基于天然产物药效团的新型mTOR信号通路抑制剂的设计合成及抗肿瘤活性研究

项目名称： 基于天然产物药效团的新型mTOR信号通路抑制剂的设计合成及抗肿瘤活性研究

项目编号： No.21462049

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 数理科学和化学

项目作者： 羊晓东

作者单位： 云南大学

项目金额： 25万元

中文摘要： 天然产物及其相关研究是药物创新的源泉。基于药效团及活性分子之间合理的分子杂合已成为药物发现的一种新策略。mTOR信号通路是调控细胞生长与增殖的一个关键通路,肿瘤等疾病的发生被认为与此通路异常有关。mTOR信号通路在60%以上的人类肿瘤中被高度激活。抑制该通路的活化已成为肿瘤治疗的新策略。本项目拟以天然产物药效团为先导，进行抗肿瘤药物分子的设计合成、生物活性及作用机制研究。以位于mTOR信号通路上的mTOR和PI3K蛋白激酶为靶点，重点利用苯并五元（杂）环和咪唑药效团，进行mTOR信号通路抑制剂的设计、合成及抗肿瘤活性研究，并对其中高生理活性化合物进行深入的构效关系和作用机制研究，进一步了解mTOR信号通路抑制剂对肿瘤生长转导信号通路的影响调控，为发现具有自主知识产权、较好选择性的抗肿瘤药物候选化合物打下基础。本项目具有较好的学术价值和潜在的应用前景，对云南地区药学研究具有较好的促进作用。

中文关键词： 天然产物药效团；组合物；mTOR 信号通路抑制剂；抗肿瘤活性；构效关系

英文摘要： Natural products and the relevant research are source of drug innovation. Molecular hybridization between pharmacophoric units and/or active compounds has become a new strategy for drug discovery in recent years. mTOR signaling pathway is a key pathway which regulates cell growth and proliferation. The occurrence of diseases such as tumors is recognized to be associated with the dysregulation of this pathway. mTOR signaling pathway is highly activated in more than 60% human tumors. Therefore, it has become a new strategy for cancer therapy to inhibit activation of mTOR signaling pathway. This project is planning to study on design, synthesis, biological activity and mechanism of drug molecules with antitumor activities, using the pharmacophore in natural products as guide. Taking mTOR and PI3K protein kinases in mTOR signaling pathway as target, this project focuses on the research of design, synthesis and antitumor activity of mTOR signaling pathway inhibitors using pharmacophore imidazole and benzo five-membered (heterocyclic) ring, and launches further investigations into structure-activity relationship and mechanism for high bioactive compounds. This project will lay solid foundation for finding candidate compounds for antitumor drugs with independent intellectual property rights and better selectivity. This

英文关键词： Natural product pharmacophores；Hybrid compounds；mTOR signaling pathway inhibitors；Antitumor activity；Structure-activity relationships