四氢异喹啉类索拉非尼衍生物设计、合成及抗肿瘤活性研究

Design,Synthesis and Antitumor Activity of Sorafenib Derivatives of Tetrahydroisoquinoline

以索拉非尼为模型化合物,利用生物电子等排原理和药效团理论,设计了6个全新的四氢异喹啉类索拉非尼衍生物。以取代四氢异喹啉、取代苯甲酸为原料,通过甲基化反应、亲核取代反应等步骤,对设计的6个全新的四氢异喹啉类索拉非尼衍生物进行合成,通过^(1)H NMR、^(13)C NMR和MS对6个新合成的目标化物结构进行了确证。选用索拉非尼为阳性对照药,采用MTT法检测了6个化合物对肺癌A549细胞、人乳腺癌MCF-7细胞、肝癌HepG2细胞的抑制活性,结果显示ZH-2对A549细胞的抑制活性为26.07μM,与索拉非尼相当;对MCF-7细胞的抑制活性为8.41μM,明显强于索拉非尼16.70μM。

Based on bioisosterism and pharmacophore theory,six new tetrahydroisoquinoline sorafenib derivatives were designed with sorafenib as a model compound.Using substituted tetrahydroisoquinoline and substituted benzoic acid as raw materials,the six designed derivatives were synthesized through methylation reaction,nucleophilic substitution reaction and other steps.The structures of the six new compounds were confirmed by^(1)H NMR,^(13)C NMR and MS.The inhibitory activities of six compounds on lung cancer A549 cells,human breast cancer MCF-7 cells and liver cancer HepG2 cells were detected by MTT method,and sorafenib was selected as the positive control drug.The results showed that the inhibitory activity of ZH-2 on A549 cells was 26.07μM,which was similar to that of sorafenib.The inhibitory activity of MCF-7 cells was 8.41μM,which was stronger than 16.70μM of sorafenib.