具有噻唑啉酮结构片段的c-Met抑制剂的设计、合成及其抗肿瘤活性研究

Design,Synthesis and Antitumor Activities of c-Met Inhibitors Possessing Thiazolinone Scaffolds

目的设计合成含有噻唑啉酮结构片段的4-芳氧基-6,7-二取代喹啉类化合物,并对其体外抗肿瘤活性进行研究。方法以c-Met激酶抑制剂cabozantinib为先导物,结合课题组已有的构效关系,运用拼合原理及局部修饰的方法,通过亲核取代、硝化、还原及缩合等反应合成目标化合物。采用均相时间分辨荧光法和3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐法对其c-Met激酶抑制活性和体外抗肿瘤活性进行了评价。采用实时动态活细胞成像法进一步评价了化合物对肿瘤细胞的杀伤作用。结果合成得到了17个新化合物,其结构经1H-NMR、13C-NMR及HRMS确证。体外生物活性测试结果显示,所有化合物对c-Met激酶、人非小细胞肺癌A549、人肝癌细胞Hep G2及人乳腺癌细胞MDA-MB-231均有一定的抑制活性,其中化合物m2对A549、Hep G2及MDA-MB-231具有较显著的杀伤作用,IC50值分别为2.45、4.01和1.05μmol·L-1。结论该系列化合物具有较好的抗肿瘤活性,具有进一步研究的意义。

OBJECTIVE To design and synthesize 4-phenoxy-6,7-disubstituted quinolines possessing thiazolinone scaffolds and investigate their in vitro antitumor activities. METHODS Taking the c-Met kinase inhibitor cabozantinib as lead compound and based on the obtained SARs, combination principles and local modification, target compounds were prepared by nucleophilic substitution, nitration, reduction and condensation, etc. The c-Met inhibition and in vitro antitumor activities were evaluated by HTRF and MTT methods, respectively. The cytotoxicity against cancer cells was evaluated by real-time dynamic living cell imaging. RESULTS Seventeen novel compounds were obtained, and their structures were confirmed by ^1H-NMR, ^13C-NMR and HRMS. In vitro bioassay indicated that all the compounds showed inhibitory activities against A549, HepG2 and MDA-MB-231 cell lines as well as c-Met kinase. Compound m2 exhibited potent cytotoxicity with IC50 values of 2. 45, 4. 01, and 1.05μmol·L^-1 , respectively. CONCLUSION The series of compounds show preferable antitumor activities, which are worthy of further study.