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
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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HepG2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HepG2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HepG2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: The novel oleanolic acid derivatives 2a-2e were synthesized by introducing an α, β-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, respectively. Derivatives 3a-3e were synthesized by substituting C-1 of compounds 2a-2e with bromine. The target compounds 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 μmol/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 addition, 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.
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Keywords:
- oleanolic acid /
- CDDO-Me /
- synthesis /
- antitumor activity
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