具有TGFbeta受体激酶抑制活性的咔啉类化合物结构优化及抗肿瘤转移功能研究

项目名称： 具有TGFbeta受体激酶抑制活性的咔啉类化合物结构优化及抗肿瘤转移功能研究

项目编号： No.81202407

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 药物学、药理学

项目作者： 陈益华

作者单位： 华东师范大学

项目金额： 23万元

中文摘要： 肿瘤转移是肿瘤致死的主要原因之一。而上皮细胞-间充质细胞转化（EMT）是肿瘤转移过程中最显著的特征之一，TGFbeta信号转导通路在肿瘤EMT过程中扮演着至关重要的作用。通过靶向TGFbeta受体激酶，借助于结构优化，前期研究发现了一类靶向TGFbeta受体激酶抑制活性的四氢-beta-咔啉类化合物，研究结果表明此类化合物对癌细胞的迁移和体内小鼠肿瘤转移都有显著的抑制作用。本项目拟在前期关于四氢-beta-咔啉类化合物结构优化的基础上，设计、合成新型用于抗肿瘤转移的药物先导化合物：（1）设计、合成不同位置取代的四氢-beta-咔啉类化合物，并总结此类化合物较为明确的构效关系；（2）确认此类化合物与TGFbeta受体激酶及下游信号转导通路的分子作用机制与模式；（3）选择体外综合评价最高的化合物进行抗肿瘤转移动物模型的效果检测，最终获得基于靶向TGFbeta受体激酶的抗肿瘤转移药物先导化合物。

中文关键词： 转化生长因子-beta；抗肿瘤转移；四氢-beta-咔啉类化合物；结构优化；

英文摘要： Tumor Metastasis, one of the main reasons of cancer death, is account for about 90% of cancer death. Epithelial-mesenchymal transition (EMT) is one of the most striking features in the process of tumor metastasis, and the transforming growth factor beta (TGFbeta) signal transduction pathway can regulate cell proliferation, division, adhesion, migration, invasion angiogenesis and immune suppression, which indicated that TGFbeta signal pathway plays a crucial role in the process of tumor EMT. Our preliminary study have been shown that one novel type of tetrahydro-beta-cabolines compounds were discovered based on targeted TGFbeta receptor kinase by means of assay screening followed by structure optimizaition. The results indicated that such compounds have a very effective inhibition of cancer cell migration and tumor metastasis in mice. The project is planned to design and synthesize novel drug lead compounds against tumor metastasis on the basis of structure optimization of tetrahydro-beta-carboline compounds through targeted TGFbeta Receptor type I kinase: (1) A series of substitution on different positions of tetrahydro-beta-carboline compounds would be designed and synthesized, and the more detailed structure-activity relationship of these compounds would be summarized; (2) the mechanism and mode of these com

英文关键词： Transforming growth factor-beta；anti-cancer metastasis；tetrahydro-beta-carbolines；structural optimization；