摘要
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~1HNMR、^(13)CNMR、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(I_4)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(Ⅱ_3)对A549肿瘤细胞表现出很强的抑制活性,在10μg/mL浓度下IC_(50)值分别为2.67和1.03μmol/L,活性明显高于5-氟尿嘧啶(IC_(50)=7.39μmol/L),值得进一步研究.
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 ~1HNMR, ^（13）CNMR, 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（I_4）（IC_（50）= 2.67 μmol/L） and olean-2-ene-[2,3-b]pyrimidine-12-ene-28-oic acid n-hextyl ester（Ⅱ3）（IC_（50）=1.03 μmol/L） have especially more potent inbitory activity on A549 tumor cells than 5-fluorouracil（IC_（50）=7.39 μmol/L）, which are worthy to be studied further.
出处
《有机化学》
SCIE
CAS
CSCD
北大核心
2017年第6期1417-1425,共9页
Chinese Journal of Organic Chemistry
基金
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)
沈阳市科技计划(No.F16-230-6-00)资助项目~~
