齐墩果酸-川芎嗪衍生物的合成及抗肿瘤活性研究  

Synthesis and Anti-tumor Activity Evaluation of Oleanolic acid-Ligustrazine Derivatives

作　　者：王璇 姜晓晔 黎七雄 WANG Xuan;JIANG Xiao-ye;LI Qi-xiong(School of Medicine,Wuhan City College,Wuhan 430083,China)

机构地区：[1]武汉城市学院医学部,湖北武汉430083

出　　处：《化学试剂》2022年第2期186-194,共9页Chemical Reagents

基　　金：湖北省教育厅科学研究计划指导性项目(B2020331)。

摘　　要：以川芎嗪为原料,经过氧化、Boekelheide重排、水解、Ing-Manske等反应制得了两个川芎嗪衍生物2-羟甲基-3,5,6-三甲基吡嗪和2-甲胺基-3,5,6-三甲基吡嗪,再利用药物拼合原理将其与齐墩果酸及其衍生物通过酯化或酰胺反应合成了8个新型齐墩果酸-川芎嗪衍生物,其结构通过^(1)HNMR、^(13)CNMR和MS确证。初步的生物活性结果表明,所合成的目标化合物对PC-3、MCF-7、HepG2和HeLa这4种肿瘤细胞均展现出了良好的抑制活性,半数抑制浓度(IC_(50))值均在20 mol/L以内,其抗肿瘤活性明显的强于先导化合物齐墩果酸与川芎嗪。构效关系研究表明,齐墩果酸与川芎嗪的拼接方式对活性影响不大,而齐墩果酸A环的修饰方式对活性影响较大,其中在齐墩果酸A环具有1-烯-3-氧代官能团的化合物对MCF-7展现出了最强的抑制活性,其IC_(50)分别为3.4、2.2 mol/L。此外,这些齐墩果酸-川芎嗪衍生物对正常MCF-10A和LO2细胞没有毒性。Initially,2-hydroxymethyl-3,5,6-trimethylpyrazine and 2-aminemethyl-3,5,6-trimethylpyrazine were synthesized with ligustrazine as starting materials by oxidation reaction,Boekelheide rearrangement reaction,hydrolysis reaction,and Ing-Manske reaction.After that,eight novel oleanolic acid-ligustrazine derivatives were obtained by esterification reaction or amidation reaction of intermediates with oleanolic acid or its derivatives.Their chemical structures were confirmed by^(1)HNMR,^(13)CNMR and Mass spectra.The preliminary biological results indicated that these derivatives showed potent inhibitory activities against PC-3,MCF-7,HepG2 and HeLa cells,and their half maximal inhibitory concentration(IC_(50))values were less than 20 mol/L,which were better than that of the lead compound oleanolic acid and ligustrazine.The structure-activity relationship showed that the coupling method of oleanolic acid with ligustrazine had little effect on the antiproliferative activity,while the modification of A ring of oleanolic acid unit had obvious effect on the activity.Among them,the derivatives with 1-en-3-oxo group in a ring of oleanolic acid unit exhibited the greatest potency against MCF-7 with the IC_(50) values were 3.4 and 2.2 mol/L,respectively.Moreover,all derivatives were nontoxic to both health MCF-10A and LO2 cells.

关 键 词：齐墩果酸 川芎嗪 结构修饰 拼合原理 微管蛋白聚合 抗肿瘤活性 

分 类 号：R914[医药卫生—药物化学]