齐墩果酸A环衍生的类似物的合成及抗肿瘤活性研究
收稿日期: 2016-10-19
修回日期: 2017-01-06
网络出版日期: 2017-02-20
基金资助
国家自然科学基金（No.21372156）、辽宁省教育厅高等学校优秀人才支持计划（No.LR2013017）和沈阳市科技计划（No.F16-230-6-00）资助项目.
Synthesis and Anti-Tumor Activities of Ring A Derived Analogues of Oleanolic Acid
Received date: 2016-10-19
Revised date: 2017-01-06
Online published: 2017-02-20
Supported by
Project supported by the National Natural Science Foundation of China (No. 21372156), the Excellent Talents in University of the Department of Education of Liaoning Province (No. LR2013017), and the Scientific Research Project of the Shenyang Science and Technology Board (No.F16-230-6-00).
以天然产物齐墩果酸为母体，采用计算机药物辅助设计，在C-kit与活性小分子进行模拟对接的基础上，在A环上引入含氮、氧杂环，同时对其C（28）位羧基进行酰胺化结构修饰，设计并合成了10个新的齐墩果酸类似物，其结构经过1H NMR、13C NMR、MS等确认.采用噻唑蓝（MTT）法，选用人口腔表皮样癌细胞（KB）和人肺癌细胞（A549）进行了初步的体外抗肿瘤活性筛选.结果表明，测试的化合物对两种细胞均具有一定的抑制活性，其中齐墩果-2，12-二烯并[3，2-d]嘧啶-28-羧酸正己酯（I4）和5'，6'-二氢-齐墩果-2-烯并[2，3-b]吡嗪-12-烯-28-酰-4"-甲基苯胺（II3）对A549肿瘤细胞表现出很强的抑制活性，在10 μg/mL浓度下IC50值分别为2.67和1.03 μmol/L，活性明显高于5-氟尿嘧啶（IC50＝7.39 μmol/L），值得进一步研究.
孟艳秋 , 邢雯 , 蒯振彧 , 张伟晨 , 李为 . 齐墩果酸A环衍生的类似物的合成及抗肿瘤活性研究[J]. 有机化学, 2017 , 37(6) : 1417 -1425 . DOI: 10.6023/cjoc201610033
By means of computer aided drug design, simulation of apoptosis inhibiting protein complex glycine receptor kinase C-kit docking with active small molecules. Ten analogues were successfully synthesized by the introduction of nitrogen-containing heterocyclic compounds at ring A and the modification of the esterification and amidation at C(28) position in the natural product oleanolic acid. Their structures were charachterized by 1H NMR, 13C NMR, MS and so forth. Their anti-tumor activities against KB, A549 cells in vitro were evaluated by methyl thiazolyl tetrazolium (MTT) assay. These results indicated that the objective of test compounds of two kinds of tumor cells have good inbitory activity, and 5',6'-dihydro-olean-2-ene-[2,3-b]pyrazin-12-ene-28-acyl-4"-monomethylaniline (I4) (IC50＝2.67 μmol/L) and olean-2-ene-[2,3-b]pyrimidine-12-ene-28-oic acid n-hextyl ester (II3) (IC50＝1.03 μmol/L) have especially more potent inbitory activity on A549 tumor cells than 5-fluorouracil (IC50＝7.39 μmol/L), which are worthy to be studied further.
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