Discovery of novel 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 5-(aminomethylene)pyrimidine-2,4,6-trione moiety as c-Met kinase inhibitors

作者：Tang, Qidong; Zhang, Guogang; Du, Xinming; Zhu, Wufu; Li, Ruijuan; Lin, Huafang; Li, Pengcheng; Cheng, Maosheng; Gong, Ping; Zhao, Yanfang^*

来源：Bioorganic & Medicinal Chemistry, 2014, 22(4): 1236-1249.

DOI：10.1016/j.bmc.2014.01.014

• c-Met
• Receptor tyrosine kinase
• Anti-tumor
• Quinoline derivatives
• Pyrimidine-2,4,6-trione

A series of novel quinoline derivatives bearing 5-(aminomethylene)pyrimidine-2,4,6-trione moiety were designed, synthesized, and evaluated for their c-Met kinase inhibitory activities and antiproliferative activities against 5 cancer cell lines (HT-29, H460, MKN-45, A549, and U87MG) in vitro. Most compounds showed moderate to excellent potency, with the most promising analogue 45 (c-Met half-maximal inhibitory concentration [IC50] = 1.15 nM) showing high selectivity versus 5 other tyrosine kinases, VEGFR-2, Flt-3, PDGFR-beta, c-Kit, and EGFR. Structure-activity relationship studies indicated that electron-donating groups on the phenyl ring at the 3-position of pyrimidine-2,4,6-trione were required to increase the electron density on the 5-(aminomethylene) pyrimidine-2,4,6-trione moiety.

• 出版日期2014-2-15
• 单位河北科技大学; 沈阳药科大学; 江西科技师范大学