CDDO-Me羧酸酯前药的设计、合成及抗炎活性

牟伊; 陈同; 黄张建; 赖宜生; 彭司勋; 季晖; 张奕华

doi:10.11665/j.issn.1000-5048.20160605

CDDO-Me羧酸酯前药的设计、合成及抗炎活性

Design, synthesis and anti-inflammatory evaluation of CDDO-Me ester prodrugs

摘要

摘要: 以齐墩果酸(OA)为起始原料，合成了2-氰基-3，12-二氧代齐墩果烷-1，9(11)-二烯-28-酸甲酯(CDDO-Me)，继而经DMF/K₂CO₃作用，制备了该化合物A环上的1，4加成物( 1 )，再用不同的脂肪羧酸和取代芳香羧酸分别与其C-3位羟基反应，合成了CDDO-Me羧酸酯前药( 2 ~ 8 )，以期得到活性较强、毒性较小的抗炎药物。采用LPS诱导小鼠巨噬细胞(RAW 264.7)释放一氧化氮(NO)的模型来评价目标化合物抗炎活性。结果表明，化合物 2 ~ 8 对细胞中NO释放显示了不同程度的抑制，其中化合物 2 ［IC₅₀=(2.34±0.67)nmol/L］和 7 ［IC₅₀=(3.83±0.97)nmol/L］抑制活性最强。此外，用MTT法评价了目标化合物对巨噬细胞RAW 264.7增殖的影响，发现它们的抑制活性显著低于CDDO-Me，提示其毒性小于CDDO-Me。

Abstract: In order to search for new anti-inflammatory agents with strong activity and less toxicity relative to CDDO-Me, the ester prodrugs 2 - 8 of CDDO-Me were synthesized by treatment of oleanolic acid(OA)with DMF/K₂CO₃ to generate 1 , followed by esterification of 1 with various aliphatic and aromatic carboxylic acids, respectively. All the target compounds showed strong inhibitory effects on LPS-induced NO production in RAW 264. 7 cells. Among them, compounds 2 and 7 possessed the most potent inhibitory effects with IC₅₀=(2. 34±0. 67)and(3. 83±0. 97)nmol/L, respectively. Moreover, MTT assay indicated that all the target compounds( 2 - 8 )displayed much weaker anti-proliferative activity against RAW 264. 7 cell lines than CDDO-Me, suggesting that they may be less toxic than CDDO-Me.

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