雷帕霉素类新型mTOR变构抑制剂的发现及其构效关系研究

项目名称： 雷帕霉素类新型mTOR变构抑制剂的发现及其构效关系研究

项目编号： No.81502935

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 谢立君

作者单位： 福建省微生物研究所

项目金额： 17.9万元

中文摘要： 免疫抑制剂雷帕霉素是第一个被发现的mTOR变构抑制剂，其衍生物已被成功开发为PI3K/AKT/mTOR通路靶向抗癌药物。因此，寻找抗癌活性显著的新型雷帕霉素衍生物是靶向抗癌药物发现的有效途径。通过前期研究，课题组合成了系列雷帕霉素衍生物，经生物学活性研究发现了抗癌活性很强的噻唑基雷帕霉素衍生物RA-1，已申请国内外发明专利。为寻找更为有效的候选化合物，本课题拟在RA-1结构基础上，采用电子等排、开环、构型翻转法并结合计算机虚拟筛选，设计出五个系列的RA-1衍生物；通过对RA-1结构中的C43位噻唑侧链进行选择性修饰，实现80个目标化合物的合成；经体内外生物学活性研究，阐明其结构与抗癌等生物学活性之间的关系。通过本课题的研究，以期发现1-2个新mTOR靶向抗癌候选药物，为形成具有自主知识产权的PI3K/AKT/mTOR通路靶向抗癌新药奠定基础。

中文关键词： 雷帕霉素；抗癌；免疫抑制；苯并噻唑；构效关系

英文摘要： The immunosuppressant drug rapamycin, was firstly identified as mTOR allosteric inhbitor, and its derivatives have been successfully developed as anti-cancer drugs. Therefore, finding rapamycin derivatives with better anti-cancer activity has been proved to be an effective way in discovering new targeted anti-cancer drugs.In our previous research, several rapamycin derivatives have been synthesized and studied on their biological activity. During the course, an analog named as RA-1 was found to have stronge anti-cancer activity. Base on above results, we have already applied for the CN and PCT patent respectively. In continuation of our previous research, we will design five novel series of RA-1 derivatives using bioisosterism, opening ring, and configuration inversion methods, as well as computer virtual screening. Following, structure modification will be carried out on the side chain of benzothiazole at C43 position in RA-1. After synthesizing target compounds, they will be screened for anti-cancer and immunosuppressive activities in vitro and in vivo. According to the above results, the structure-activity relationship will be analyzed. Our aim is to find one/two novle mTOR targeted candidate drugs, which will be expected to become the new anti-cancer drug of PI3K/AKT/mTOR pathway in the near future.

英文关键词： rapamycin;anti-cancer;immunosuppression;benzothiazole;structure activity relationship