真菌是结构新颖、功能独特的天然产物的重要来源。从真菌中发现的针对不同疾病的重要药物如抗菌的青霉素、降胆固醇的洛伐他汀，以及免疫抑制剂环孢霉素等，都充分说明真菌次生代谢产物在天然药物研究与开发中占据的重要地位。 本研究以西藏特殊生境真菌为研究材料，通过对菌株小规模发酵制备的代谢产物粗提物进行初步活性与化学指纹分析，并从中选择菌株进行放大发酵；对经过分离纯化获得的纯化合物进行结构解析与多靶标活性评价，发现结构新颖、活性多样的次生代谢产物，为创新药物及新型农药的研究与开发提供候选化合物。本论文的研究对象为四株西藏特殊生境真菌，包括两株冬虫夏草定殖真菌、一株西藏冰川真菌和一株虫生真菌，通过对它们次生代谢产物的化学研究，共获得了30个化合物，其中17个为新结构。同时，利用各种现代波谱技术如质谱、核磁共振谱与X-ray单晶衍射，结合化学降解、衍生物制备等方法完全阐明了新结构化合物的平面与立体结构，并对它们进行了针对不同病原细菌、真菌以及植物病原真菌(共15种)的抗菌综合活性评价，不同肿瘤细胞株的细胞毒活性评价，以及细胞水平(C8166)抑制HIV-1病毒复制的活性评价。通过系统活性评价发现较高比例的新化合物对一种或多种筛选靶标具有不同程度的抑制活性。 对四株西藏特殊生境真菌的初步研究结果表明特境真菌能够产生结构多样，活性广泛的次生代谢产物，从一定程度上说明基于真菌的特殊生存环境或生存策略选择菌株进行研究的理性筛选方式的可行性。上述研究发现的化合物不仅为候选药物的发现提供了备选化合物，也为今后以次生代谢产物为探针去合理解释生态现象提供了化学依据。这些结果也进一步表明利用化学生态学原理对真菌进行化学研究的必要性。 关键词：冬虫夏草定殖真菌；虫生真菌；新结构；生物活性

 Fungi have proven to be prolific producers of new bioactive natural products with diverse structural features. Many important medicines have been discovered or derived from fungal secondary metabolites, such as penicillin, lovastatin, and cyclosporin A. These examples indicated that fungal secondary metabolites play an important role in natural products drug discovery. Fungal species inhabiting unique environments in Tibet were subjected to our chemical investigations in this study. The HPLC-PDA finger-prints of the organic solvent extracts from small-scale fermentations of these fungi combing with the results from initial bioassays were used as criteria to select fungal species for further studies, and the promising strains were further grown in solid-substrate fermentation cultures in larger scales to produce enough extracts for fractionation. On the basis of above considerations and the results from preliminary evaluations, four fungal species including two strains of Cordyceps-colonizing, one strain of Tibet glacier, and one strain of entomogenous fungi were selected for bioassay-directed chemical investigations. By application of different separation techniques using various stationary and mobile phases, such as silica gel, Sephadex LH-20 column chromatography, and reversed-phase high performance liquid chromatography, a total of 30 secondary metabolites have been isolated, and 17 of them are new compounds belonging to different structural classes. The structures of these new metabolites were elucidated primarily by nuclear magnetic resonance and mass spectrometry methods, in combination with X-ray diffraction analysis and chemical degradations and derivatizations, such as the modified Mosher and Marfey's methods. These metabolites were evaluated against a panel of bacteria, fungi, and the plant pathogenic fungi, as well as different human tumor cell lines and HIV-1 virus infected C8166 cells for their antimicrobial, antitumor, and anti-HIV-1 activities. The majority of the new metabolites showed inhibitory effects against one or more targets in our bioassays. Chemical studies of selected four strains of the fungi inhabiting unique environments in Tibet have resulted in the discovery of a variety of bioactive metabolites, many of them possess unique structural features and significant antibacterial, antifungal, anti-HIV, and antitumor effects, suggesting that the inhabit and living strategy are important factors to consider to select fungi for investigations. The discovery of these new metabolites not only provide candidates for discovery of bioactive lead compounds with therapeutic potential, but also provide insights into the chemical basis for observed ecological phenomena. These preliminary results further demonstrated that fundamental principles of chemical ecology should be applied to study the chemistry of fungi. Keyword: Cordyceps-colonizing fungi; Entomogenous fungi; New structure; Bioactivity