新型CDDO-Me类似物的合成及抗肿瘤活性

发布时间：2018-05-22 18:56

本文选题：齐墩果酸 + CDDO-Me　；参考：《中国药科大学学报》2015年03期

【摘要】：以齐墩果酸(OA)为起始原料,经9步反应合成了C环含有α,β-不饱和酮结构的2-氰基-3,12-二氧代齐墩果烷-1,9(11)-二烯-28-酸甲酯(CDDO-Me)活性类似物1,再将不同的脂肪羧酸和芳杂环羧酸分别与其C-3位羟基酯化,设计、合成了新型CDDO-Me类似物(2a~2e),并进一步将C-1位溴代,得到化合物3a~3e。采用MTT法测定了目标化合物对肺癌细胞A549、肝癌细胞Hep G2以及肺上皮细胞BEAS-2B的增殖抑制活性。结果表明,目标化合物对Hep G2细胞和A549细胞的增殖均显示了不同程度的抑制,其中化合物3b和3c的抑制活性最强[IC50=(6.13±1.16)μmol/L,IC50=(5.49±1.03)μmol/L],优于先导物1,与CDDO-Me相当。此外,目标化合物对正常细胞BEAS-2B的抑制活性显著小于对上述两种肿瘤细胞的抑制活性,显示了较高的肿瘤细胞选择性,其中3e对Hep G2的选择性最高,其抑制作用是正常细胞的10倍,值得进一步研究。
[Abstract]:Oleanolic acid (OAA) was used as the starting material. The active analogue of 2-cyano-3azo-12-dioxo-oleanane containing 伪, 尾 -unsaturated ketone in C ring was synthesized by 9-step reaction. Then different fatty carboxylic acids and aromatic heterocyclic carboxylic acids were esterified with their C-3 hydroxyl groups respectively. A new type of CDDO-Me analogue was synthesized and further brominated at the C-1 position to obtain the compound 3ah3e. The inhibitory activity of the target compounds on the proliferation of lung cancer cell line A549, hepatocarcinoma cell line Hep G2 and lung epithelial cell BEAS-2B was determined by MTT assay. The results showed that the target compounds inhibited the proliferation of Hep G2 cells and A549 cells to varying degrees, and the inhibitory activity of compounds 3b and 3c was the highest [IC50=(6.13 卤1.16 渭 mol / L LIC50 + 1.03 渭 mol/L], which was superior to the precursor 1 and was similar to CDDO-Me. In addition, the inhibitory activity of the target compound on BEAS-2B in normal cells was significantly lower than that on the two kinds of tumor cells mentioned above, showing a high selectivity of tumor cells, and 3e showed the highest selectivity to Hep G2. Its inhibitory effect is 10 times of that of normal cells, so it is worth further study.
【作者单位】：中国药科大学新药研究中心天然药物活性组分与药效国家重点实验室江苏省代谢性疾病药物重点实验室;
【基金】：国家自然科学基金资助项目(No.81273378,No.21472244,No.21372261,No.81202408)~~
【分类号】：R914.5;R96

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