含喹啉结构的氨甲环酸衍生物的合成及生物活性研究

Synthesis and biological activity evaluation of tranexamic acid derivatives containing quinoline moiety as antitumor agents

目的设计合成对血管内皮生长因子受体2(VEGFR2)具有抑制作用的含喹啉结构的氨甲环酸衍生物,并进行体外抗肿瘤活性评价。方法基于分子杂交技术,以氨甲环酸作为连接子,喹啉结构为ATP结合区域,设计了含有喹啉结构的氨甲环酸衍生物。以间位和对位三氟甲基苯胺为原料,分别经取代、环合、水解、脱羧、氯代、亲核取代反应得到相应的羧酸,然后与不同的胺发生缩合反应得到目标化合物8a~8l,测试目标化合物对人肺癌细胞株(A549)的体外抑制活性。结果与结论合成了12个未经文献报道的新化合物,其结构均经HR-MS、^(1)H-NMR确证。体外生物活性评价结果表明,在50μmol·L^(-1)浓度下,除了目标化合物8h外,其他目标化合物对A549细胞生长的抑制率均与阳性对照索拉非尼相当,其中化合物8c、8e和8f对肿瘤细胞生长的抑制率高于阳性对照;在10μmol·L^(-1)浓度下,化合物8f、8h~8l对A549细胞生长的抑制率达50%以上。

Vascular endothelial growth factor receptor(VEGFR)has become an ideal drug target because of its stable overexpression in tumors.Based on the structural characteristics of listed VEGFR2 inhibitors,a series of tranexamic acid derivatives containing quinoline structure were designed by adopting the hybridization strategy of dominant fragments with replacing the aromatic ring region with tranexamic acid with multi-target antitumor activity as linker,and selecting quinoline fragments of VEGFR2 inhibitors newly listed in recent years as ATP binding region.Various anilines were used as raw materials,which were subjected to substitution,cyclization,hydrolysis,decarboxylation,chlorination,nucleophilic substitution,condensation reaction with different amines to give the target compounds.The antitumor activity screening results showed that all the designed compounds had a certain inhibitory effect on human lung cancer cell line A549.Almost all the target compounds except 8 h have shown similar inhibition ratios against human lung cancer cell line A549 to the positive control drug sorafenib at the concentration of 50μmol·L^(-1),and the inhibitory ratios of compounds 8 c,8 e and 8 f on tumor cells at the same concentration were higher than that of sorafenib.Meanwhile,compounds 8 f,8 h-8 l still have more than half of the inhibition ratios on A549 cells at the concentration of 10μmol·L^(-1).