以mTOR激酶为靶点的齐墩果酸衍生物的设计、合成及抗肿瘤活性研究

宋艳玲; 李玲; 刘忠岩; 李杰; 张蓬勃

doi:10.16438/j.0513-4870.2018-0890

以mTOR激酶为靶点的齐墩果酸衍生物的设计、合成及抗肿瘤活性研究

Design, synthesis and anticancer activity studies of oleanolic acid derivatives targeting mTOR

摘要

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、¹³C 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I₃和Ⅱ₃对HepG2细胞显示出较强的活性（IC₅₀=9.4和5.5 μmol·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I₃和Ⅱ₃进行mTOR激酶的抑制活性测试，结果表明化合物I₃和Ⅱ₃对mTOR激酶具有较强的抑制作用（IC₅₀=0.83和0.26 μmol·L^-1）。

Abstract: Ten novel oleanolic acid (OA) derivatives containing urea or thiourea group were designed and synthesized, the chemical structures were confirmed by ¹H NMR, ¹³C 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 Ⅱ₃ exhibited 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 Ⅱ₃ were further evaluated for the inhibitory activity against mTOR kinase. The results showed that I₃ and Ⅱ₃ exhibited strong inhibitory effect on mTOR kinase with IC₅₀ values of 0.83 and 0.26 μmol·L^-1.

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