抑制Hedgehog信号通路的植物C21甾体化合物的构效关系、结构优化及抗肿瘤作用研究

项目名称： 抑制Hedgehog信号通路的植物C21甾体化合物的构效关系、结构优化及抗肿瘤作用研究

项目编号： No.21472175

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 环境科学、安全科学

项目作者： 李晓誉

作者单位： 浙江省医学科学院

项目金额： 80万元

中文摘要： 近年来研究发现多种肿瘤中Hedgehog信号通路异常激活，因此靶向该通路的抑制剂成为抗肿瘤药物研究的新热点。植物C21甾体化合物具有抗肿瘤作用，前期研究发现：细胞毒性、基因芯片及双荧光素酶报告基因实验研究发现植物孕甾体化合物能抑制Hedgehog信号通路活性，并推测其抑制肿瘤细胞活性可能与抑制Hedgehog信号通路活性有关。本项目拟系统地建立植物中各种类型的C21甾体化合物库，以Hedgehog信号通路为靶标进行活性筛选，并采用CoMFA模型进行构效关系分析，根据构效关系进一步结构优化以及活性再筛选；然后采用Hedgehog信号通路依赖的基因敲除小鼠模型对活性化合物进行抗肿瘤作用评价,从而获得新型的植物来源Hedgehog信号通路抑制剂，为靶向特异性的抗肿瘤新药开发提供候选化合物。

中文关键词： Hedgehog信号通路；C21甾体化合物；构效关系；结构优化；抗肿瘤作用

英文摘要： Since activation of the Hedgehog signaling pathway is implicated in several types of human cancers, inhibitors of this pathway could be promising anticancer agents. C21 steroids from plants have antitumor effect. Studies of cell toxicity, gene chip and dual luciferase report gene found that C21 steroids could inhibit the activity of Hedgehog signaling pathway, suggesting that the inhibitory activity against tumor cell may be associated with inhibitory activity against Hedgehog signaling pathway. This project intends to set up compounds library of C21 steroids from plants systematically, with Hedgehog signaling pathway as a target for active screening. By the analysis of structure-activity relationship with CoMFA model, stucture optimization of leading compounds will be done and a series of new C21 steroids will be devised and synthetized. Then, antitumor effects of active compounds will be evaluated based on the mode of gene knockout mice relying on the Hedgehog signaling pathway. This study aims at finding new Hedgehog signaling pathway inhibitors as candidates for targeting antitumor drugs.

英文关键词： Hedgehog signaling pathway;C21 steroids;structure-activity relationship;structure optimization;antitumor effects