海洋西松烷二萜类成分溯源探索与新结构活性先导化合物发现

The cembrane diterpenoids are one of the hotspot compounds in the study of marine natural drugs because of their abundant chemical diversity and prominent biological functions. However, the total synthesis of this kind of components faced many difficulties, and it is difficult to obtain a large number of them effectively, which has become the bottleneck of the research on the deep utilization of this resource. Some studies have shown that the symbiont microorganisms may be the true source of cembrane diterpenoids. At the same time, our research team recently obtained cembrane diterpenoids from a Paracel Islands sponge symbiotic fungus, which is the first time to get this characteristic component from marine symbiotic bacteria. Therefore, the project is going to use advanced Molecular-Networking technology to carry out research on the symbiotic microorganisms of soft coral which is rich in cembrane diterpenoids, exploring the origin of the cembrane diterpenoids, and exploring the novel structural and functional molecules. On the basis of tracing cembrane diterpenoids, an optimization of fermentation conditions will be studied to explore the chemical diversity and biological functions of cembrane diterpenoids isolated from symbiotic bacteria. The project is hoped to explore new method in deep utilization of marine biological resources.

软珊瑚来源的西松烷二萜具有丰富的化学多样性和突出的生物学功能，是海洋天然药物研究的热点化合物。然而,该类成分的全合成面临诸多困难,难以有效大量获得,成为这一资源深度利用研究的瓶颈。有研究显示，软珊瑚共生微生物可能是西松烷二萜的来源。同时，课题组最近从一种西沙群岛海绵共生真菌中也获得了西松烷二萜类化合物，这是首次从海洋共生菌中获得该类特征成分。因此，项目拟运用先进的分子网络Molecular-Networking导向技术，对富含西松烷二萜的软珊瑚的共生菌开展研究，深度探索溯源西松烷二萜，发掘新颖结构功能分子。在此基础上，结合发酵条件优化，深入研究共生微生物来源西松烷二萜的化学多样性和生物学功能，探索海洋生物资源深度利用研究的新途径。

Sarcophyton sp.共附生青霉菌Penicillium citrinum，Sinularia sp.来源真菌Penicillium sclerotiorum，Sinularia sp.来源真菌Penicillium citrinum，以及未鉴定宿主软珊瑚共生菌Talaromyces variabilis，Aspergillus flavipes，Aspergillus sydowii，Cladosporium halotolerans，Aspergillus pseudoglaucus（未结题），Talaromyces variabilis（未结题），Wallemia sp. （未结题）和Cladosporium ramotenellum（未结题），共11株软珊瑚共生菌的次级代谢产物和生物活性研究已经基本结束。同时，研究了2种宿主软珊瑚Sinularia dansa、Sarcophyton elegans和Clavularia inflata。产稀松烷二萜共生菌需要借助分子网络等在线检测技术，该项技术正在完善提升中。目前，已经在该方面取得了重要突破。相关论文正在整理发表中。从以上生物物种中共分离鉴定次级代谢产物分子281个，包括新结构分子88个，新骨架分子7个。11个化合物表现出有效的细胞毒、抗菌、以及抑制血管生长等活性。发表学术研究论文16篇，包括Journal of Natural Products，Marine Drugs，Phytochemistry等。我们自行设计了基于谱学的模块化自组装程序Python-“Dooerafa”，结合分子力场（molecular mechanic force filed）和量子化学辅助计算（DFT-GIAO-13C NMR）等方法，从2507个结构中寻找出正确结构，即一个首次发现的imidazo[4,5,1-ij]pyrrolo[3,2-f]quinolin-7(8H)-one新骨架。