Wang Xiaoqiang, Jiang Nan, Zhao Sijia, Xi Shuancheng, Wang Jiao, Jing Tongfei, Zhang Wenyu, Guo Ming, Gong Ping, Zhai Xin
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
Bioorg Med Chem. 2017 Feb 1;25(3):886-896. doi: 10.1016/j.bmc.2016.12.002. Epub 2016 Dec 12.
Two novel series of 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives bearing 1H-imidazole-4-carboxamido or (E)-3-hydrosulfonylacrylamido motifs (16-31 and 32-42) were designed, synthesized and evaluated for their in vitro cytotoxic activity. Most of the compounds exhibited moderate to excellent potency against tested three cell lines, and fifteen compounds were further examined for their inhibitory activity against c-Met kinase. The most promising compound 16 (c-Met kinase [IC]=1.1nM) demonstrated high selectivity and remarkable cytotoxicity against HT-29, MKN-45 and A549 cells with IC values of 0.08, 0.22 and 0.07μM, which were 3.1-, 1.4- and 2.1-fold more active than Foretinib. The preliminary structure-activity relationships as well as molecular docking disclosed that 1H-imidazole-4-carboxamido as a linker was of great importance for the antitumor activity.
设计、合成了两个新型系列的带有1H-咪唑-4-甲酰胺基或（E）-3-氢磺酰基丙烯酰胺基序的6,7-二取代-4-（2-氟苯氧基）喹啉衍生物（16 - 31和32 - 42），并对其体外细胞毒性活性进行了评估。大多数化合物对测试的三种细胞系表现出中等至优异的活性，对十五种化合物进一步考察了它们对c-Met激酶的抑制活性。最有前景的化合物16（c-Met激酶[IC]=1.1 nM）对HT-29、MKN-45和A549细胞表现出高选择性和显著的细胞毒性，IC值分别为0.08、0.22和0.07 μM，活性分别比Foretinib高3.1倍、1.4倍和2.1倍。初步的构效关系以及分子对接表明，1H-咪唑-4-甲酰胺基作为连接基对抗肿瘤活性至关重要。
