新型葡萄糖-2,5-二酮哌嗪衍生物的设计、合成与细胞毒活性

Design,synthesis and cytotoxicity of novel glycosyl-2,5-diketopiperazine derivatives

从海洋天然产物中挖掘高细胞毒活性化合物成为近年来抗肿瘤药物研究工作的一项重要内容。本研究以2,5-二酮哌嗪海洋天然产物Piperafizine B为修饰骨架,在其哌嗪环6位的苄叉邻位引入位阻较大的四乙酰基葡萄糖或葡萄糖基团,共合成了14个2,5-二酮哌嗪衍生物(1a-i,2a-f)。溶解性实验结果初步表明,相较于PiperafizineB,衍生物的脂溶性(1.5~27.9mg·mL^(-1),溶剂为二甲亚砜(dimethylsulfoxide,DMSO))与水溶性(0.1~0.9mg·mL^(-1),溶剂为磷酸缓冲液,pH7.4)均明显改善。衍生物的细胞毒活性评价结果表明,部分四乙酰基萄糖衍生物的细胞毒活性较好,半抑制率浓度值(IC50)为1.0~9.1μmol·L^(-1),并对Huh-7细胞的生长抑制活性具有一定的选择性(3.3~4.5μmol·L^(-1))。化合物1c的细胞毒活性最好,对癌细胞株K562、A549及Huh-7的IC_(50)值分别为1.0、3.6与3.3μmol·L^(-1)。而将乙酰基水解后的葡萄糖衍生物无明显细胞毒活性(IC50>10μmol·L^(-1))。

Exploring the cytotoxic compounds from marine natural products is one of the most important tasks for the discovery of anticancer agent in recent years.In this study,based on the marine natural product Piperafizine B,fourteen novel glycosyl-2,5-diketopiperazine derivatives(1a-i,2a-f)have been designed and synthesized by the glycosylation on the side phenol group at the 6-position of the 2,5-diketopiperizine ring.The solubilities of the derivatives are obviously improved in both DMSO(dimethyl sulfoxide,1.5~27.9mg·mL^(-1))and phosphate buffer(0.1~0.9mg·mL^(-1),pH=7.4).The cytotoxicity results show that some of the derivatives present good activities with the IC_(50) values ranging from 1.0~9.1μmol·L^(-1),and exhibit selective inhibitory activities on Huh-7 cell lines.Among the derivatives,compound 1c has the best inhibitory abilities on the cell lines K562,A549 and Huh-7 with an IC50 values at 1.0,3.6 and 3.3μmol·L^(-1),respectively,while compounds 2a-f have no observable cytotoxicity.