摘要
本文以齐墩果酸(oleanolic acid, OA)为先导化合物进行结构优化,通过引入mTOR小分子抑制剂的重要药效基团脲基或硫脲基,同时拼合多种生物活性片段,设计并合成了10个新的衍生物,其结构经~1H NMR、^(13)C NMR和HR-MS确证。对所合成的目标化合物以人肝癌细胞(HepG2)和人胃癌细胞(SGC7901)进行体外抗肿瘤活性测试,结果表明目标化合物对两种肿瘤细胞的抑制活性均明显强于OA,其中I_3和II_3对HepG2细胞显示出较强的活性(IC_(50)=9.4和5.5μmol·L^(-1))。分子模拟对接研究表明,目标化合物和mTOR激酶均具有较好的结合能力。对化合物I_3和II_3进行mTOR激酶的抑制活性测试,结果表明化合物I_3和II_3对mTOR激酶具有较强的抑制作用(IC_(50)=0.83和0.26μmol·L^(-1))。
Ten novel oleanolic acid(OA) derivatives containing urea or thiourea group were designed and synthesized, the chemical structures were confirmed by1 H NMR,13 C NMR and HR-MS. All of these compounds were evaluated for the inhibitory activity against growth of HepG2 and SGC7901 cells. The results showed that compounds I3 and II3exhibited significant antitumor activities with IC50 of 9.4 and 5.5 μmol · L-1, respectively.Molecular docking studies showed that all these compounds exhibit inhibitory ability against mTOR kinase.Compounds I3 and II3were further evaluated for the inhibitory activity against mTOR kinase. The results showed that I3 and II3exhibited strong inhibitory effect on mTOR kinase with IC50 values of 0.83 and 0.26 μmol·L-1.
作者
宋艳玲
李玲
刘忠岩
李杰
张蓬勃
SONG Yan-ling;LI Ling;LIU Zhong-yan;LI Jie;ZHANG Peng-bo(Institute of Pharmaceutical and Biological Engineering,Shenyang University of Chemical Technology,Shenyang 110142,China)
出处
《药学学报》
CAS
CSCD
北大核心
2019年第2期335-342,共8页
Acta Pharmaceutica Sinica
基金
辽宁省自然科学基金资助项目(2015020687)
关键词
齐墩果酸衍生物
合成
分子对接
抗肿瘤活性
oleanolic acid derivative
synthesis
molecular docking
anti-tumor activity
