天然产物Artanomalide D及其类似物的全合成和抗肿瘤构效关系研究

项目名称： 天然产物Artanomalide D及其类似物的全合成和抗肿瘤构效关系研究

项目编号： No.81202421

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： 秦向阳

作者单位： 中国人民解放军第四军医大学

项目金额： 24万元

中文摘要： 天然产物是生物活性物质和创新药物的重要来源。天然产物Artanomalide D是一种来源于传统中草药南刘奇奴，具有显著抗肿瘤活性的萜类化合物，而且具有高度复杂、新颖的多环结构。对Artanomalide D及其类似物进行全合成和抗肿瘤活性研究，不仅能够拓宽复杂萜类化合物的设计与合成方法，更为寻找高效低毒的抗肿瘤候选药物结构提供有效途径。 本课题拟通过Diels-Alder反应，采用汇聚式合成的策略，进行Artanomalide D及其类似物的不对称全合成,以分子间串联的烯丙基硼化和内酯化反应作为关键反应，一步构建a-亚甲基-γ-丁内酯基团和两个手性中心，并以烯烃复分解环化反应（RCM）为关键反应构建5/7/5三环骨架结构。在此基础上对Artanomalide D的类似物进行合成并测试其抗肿瘤活性，为最终获得具有自主知识产权的新型抗肿瘤候选药物提供实验数据、奠定理论基础。

中文关键词： Artanomalide D；抗肿瘤；狄尔斯-阿尔德环加成反应；烯烃复分解；

英文摘要： Natural products are viewed as an important origin of biologically active substances and innovative drugs. Deriving from the traditional Chinese herbs (Nan-Liu-Ji-Nu), Artanomalide D shows significant anti-tumor activity. It consists of highly complex and novel multi-ring structures. The total synthesis of Artanomalide D and its analogues and the study of anti-tumor activity can broaden the horizon of designing and synthesizing complex terpenoid compounds, and also provide an effective way for finding anti-cancer drug candidates structure with efficiency and low toxicity. We propose to carry out the Diels-Alder ring addition reaction, by the strategy of convergent synthesis, to accomplish the asymmetric total synthesis of Arteminolide D and its analogs. The intermolecular allylboration and lactonization tandem reaction is applied as the key steps in building the α-methylene-γ-lactone with two chiral centers. In addition, ring closing metathesis reaction （RCM）is assumed to build the 5/7/5 tricyclic system. Accordingly, the analogues of Arteminolide D will be synthesized and their anticancer activities will be tested in order to access to the experimental data and the theoretical basis for obtaining new antitumor drug candidates with independent intellectual property rights.

英文关键词： Artanomalide D；Antitumor；Diels-Alder cycloaddition；Ring closing metathesis；