天然活性多不饱和脂肪酸羟基和环氧两类衍生物的合成，抗白血病作用及机制研究

项目名称： 天然活性多不饱和脂肪酸羟基和环氧两类衍生物的合成，抗白血病作用及机制研究

项目编号： No.81200394

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学一处

项目作者： 李珍

作者单位： 南方医科大学

项目金额： 23万元

中文摘要： 最新研究报道EPA羟基代谢产物（Δ12-PGJ3）能靶向杀伤白血病干细胞，防止肿瘤复发。但是，天然来源的多不饱和脂肪酸的活性羟脂类代谢产物含量低，成分复杂，难以获取。项目申请人在国际杂志上首次报道了通过化学方法可一步合成亚油酸的羟基类衍生物，该方法方便，快捷，可用于工业化生产。并且我们的前期研究也发现亚油酸的羟基衍生物比先导化合物的体外抗肿瘤效果更强，且安全无毒。在此基础上，本课题拟以四种多不饱和脂肪酸（LA，LNA，DHA，EPA）为原料，合成一系列的羟基和环氧类衍生物，通过体外白血病细胞和白血病干细胞的增殖、凋亡和克隆化等实验，并构建小鼠白血病模型进一步考察多不饱和脂肪酸羟基和环氧类衍生物抗白血病的作用及作用机制，深入探讨它们对ATM/p53信号途径的干预作用；最后拟用分子模拟进行分析，阐明其构效关系，为进一步优化结构，寻找新的高效低毒化合物，开发具有自主知识产权的新药研究提供基础。

中文关键词： 9S-HOD；白血病细胞；蛋白质组学；细胞凋亡；

英文摘要： EPA-derived hydroxyl metabolite has been recently reported to target leukemia stem cells.However, naturally occurring oxylipins from polyunsaturated fatty acid(PUFA) were low content and complicated ingredients. A reliable and easy chemical method for synthesis of hydroxyl derivatives of LA has been reported by proposer.In the preliminary research, we found that the hydroxyl derivatives of LA were more effective than lead compound (linoleic acid and conjugated linoleic acid) against several cancer cell lines, and they were safety. Based on the study above, this project is to synthesize hydroxyl and epoxy derivatives from PUFA and investigate the effect of derivatives on leukemia (stem) cells and its mechanism in vitro and in vivo. The PUFA-derivatives will be evaluated for their cytotoxicity using MTS assay on leukemia cells and leukemia stem cells (LSC). The apoptosis and colony-forming ability of LSC will be assessed by flow cytometry and colony-forming assay. Western blot will be used to determine the regulation of ATM/p53 signal pathway by derivatives at the levels of protein. Finally, molecular modeling will be applied to study the quantitative structure and anti-leukemia activity relationship of hydroxyl and epoxy derivatives of PUFA for further generating of new derivatives and predicting their anti-leuke

英文关键词： 9s-hydroxy-octadecadienoic acid；leukemia cell；proteomics；apoptosis；