摘要
目的 设计合成一系列5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶衍生物作为EGFR激酶抑制剂,评价其体外抗人源肺癌A549细胞增殖活性。方法 依据厄洛替尼与EGFR活性位点的结合模式进行分子对接研究,设计并合成了一系列新型5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶衍生物。采用MTT法对所有目标化合物进行体外抗人源肺癌A549细胞增殖抑制活性评价。结果与结论共合成12个目标化合物,其结构经ESI-MS、IR、^(1)H-NMR谱确证。部分化合物具有明显的抗人源肺癌A549细胞增殖活性,其中7-(4-羟基苯基)-4-(3-甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(9b)表现出最强的抑制活性。初步总结了部分目标化合物的构效关系。
Overexpression of the epidermal growth factor receptors(EGFR) is found in a variety of cancers.Based on molecular docking studies which were performed to position erlotinib and the target compounds into the EGFR active site to determine the probable binding model, a novel series of 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives as the potential EGFR kinase inhibitors were designed and synthesized.The synthetic route for the target compounds started from 4-(4-hydroxyphenyl)cyclohexanone to afford the key intermediate 4-chloro-7-(4-ethoxyphenyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine(5) through etherification reaction, Gewald reaction, cyclic reaction and chlorination in turns.The target 7-(4-ethoxyphenyl)-4-arylthio-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines(6 a-6 f) were obtained from compound 5 and arylthiol at presence of triethylamine.The target compounds 6 d-6 f were treated by anhydrous aluminum trichloride as a deethylation reagent to yield 7-(4-hydroxyphenyl)-4-arylthio-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives(7 a-7 c).The target compounds 7-(4-hydroxyphenyl)-4-(methoxyphenylthio)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines(9 a-9 c) were obtained from the intermediate compound 4-chloro-7-(4-hydroxyphenyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine(8) which was obtained from comound 5 via deethylating reaction.Twelve target compounds 6 a-6 f,7 a-7 c,9 a-9 c were evaluated for anti-proliferative activities against A549 cell line in vitro using the MTT colorimetric assay and EGFR inhibitory activity, and some of them exhibited significant anti-proliferative activity.Of all target compounds, 7-(4-hydroxyphenyl)-4-(3-methoxyphenylthio)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine(9 b) exhibited the most potent inhibitory activity.The preliminary structure-activity relationships of some target compounds were summarized.
作者
晏江庆
吴欣琪
孙铭芊
戴煜昕
孙冰
黄二芳
金辄
胡春
YAN Jiang-qing;WU Xin-qi;SUN Ming-qian;DAI Yu-xin;SUN Bing;HUANG Er-fang;JIN Zhe;HU Chun(Key Laboratory of Structure-Based Drug Design&Discovery(Shenyang Pharmaceutical University),Ministry of Education,Shenyang 110016,China)
出处
《中国药物化学杂志》
CAS
CSCD
2022年第10期741-752,共12页
Chinese Journal of Medicinal Chemistry
基金
National Science Foundation of China(NSFC)(21072130)
Program for Innovative Research Team of the Ministry of Education of China(IRT_14R36)。
