2-苯氨基喹啉衍生物的设计、合成及其抗肿瘤活性研究  

Design, synthesis, and antitumor activity of 2-anilinoquinoline derivatives

作　　者：宁虎林 郭易华 李凤凤 李荣东[1] NING Hulin;GUO Yihua;LI Fengfeng;LI Rongdong(Hunan University of Chinese Medicine,Changsha,Hunan 410208,China;Hunan Jiudian Pharmaceutical Co.,Ltd.,Changsha,Hunan 410000,China)

机构地区：[1]湖南中医药大学,湖南长沙410208 [2]湖南九典制药股份有限公司,湖南长沙410000

出　　处：《湖南中医药大学学报》2024年第5期802-810,共9页Journal of Hunan University of Chinese Medicine

基　　金：湖南中医药大学药学一流学科开放基金重点项目(2021YX01)。

摘　　要：目的 在喹啉环的C-2位引入亲脂性苯胺基团,C-7位引入亲水性基团,得到新型2-苯氨基喹啉衍生物,探究其抗肿瘤细胞增殖活性。方法 以DL-苯丙氨酸、L-苯丙氨酸和D-苯丙氨酸为原料合成关键中间体,与喹啉母核连接合成一系列2-苯氨基喹啉衍生物。采用CCK-8法测试目标化合物对人肝癌细胞(HepG2)和非小细胞肺癌细胞(A549)的抗增殖活性。通过Autodock软件测试目标化合物与血管内皮生长因子受体(vascular endothelial growth factor receptor,VEGFR)、表皮生长因子受体(epidermal growth factor,EGFR)蛋白的结合效果。结果 合成了16个新型2-苯氨基喹啉衍生物,经1H NMR、LC-MS确证其结构。体外抗肿瘤实验结果表明,目标化合物T-7与T-8的抗肿瘤活性与阳性对照药吉非替尼以及乐伐替尼相当。Autodock软件预测结果与体外抗肿瘤实验结果一致。结论 新型2-苯氨基喹啉衍生物具有抗肝癌和非小细胞肺癌的作用,为进一步探究喹啉衍生物类抗肿瘤药物打下基础。Objective To yield a novel 2-anilinoquinoline derivative by introducing a lipophilic aniline group at the C-2 position of the quinoline ring and a hydrophilic group at the C-7 position,and to explore its anti-tumor cell proliferation activity.Methods Key intermediates were synthesized from DL-phenylalanine,L-phenylalanine,and D-phenylalanine,and a series of 2-anilinoquinoline derivatives were synthesized by linking them with quinoline nuclei.The anti-proliferative activity of the target compound on human liver cancer cells(HepgG2)and non-small cell lung cancer cells(A549)was tested using the CCK-8 method.The binding effects of the target compound with vascular endothelial growth factor receptor(VEGFR)and epidermal growth factor receptor(EGFR)proteins were determined by Autodock software.Results Sixteen new 2-anilinoquinoline derivatives were synthesized,and their structures were confirmed by 1H NMR and LC-MS.The results of in vitro anti-tumor experiments showed that the anti-tumor activities of target compounds T-7 and T-8 were comparable to those of the positive control medicines,Gefitinib and Lenvatinib.The test results of Autodock software were consistent with the results of in vitro anti-tumor experiments.Conclusion The novel 2-anilinoquinoline derivatives have effects against liver cancer and non-small cell lung cancer,laying a theoretical foundation for further exploration of quinoline derivatives as anti-tumor agents.

关 键 词：2-苯氨基喹啉 肝癌 肺癌 细胞增殖 化学合成 

分 类 号：R284.3[医药卫生—中药学]