Design, synthesis, and biological evaluation of novel 4-anilinoquinazoline derivatives bearing amino acid moiety as potential EGFR kinase inhibitors

作者：Zheng, You-Guang^*; Su, Jun; Gao, Cai-Yun; Jiang, Ping; An, Lin; Xue, Yun-Sheng; Gao, Jian; Liu, Yi^*

来源：European Journal of Medicinal Chemistry, 2017, 130: 393-405.

DOI：10.1016/j.ejmech.2017.02.061

• 4-Anilinoquinazoline derivatives
• Amino acid moiety
• HepG2
• Apoptosis

In this study, a series of 4-anilinoquinazoline derivatives bearing amino acid moiety were designed, synthesized and evaluated for biological activities. The synthesized compounds were screened for anticancer activity against human hepatocellular carcinoma cell HepG2 using SRB assay. In vitro cell growth inhibition assays indicated that compound 6m exhibited moderate inhibitory activities only against human hepatocellular carcinoma cells HepG2 with IC50 of 8.3 mu M. Synthetic derivatives showed excellent selectivity, such as compound 6m demonstrated a strong inhibition of EGFR ( IC50 = 0.0032 mM), with selectivity of over 2000-fold over other kinases. Apoptosis analysis revealed that compound 6m caused obvious induction of cell apoptosis. 6m significantly down-regulated the expression of Bcl-2 and up-regulated the expression of Bax, decreased mitochondrial membrane potential ( Delta psi m), promoted the mitochondrial cytochrome c release into the cytoplasm, activated caspase-3, and finally induced apoptosis of HepG2 cells. Molecular docking indicated that compound 6m could bind well with EGFR. Therefore, compound 6m may be a potential agent for cancer therapy deserving further research.

• 出版日期2017-4-21
• 单位徐州医科大学