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

作　　者：牟伊[1,2,3,4] 陈同[1,5] 黄张建[1,2] 赖宜生[1,2] 彭司勋[1,2] 季晖[1,5] 张奕华[1,2] 

机构地区：[1]中国药科大学天然药物活性组分与药效国家重点实验室,南京210009 [2]中国药科大学江苏省代谢性疾病药物重点实验室,南京210009 [3]中国药科大学 [4]泰州学院医药与化学化工学院,泰州225300 [5]中国药科大学药理学教研室,南京210009

出　　处：《中国药科大学学报》2016年第6期661-665,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,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（RAW264.7）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[IC（50）=（2.34±0.67）nmol/L]和7[IC（50）=（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。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.

关 键 词：齐墩果酸 CDDO-Me 前药 抗炎活性 合成 

分 类 号：R914[医药卫生—药物化学] R96[医药卫生—药学]