ent-贝壳杉烷二萜二聚体衍生物的合成、抗肿瘤活性评价和机制研究

项目名称： ent-贝壳杉烷二萜二聚体衍生物的合成、抗肿瘤活性评价和机制研究

项目编号： No.21502121

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 环境科学、安全科学

项目作者： 李达翃

作者单位： 沈阳药科大学

项目金额： 21万元

中文摘要： 天然活性分子是药物研发中先导物的重要来源，其中萜类化合物一直是人们研究的热点。目前随着分离鉴定技术的提高，越来越多的天然二聚体分子被获得与鉴定，这些二聚体通常具有新颖而复杂的化学结构，分子中含有较单体更多的氢键供体、受体和活性官能团，表现出优良的生物活性。在前期研究中，我们从天然活性分子冬凌草甲素出发，合成了多种骨架类型的ent-贝壳杉烷二萜单体，进行了抗肿瘤、抗菌等活性测试和机制研究；此外，初步尝试了二聚体衍生物的合成并获得成功。在此基础上，本课题拟对ent-贝壳杉烷二萜二聚体开展系统的药物化学研究。根据已有构效关系，运用药物设计中的拼合原理，将活性强、成药性好的ent-贝壳杉烷二萜单体衍生物进行连接，获得多种类型的二聚体衍生物（直接拼合型、NO供体型和探针分子型等），并通过测试抗肿瘤活性，总结构效关系，进一步进行结构优化以及作用机制研究，期望寻找获得具有自主知识产权的抗肿瘤候选药物。

中文关键词： 天然产物；冬凌草甲素；抗肿瘤活性；构效关系；作用机制

英文摘要： Natural bioactive molecules are important sources of the lead compounds in drug discovery, of which, terpenoids are always the research hotspot. With the development of isolation and identification, more and more natural dimer molecules have been obtained and identified. These dimers, with novel and complex structures, have more hydrogen bond donors and receptors, and exhibit better biological activities than monomer molecules. In our previous work, a variety of ent-kaurane monomers with different skeletons have been synthesized starting from oridonin. The antitumor and antibacterial activity tests, as well as mechanistic studies, were carried out. In addition, the preliminary attempt in the synthesis of dimer derivatives was succeeded. In this project,we will do systemic medicinal chemistry research on ent-kaurane diterpenoid dimers. On the basis of SAR and the combination principle in drug design, novel natural-like ent-kaurane dimer derivatives, such as combination drug type, NO-donor type and fluorescent probe molecule type will be synthesized by linking active and drug-like ent-kaurane monomer derivatives together. The antitumor activity evaluation and mechanistic studies will be carried out and SAR will be summarized. By these work, antitumor drug candidate with independent intellectual property rights will be expected to be obtained.

英文关键词： natural product;oridonin;anti-tumor activity;structure-activity relationship;mechanism of action