目的 为寻找活性强的抗非小细胞肺癌(NSCLC)药物,设计、合成了10个结构新颖的香豆素-苯胺嘧啶拼合物7a~7j,并对其抗NSCLC活性进行了初步探讨。方法 通过拼合原理,将苯胺嘧啶与香豆素衍生物进行缩合得到目标化合物,采用四甲基偶氮唑蓝(MTT)法对其抗NSCLC细胞增殖活性进行了研究,并应用分子对接技术模拟目标物与表皮生长因子受体(EGFR)的结合模式。结果 目标化合物7a~7j的结构经MS、1H-NMR及13C-NMR谱确证;生物活性测试结果表明,目标物对NSCLC细胞株H1975细胞增殖具有不同程度的抑制活性(IC50=2.70~17.59 μmol·L-1),其中6个化合物的抑制活性优于对照药吉非替尼(IC50=9.18 μmol·L-1)。结论 化合物7j(IC50=2.70 μmol·L-1)抗H1975细胞增殖活性较强,值得深入研究。
Abstract
OBJECTIVE To design and synthesize a series of combined compounds of coumarins and anilinopyrimidines (7a-7j) investigate their anti-NSCLC activities in vitro. METHODS The target compounds were obtained by condensation of anilinopyrimidines and coumarin derivatives via the combination principle, then the anti-NSCLC activity of these compounds was studied by MTT. Molecular docking studies were performed to afford the binding mode of the compound and EGFR. RESULTS The structures of the target compounds were confirmed by MS, 1H-NMR and 13C-NMR. Compounds 7a-7j displayed different degrees of inhibitory activities on the proliferation of NSCLC cell line H1975 (IC50=2.70-17.59 μmol·L-1). Six compounds showed higher anti-proliferative activity on H1975 cells than gefitinib (IC50=9.18 μmol·L-1). CONCLUSION Compound 7j (IC50=2.70 μmol·L-1) has the best inhibitory effect on H1975 cells, suggesting that 7j may be a potential anti-NSCLC agent for further investigation.
关键词
香豆素 /
苯胺嘧啶 /
非小细胞肺癌 /
表皮生长因子受体 /
抗肿瘤
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Key words
coumarin /
anilinopyrimidine /
NSCLC /
EGFR /
antitumor
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中图分类号：
R914
R965
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参考文献
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脚注
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基金
国家自然科学基金项目资助(21402012);山西省应用基础研究计划项目资助(201801D221082);山西省重点学科建设经费资助;山西省“1331工程”重点创新团队建设计划资助
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