School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou, 450001, PR China.
School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou, 450001, PR China.
Eur J Med Chem. 2019 Jun 15;172:36-47. doi: 10.1016/j.ejmech.2019.03.030. Epub 2019 Mar 17.
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 MTT 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.
一系列新型 2,4-二取代喹唑啉被合成，并通过 MTT 法评估了它们对五种人癌细胞（MDA-MB-231、MCF-7、PC-3、HGC-27 和 MGC-803）的抗肿瘤活性。其中，化合物 9n 对乳腺癌细胞表现出最强的细胞毒性。化合物 9n 还显著抑制 MDA-MB-231 和 MCF-7 细胞的集落形成和迁移。同时，化合物 9n 诱导细胞周期停滞在 G1 期并诱导细胞凋亡，以及增加细胞内 ROS 的积累。此外，化合物 9n 通过降低抗凋亡蛋白 Bcl-2 的表达和增加促凋亡蛋白 Bax 和 p53 的表达，在体外发挥抗肿瘤作用。机制上，化合物 9n 显著降低了 p-EGFR 和 p-PI3K 的表达，表明化合物 9n 通过干扰 EGFR-PI3K 信号通路靶向乳腺癌细胞。分子对接表明，化合物 9n 确实可以结合到 EGFR 的活性口袋中。所有这些发现表明，化合物 9n 可能是一种有价值的针对乳腺癌细胞的抗肿瘤药物的先导化合物。
