大黄酸-缬氨酸加合物的合成及初步抗肿瘤活性

以大黄酸为原料,经酯化、烷基化、水解及缩合等反应步骤合成了12个大黄酸-缬氨酸加合物.目标化合物经1H NMR,~(13)C NMR和HRMS进行了结构确证.以顺铂和阿霉素为阳性对照药,采用四甲基偶氮唑盐(MTT)法考察了目标化合物的体外抗肿瘤(Hela,MCF-7,HepG2,KB和HEK293T等5株细胞)活性.结果表明,化合物5l显示出较好的抗肿瘤活性,其IC50值在1.6~9.4μmol/L之间.作用机制研究结果表明,化合物5l能够与DNA发生较强的结合作用.

Synthesis and Antitumor Activities of Rhein-Valine Adducts

In order to search for novel leading compounds endowed with better antitumor activities, twelve novel rhein?valine derivatives were designed and synthesized by modification of position?1, 3 and 8 of rhein nucleus, and their structures were confirmed by 1 H NMR, 13 C NMR and HRMS. All the target compounds were tested for cytotoxic activity against five cancer cell lines including Hela, MCF?7, HepG2, KB and HEK293T by methyl thiazolyl tetrazolium( MTT) method in vitro. The results demonstrate that compound 5l displayed a broad spectrum of cytotoxic activities with IC50 value of lower than 10μmol/L against all tumor cell lines, compounds 5e, 5i and 5j only demonstrated moderate cytotoxic activities(IC50<50 μmol/L). Primary structure?activity relationships( SARs) analysis indicated that the 3?phenylpropoxyl substituents in position?1,8 of rhein nucleus were the suitable pharmacophoric group giving rise to significant antitumor agents. In addi?tion, compound 5l was found to exhibit remarkable DNA intercalating effects.