2-乙酰氧亚氨基积雪草酸衍生物的合成及抗肿瘤活性研究  

Synthesis of 2-acetoxyimino asiatic acid derivatives and their antitumor activity

作　　者：林碧琦 孟艳秋[1] LIN Bi-qi;MENG Yan-qiu(Department of Pharmaceutical Engineering.Shenyang University of Chemical Technology,Shenyang 110142.China)

机构地区：[1]沈阳化工大学制药工程研究室,沈阳110142

出　　处：《中国新药杂志》2020年第19期2221-2228,共8页Chinese Journal of New Drugs

基　　金：国家自然科学基金资助项目(21372156);辽宁省创新团队资助项目(LT2017009);辽宁省教育厅科研项目(LFD2017004);辽宁省重点研发计划项目(2019JH2/10300034)。

摘　　要：目的:设计合成2类共10个具有抗肿瘤活性的积雪草酸衍生物。方法:以血管内皮生长因子(vascular endothelial growth factor,VEGF)为靶点,用计算机辅助药物设计方法设计化合物;以积雪草酸为先导化合物,在A环的C-3和C-23位引入异亚丙基,在C-2位上引入乙酰氧亚氨基,并将C-28位羧基成酯或者酰胺化形成衍生物;采用噻唑蓝(MTT)法,选用人胃癌细胞SGC7901和人肺癌细胞A549进行细胞毒活性测试。结果:化合物结构经核磁共振(nuclear magnetic resonance,NMR)和质谱(mass spectrum,MS)确证。目标化合物能抑制SGC7901和A549的增殖,且强于母体积雪草酸,其中化合物11和13抑制作用最为显著并强于吉非替尼。结论:新合成的积雪草酸衍生物有较强的抗肿瘤活性,可对其深入研究。Objective:Two types of asiatic acid derivatives,totally 10 compounds,with antitumor activity were designed and synthesized.Methods:With VEGF as the target,compounds were designed by the method of computer-aided design.Using asiatic acid as the lead compound,isopropylidene group was introduced at C-3 and C-23 positions of the A ring,the acetoxyimino group was introduced at C-2 position,and the carboxyl group was esterified or amidated at the position C-28 to form derivatives.The cytotoxic activity was determined by MTT assay in human gastric cancer cells(SGC7901)and human lung cancer cells(A549).Results:The structures of the compounds were confirmed by NMR and MS.The target compound inhibited the proliferation of SGC7901 and A549,being stronger than asiatic acid.The inhibition rates of compounds 11 and 13 are the most significantly stronger than that of gefitinib.Conclusion:The newly synthesized asiatic acid derivatives have strong antitumor activity and are worthy of further studying.

关 键 词：积雪草酸衍生物 计算机辅助药物设计 抗肿瘤活性 流式检测 

分 类 号：R914.5[医药卫生—药物化学]