基于HIF-2靶点的新型肿瘤抑制剂—米仔兰属植物中特异性环戊烷并苯呋喃/苯吡喃类衍生物的发现及作用机制研究

缺氧诱导因子-2（HIF-2）是近年来新发现的肿瘤细胞缺氧应答反应调节因子，仅在少数肿瘤细胞中有异常表达，是多种肿瘤基因表达通路及信号转导通路的一个汇集点，主要参与肿瘤血管生成、肿瘤细胞增殖与存活及糖酵解等调节，可作为一个潜在的分子靶标进行新型靶向抗肿瘤药物的研究与开发。 我们在对台湾米仔兰的前期研究中，发现了8个米仔兰属植物特有的、具有显著HIF-2抑制活性的环戊烷并苯呋喃/苯吡喃类新颖结构化合物。本项目拟在此工作基础上，选择椭圆叶米仔兰和缩序米仔兰为研究对象，从中定向分离该属植物特异性的环戊烷并苯呋喃/苯吡喃类成分，并对该类化合物进行靶向HIF-2抑制抗肿瘤活性筛选、构-效关系和作用机制研究，以期获得具有潜在药用价值的新型抗肿瘤先导化合物。本课题的开展将为合理开发利用我国丰富的米仔兰属药用植物资源积累一定的资料，为HIF-2抑制类新型抗肿瘤药物的研究与开发提供一定的科学依据。

Hypoxia-inducible factor-2 (HIF-2),which has been found as a new regulatory factor in recent years that is activated in response to intratumoural hypoxia,is highly expressed in few tumor cell lines under the condition of normoxia and a focal point for a variety of cancer gene expression pathways and signal transduction pathways. It plays a pivotal role in regulation of tumor angiogenesis, tumor cell proliferation and survival and glycolysis in tumor cells, and has become as a potential therapeutic target for research and development of new anticancer drugs. In the course of our systematic investigations toward the isolation of bioactive metabolites from Aglaia formosana, eight novel cyclopenta[b]benzofuran/benzopyrans characteristic of the plants of the genus Aglaia that showed significant HIF-2 inhibition have been isolated. This project will deal with the discovery of natural product-based on HIF-2 inhibitors from two plants of the genus Aglaia (A. elliptifolia and A. abbreviata) on the basis of an earlier period of experiments of chemistry and bioactivities. The aim of this research is to search for characteristic cyclopenta[b]benzofuran/benzopyrans from the Aglaia genus , to evaluate for anti-HIF-2 activity, structure-activity relationship and mechanism of action of this type of compounds, and to obtain the potential new antitumor leads. This research will be to afford more theoretic and experimental data for investigation of rich source of the Chinese Aglaia plants and to provide certain scientific data for the discovery of new anti-cancer drugs targeting HIF-2.