基于代谢组指纹信息，挖掘海鞘共附生真菌的抗脑胶质瘤活性化合物

Brain glioma is a kind of fatal central nervous disease, and new anti-brain glioma drugs are urgently needed at home and abroad. Marine microorganisms are the new source of medicine, especially the ascidian-derived fungi. In order to find the marine drugs with anti-brain glioma activity, 100 strains of ascidian-derived fungi from the South China Sea were used in this project. Using the UHPLC-HRMS、MS/MS、1D and 2D NMR combination technique, fingerprint characterization and anti-brain glioma activity were screened for each fungus metabolic group, and the metabolic group fingerprint information database of ascidian-derived fungi was established, so as to obtain the strains with distinct activity and special fingerprint. This project aims to select the target strains, according to the methods of OSMAC, co-culture and chemical epigenetic modification, amplified fermentation culture; the anti-glioma activity compounds and their analogues were discovered efficiently by the direction of metabolic group fingerprint information database of ascidian-derived fungi. The scientific significance of this project is to establish the metabolic group fingerprint information database of the ascidian-derived fungi from the South China Sea, to obtain anti-brain glioma activity compounds efficiently, and to seek a breakthrough in the discovery method of pharmacologically active natural products. It also lays a foundation for further systematic development and research on the resources of marine ascidian-derived fungi.

脑胶质瘤是一种致命的中枢神经疾病，国内外迫切需要新的抗胶质瘤药物。海洋微生物是新的药源宝库，尤其是海鞘共附生真菌的研究前景广阔。为了寻找抗脑胶质瘤活性的海洋药物，本项目前期基于100株南海海鞘共附生真菌，采用UHPLC-HRMS、MS/MS、1D和2D NMR组合技术对每株真菌的代谢组进行指纹表征和抗脑胶质瘤活性筛选，建立了海鞘共附生真菌的代谢组指纹信息数据库，筛选出活性显著、指纹图谱特殊的菌株。本项目以筛选获得的目标菌株为研究对象，根据OSMAC、共培养、化学表观遗传修饰等方法，放大发酵培养，利用代谢组指纹信息，高效去重复，快速跟踪分离鉴定抗脑胶质瘤活性化合物及其类似物。建立南海海鞘共附生真菌的代谢组指纹信息数据库，不仅有助于高效获得抗脑胶质瘤活性化合物，而且寻求在活性天然化合物发现方法的突破，为新活性先导化合物的发现提供方法借鉴，也为海鞘共附生真菌资源进一步系统性开发和研究奠定基础。

脑胶质瘤是一种致命的中枢神经疾病，国内外迫切需要新的抗胶质瘤药物。海洋微生物是新的药源宝库，尤其是海鞘共附生真菌的研究前景十分广阔。本项目执行中，我们建立了100余株海鞘共附生真菌的代谢组指纹信息数据库，成功筛选出5株活性显著、化学结构新颖的潜力菌株Trichobotrys effuse 4729，Diaporthe sp. SYSU-MS4722，Roussoella siamensis SYSU-MS4723，Penicillium sp. 4829，Amphichorda felina SYSU-MS7908。基于代谢组信息，从这些海鞘共附生真菌中发现系列新颖的抗脑胶质瘤活性的吡咯烷酮和山酮类化合物，同时也发现了抗炎、抗氧化和乙酰胆碱酯酶抑制活性的化合物；同时基于代谢组信息，对其他海洋真菌的活性分子进行高效挖掘和应用，并对复杂海洋天然产物的立体化学进行研究。系统和深入研究这些菌株的次级代谢产物的化学成分中，分离纯化得到化合物90余个，包括新化合物30余个，其中新骨架6个，筛选出10个具有抗脑胶质瘤活性的化合物，进一步探讨了化合物trichobamide A的促使脑胶质瘤细胞凋亡机制。我们还首次在天然产物研究中应用惰性油封纳液滴结晶法，并改良了惰性油封纳液滴结晶法，有利于常规实验条件下使用。本项目执行过程中，共发表高质量 SCI 论文 13 篇， 其中一篇 ESI 高引， 国内发明专利授权 2 项，申请国内发明专利 3 项。本项目的完成，为海鞘共附生真菌资源进一步系统性开发和研究奠定基础，为寻找治疗脑胶质瘤新药开拓了一条新的思路，同时也为有机合成和药物合成提供新的模板结构。