Liu Ju, Yang Di, Yang Xiuxiu, Nie Minhua, Wu Guodong, Wang Zhunchao, Li Wei, Liu Yajing, Gong Ping
Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China; College of Pharmacy of Liaoning University, Key Laboratory of New Drug Research and Development of Liaoning Province, 66 Chongshan Road, Huanggu District, Shenyang 10036, PR China.
Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
Bioorg Med Chem. 2017 Aug 15;25(16):4475-4486. doi: 10.1016/j.bmc.2017.06.037. Epub 2017 Jun 27.
A series of novel 4-phenoxyquinoline derivatives containing 3-oxo-3,4-dihydroquinoxaline moiety were synthesized and evaluated for their c-Met kinase inhibitory activity and antiproliferative activity against five cancer cell lines (HT-29, H460, A549, MKN-45 and U87MG) in vitro. Most of the compounds exhibited moderate-to-significant cytotoxicity as compared with foretinib. The most promising compound 41 (with c-Met IC value of 0.90nM) showed remarkable cytotoxicity against HT-29, H460, A549, MKN-45 and U87MG cell lines with IC values of 0.06μM, 0.05μM, 0.18μM, 0.023μM and 0.66μM, respectively, and thus it was 1.22- to 3.50-fold more potent than foretinib. Their preliminary structure-activity relationships (SARs) studies indicate that electron-withdrawing groups on the terminal phenyl rings are beneficial for improving the antitumor activity.
合成了一系列含有3-氧代-3,4-二氢喹喔啉部分的新型4-苯氧基喹啉衍生物，并对其c-Met激酶抑制活性和对五种癌细胞系（HT-29、H460、A549、MKN-45和U87MG）的体外抗增殖活性进行了评估。与福瑞替尼相比，大多数化合物表现出中度至显著的细胞毒性。最有前景的化合物41（c-Met IC值为0.90nM）对HT-29、H460、A549、MKN-45和U87MG细胞系表现出显著的细胞毒性，IC值分别为0.06μM、0.05μM、0.18μM、0.023μM和0.66μM，因此其效力比福瑞替尼高1.22至3.50倍。它们的初步构效关系（SAR）研究表明，末端苯环上的吸电子基团有利于提高抗肿瘤活性。
