新型6,7-二甲氧基-4-(2-氟苯氧基)喹啉类c-Met抑制剂的设计、合成及生物活性研究

Design,Synthesis and Antitumor Activities of Novel 6,7-Dimethoxyl-4-(2-fluorophenoxy)quinolines as c-Met Inhibitors

基于卡博替尼(cabozantinib)和foretinib的化学结构,通过改变中间链,设计合成了一系列含有哌嗪酰胺的6,7-二甲氧基-4-(2-氟苯氧基)喹啉类c-Met抑制剂。这些化合物未见文献报道,其结构通过MS和NMR确证。采用酶联免疫吸附测定(ELISA)法和MTT法测定了目标化合物对c-Met的抑制活性和对人结肠癌细胞(HT-29)、人肺癌细胞(H460)、人非小细胞肺癌细胞(A549)和人胃癌细胞(MKN-45)的细胞毒性。结果表明,4-(4-氯苯基)-N-[4-[(6,7-二甲氧基-4-喹啉)氧基]-3-氟苯基]哌嗪-1-甲酰胺(1b)、4-(3-氯苯基)-N-[4-[(6,7-二甲氧基-4-喹啉)氧基]-3-氟苯基]哌嗪-1-甲酰胺(1h)和4-(2-氯苯基)-N-[4-[(6,7-二甲氧基-4-喹啉)氧基]-3-氟苯基]哌嗪-1-甲酰胺(1j)对HT-29、H460、A549和MKN-45细胞的抑制活性明显优于对照药卡博替尼。其中,化合物1h和1j对c-Met具有较强的抑制活性,其IC50值分别为0.007 2和0.009 8 μmol/L。

A series of 6,7-dimethoxy-4-(2-fluorophenoxy)quinoline derivatives containing piperazinamide were designed and synthesized as potential c-Met inhibitors based on cabozantinib and foretinib by modification on the intermediate chain.The structures of the new compounds were confirmed by MS and NMR.All novel target compounds were evaluated for their c-Met inhibitory activity and cytotoxicity against human colon cancer cells(HT-29),human lung cancer cells(H460),human non-small cell lung cancer cells(A549) and human gastric cancer cells(MKN-45) using enzyme-linked immunosorbent assay(ELISA) and MTT assay.The results showed that the inhibitory activities of 4-(4-chlorophenyl)-N-[4-[(6,7-dimethoxyquinolin-4-yl)oxy]-3-fluorophenyl]piperazine-1-carboxamide(1b),4-(3-chlorophenyl)-N-[4-[(6,7-dimethoxyquinolin-4-yl)oxy]-3-fluorophenyl]piperazine-1-carboxamide(1h) and 4-(2-chlorophenyl)-N-[4-[(6,7-dimethoxyquinolin-4-yl)oxy]-3-fluorophenyl]piperazine-1-carboxamide(1j) against HT-29,H460,A549 and MKN-45 cells were significantly better than those of cabozantinib.And compounds 1h and 1j had strong c-Met inhibitory activities with IC50 values of 0.007 2 and 0.009 8 μmol/L,respectively.