几种新高等真菌活性次生代谢产物的研究

The large biodiversity of higher fungi, which have formed an evolutionary pre-selected mechanism of metabolism during the long-term evolution so as to resist the entire life cycle to reach the purpose of self-defense and survival, could produce diversified functional secondary metabolites possessing various chemical structures and bioactivity. Thus the diversification of higher fungi and their abundant and fascinating secondary metabolites provides a huge resource for extending the chemodiversity and for finding new lead structures for new drugs and agricultural chemicals. Our research group have studied the biodiversity of higher fungi from Sichuan Basin for more than 20 years and discovered two new higher fungi, Antrodia subxantha and Xylaria coprinicola, as well as a seris of new records in China. We found the artificial cultures, such as fermentation broth, mycelium and fruit bodies have antitumor, antifungal and insecticidal activites. Their active secondary metabolites are unknown. In this project, the artificial cultures would be cultured and tested against clinical malignant cell, important pathogenic fungus and pest of crops. The active secondary metabolites would be extracted and isolated by chromatography and identified by spectrum methods. The major purpose of the project is to reveal the active secondary metabolites in the new higher fungi in order to find new lead structures for new drugs and agricultural chemicals.

高等真菌次生代谢产物结构丰富，具有广泛的生理活性，是新药和新农药创制的重要源泉。我国西南地区拥有丰富的高等真菌资源，本课题组在长期对四川盆地高等真菌生物多样性的研究中，发现了拟黄薄孔菌和嗜鸡腿菇炭角菌等新高等真菌及系列中国新记录种，前期研究中实现了这些新高等真菌的人工培养，发现其发酵液、菌丝体和子实体等具有抗肿瘤、抗真菌和杀虫等活性。在此基础上，本项目拟研究这些新高等真菌的液体发酵和固体培养技术，从而实现发酵液、菌丝体和子实体等的规模培养；深入进行抗临床恶性肿瘤、抗农作物病原真菌和杀虫活性测试，在活性指导下主要运用各种色谱方法分离活性化合物，运用质谱、核磁等波谱技术鉴定其结构，从而阐明这些新高等真菌的活性次生代谢产物，获得新药和新农药创制的结构新颖的活性化合物，同时为这些新高等真菌资源的利用、为揭示相关次生代谢产物在生存竞争中的生态学功能奠定基础。

高等真菌次生代谢产物结构丰富，具有广泛的生理活性，是新药和新农药创制的重要源泉。本项目对纵条纹炭角菌、拟黄薄孔菌、瑞克纤孔菌、海绵胶煤炱菌、竹生炭角菌、光轮层炭壳菌等四川新发现的几种高等真菌进行液体发酵和固体培养，通过抗临床恶性肿瘤、抗农作物病原真菌和杀虫活性测试，发现海绵胶煤炱菌、条纹炭角菌、橙盖鹅膏菌、光炭轮菌和南方灵芝等具有较强的抗肿瘤活性，条纹炭角菌、瑞克纤孔菌、木蹄层孔菌、红缘拟层孔菌、高木蹄层孔菌对植物病原真菌和细菌具有较好的抑菌效果，巴西拟隐盘孢菌和红平菇对甲氧西林耐药菌MRSA具有较好的抗菌活性。在活性指导下，主要运用各种色谱方法和质谱、核磁等波谱技术，从纵条纹炭角菌、南方灵芝、橙盖鹅膏菌、光炭轮菌、巴西拟隐盘孢菌和红平菇等高等真菌中分离得到59个次生代谢产物，其中5个为新的次生代谢产物。从纵条纹炭角菌中分离得到具有较好抗肿瘤和杀线虫活性的新骨架次生代谢产物环七酯肽A；从南方灵芝中分离到对结肠癌细胞SW620有较好的抑制率的新次生代谢产物灵芝烯酸G甲酯；从巴西拟隐盘孢菌分离到对甲氧西林耐药菌（MRSA）具有中等强度的抑菌活性的新次生代谢产物ethyl 8-hydroxy-9-oxo-9H-xanthene-1-carboxylate 和 1,8-dihydroxy-2-(1-hydroxyethyl) anthracene-9,10-dione；从橙盖鹅膏菌子实体中分离得到4个有强烈细胞毒活性的次生代谢产物麦角甾醇、过氧麦角甾醇、9(11)-脱氢过氧麦角甾醇、脑苷脂D，其中过氧麦角甾醇在一定浓度和时间范内对人卵巢癌SKOV3 和A2780S 细胞增殖具有明显抑制作用，可能与其阻滞细胞周期和诱导细胞凋亡有关。通过这些高等真菌活性次生代谢产物的研究，阐明了这些新高等真菌的活性物质基础，并获得新药和新农药创制的结构新颖的活性化合物。