-min ^{[1
,2
]}

机构：

[1] Zhengzhou Univ, Sch Pharmaceut Sci, Zhengzhou 450001, Henan, Peoples R China

[2] Collaborat Innovat Ctr New Drug Res & Safety Eval, Zhengzhou 450001, Henan, Peoples R China

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 172卷

基金：

中国国家自然科学基金;

关键词：

Quinazoline; Breast cancer; EGFR-PI31; BIOLOGICAL EVALUATION; DERIVATIVES; PI3K/AKT/MTOR; GEFITINIB; PATHWAY; DESIGN; GROWTH;

D O I：

10.1016/j.ejmech.2019.03.030

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of novel 2,4-disubstituted quinazolines were synthesized and evaluated for their anti-tumor activity against five human cancer cells (MDA-MB-231, MCF-7, PC-3, HGC-27 and MGC-803) using MIT assay. Among them, compound 9n showed the most potent cytotoxicity against breast cancer cells. Compound 9n also significantly inhibited the colony formation and migration of MDA-MB-231 and MCF-7 cells. Meanwhile, compound 9n induced cell cycle arrest at G1 phase and cell apoptosis, as well as increased accumulation of intracellular ROS. Furthermore, compound 9n exerted anti-tumor effects in vitro via decreasing the expression of anti-apoptotic protein Bcl-2 and increasing the pro-apoptotic protein Bax and p53. Mechanistically, compound 9n markedly decreased p-EGFR and p-PI3K expression, which revealed that compound 9n targeted breast cancer cells via interfering with EGFR-PI3K signaling pathway. Molecular docking suggested that compound 9n could indeed bind into the active pocket of EGFR. All the findings suggest that compound 9n might be a valuable lead compound for anti-tumor agents targeting breast cancer cells. (C) 2019 Elsevier Masson SAS. All rights reserved.

引用

页码：36 / 47

页数：12

共 32 条

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