中国南海软珊瑚中活性西松烷型二萜的合成和肿瘤多靶点抑制活性筛选

Soft corals of the genus Sinularia have been well recognized as a rich source of bioactive cembranoids with intriguing structural features. Flexibilide, as a representative of such substances, was well discovered in many species of the genus Sinularia, with rich amount and widespread biological activities. In recent years, several flexibilide related cembranoid derivatives have been discovered in Sinularia, with beautiful structures and strong biological activities, while tiny amounts. Our group has previously isolated gram-scale flexibilide from South China Sea soft coral, and found it to comprise potent inhibitory activity towards tumor targeting IRE1/XBP1 signal pathway. This project would take flexibilide as a start point, to focus on the biomimetic semi-synthesis and structure modification of flexibilide related cembranoid derivatives which were already discovered with beautiful structures and significant biological activities. With all the synthetic compounds, a small deterpene library could be built up for the screening of multi-targeted antitumor activities, such as IRE1/XBP1, NF-κB, PTP1B, PARP, to finally discover the lead compounds after the structure activity relationship analysis. Our group is specialized on the marine natural product chemistry. Biomimetic synthesis is the currently hot strategy on natural product synthesis, featured by its efficiency and green chemistry. The evaluation of multi-targeted antitumor activities is an effective way to achieve the specific and efficient lead compounds towards tumor therapy. Hence, this project is significant for the discovery of multi-targeted antitumor drug and the rational utilization of marine natural resources.

Sinularia属指型软珊瑚富含结构新颖，生物活性多样的西松烷型二萜类化合物，如flexibilide。本小组前期工作分离到了克级以上的flexibilide，并发现其对于肿瘤靶向IRE1/XBP1信号通路有显著的抑制作用。而近年来多个与其相关的结构新颖，活性卓越的微量化合物在该属被发现。本项目以flexibilide为出发点，拟对从该属已发现的相关结构新颖且活性显著的微量化合物进行仿生半合成研究，并进行结构修饰，进而建立小型化合物库以供肿瘤多靶点抑制活性筛选，通过构效关系分析进一步得到结构优化的药物先导化合物。本课题组以海洋天然产物研究为特色。仿生合成是近年来天然产物合成的研究热点，以经济高效且绿色环保为特征。肿瘤多靶点药物活性筛选有助于获得特异性高效的抗肿瘤药物先导化合物。因此，本项目对于发现新型肿瘤特异性多靶点治疗药物和对海洋资源的合理利用具有重要的意义。

Sinularia属和Sarcophyton属软珊瑚富含结构新颖，生物活性多样的西松烷型二萜类化合物。本小组前期从Sinularia属软珊瑚中分离到了大量西松烷型二萜flexibilide，并发现其对于肿瘤靶向IRE/XBP1信号通路有显著的抑制作用。本项目以flexibilide为出发点，对这两个属的软珊瑚进行了化学多样性研究，富集了flexibilide及其相关化合物共计10g以上，同时分离发现了60多个西松烷及其相关二萜类化合物，包括21个新化合物（8个全新骨架化合物），并发现部分化合物具有抗肿瘤活性及与肿瘤相关的抗炎和免疫活性，极大丰富了该类化合物的化学和生物活性多样性。同时，我们还对富集的大含量西松烷型二萜进行了结构改造，获得衍生物23个，通过构效关系分析最后获得3个有苗头的作用于IRE/XBP1信号通路的抗白血病的化合物，活性最强的化合物的细胞毒活性达到了亚微摩级别，值得深入开发研究。因此，本项目对于发现新型肿瘤特异性靶向治疗药物及相关炎症和免疫治疗药物，以及对海洋资源的合理利用具有重要的意义。