新型CDDO-Me类似物的合成及抗肿瘤活性  

Synthesis and antitumor activities of novel CDDO-Me analogues

作　　者：乔祎雪 牟伊[1] 黄张建[1] 艾勇[1] 康峰华 赖宜生[1] 张奕华[1] 

机构地区：[1]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,南京210009

出　　处：《中国药科大学学报》2015年第3期289-293,共5页Journal of China Pharmaceutical University

基　　金：国家自然科学基金资助项目(No.81273378;No.21472244;No.21372261;No.81202408)~~

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。The novel oleanolic acid derivatives 2a-2e were synthesized by introducing an a, r-unsaturated ketone moiety to C-ring of oleanolic acid （OA） via a nine-step reaction sequence, yielding an active CDDO-Me analogue （1）, followed by coupling of C3-OH of 1 with various aliphatic and aromatic carboxylic acids, respective- ly. Derivatives 3a-3e were synthesized by substituting C-1 of compounds 2a-2e with bromine. The target com- pounds were characterized by IR, MS and 1H NMR spectra. All the target compounds showed strong inhibitory effects against two tumor cell lines （ HepG2 and A549） to a varying extent. The anti-proliferative activities of active compounds 3b and 3c （IC50 =6. 13 ± 1.16 μ mol/L and IC50 =5.49 ± 1.03 μmol/L, respectively） against HepG2 and A549 were more potent than compound 1 and comparable to the positive control CDDO-Me. In addi- tion, all the target compounds displayed much weaker anti-proliferative activity against the two tumor cell lines than that against normal BEAS-2B cells. Compound 3c showed ten-fold selective inhibition against HepG2 relative to BEAS-2B cells, and is thus worthy of further study.

关 键 词：齐墩果酸 CDDO-Me 合成 抗肿瘤活性 

分 类 号：R914.5[医药卫生—药物化学] R965[医药卫生—药学]