由于氟原子独特的性质，将氟引入到药物先导化合物之中是新药研发的重要途径之一。本项目以具有抗肿瘤活性的去甲斑蝥素为研究对象，在前期研究基础上，根据现有的构效关系以及含氟基团的特性，利用化学空间分析法在去甲斑蝥素的骨架结构上引入氟、二氟烷基、三氟甲基、硫三氟甲基等含氟基团，合成一系列的去甲斑蝥素含氟衍生物。并进一步在细胞和分子水平上研究目标分子的抗肿瘤活性以及对蛋白磷酸酯酶PP1，PP2A的抑制作用，分析构效关系和作用机制，系统的研究氟这一重要的原子对去甲基斑蝥素抗肿瘤活性的影响。通过本项目的研究，希望可以发现1-2个比去甲斑蝥素抗肿瘤活性更高、毒性更小的新化合物，并进一步补充和完善去甲斑蝥素的作用机制和构效关系，为后续进一步的研究奠定基础。

Owing to the unique properties of fluorine atom, the introduction of the atom into lead compounds is one of the most important strategy to access to new drugs. In this project, we tried to introduce different fluoro-containing group (fluoro-, difluoroalkyl-, trifluoromethyl- and ect) into the skeleton of norcantharidin based on known structure-function relationship and our previous result. Then, a new compound library of fluorination modified norcantharidin will be established. We will study the anti-cancer activity and inhibition of protein phosphatase of those compounds, and analyze structure-function relationship and mechanism of action. Systematic study will be done to evaluate the influence of fluorine atom on the anti-cancer activity of norcantharidin. we hope 1-2 new derivatives with higher anti-cancer activity and lower toxicity vs norcantharidin canbe get. the successful implement of this project can also supplement and perfect the structure-function relationship of cantharidin. and make good groundwork for the future study.