黄柄曲霉新颖次生代谢产物化学成分及生物活性研究

Microorganisms have become the most important resources of bioactive natural products, and researches on their secondary metabolites are hot topics. Inducing fungi to form “un-natural” natural products with inhibitors or activators is an effective method in searching for structural intriguing and bioactive compounds. In the previous research of searching for fungi from the herb Herba Anoectochili, we have gotten an interesting fungus, Aspergillus flavipes, whose secondary metabolites exhibit significant activity against HK-II. Previous studies on the chemical constituents of A. flavipes have revealed that it can produce many unprecedented cytochalasans, some of which exhibited significant activity toward HK-II. The HPLC analysis for extract of A. flavipes revealed that there are many cytochalasans in the fermentation products of A. flavipes. This study will systematically investigate the secondary metablites of A. flavipes with different fermentation conditions, such as different culture mediums or adding enzyme inhibitors. Based on the isolated cytochalasans, the anti-tumor mechanism will be researched and illuminated, which will greatly benefit the medicinal development of cytochalasans.

微生物是活性天然产物的重要来源，对其次级代谢产物的研究已成为热点。通过添加酶抑制剂等，促使真菌产生“非天然”的活性化合物成为寻找新颖活性先导化合物的有效策略。本课题组前期对金线莲内生真菌进行了大量的筛选，获得一株次级代谢产物具有抑制已糖激酶-2（HK-II）活性的黄柄曲霉。对黄炳曲霉发酵产物初步的化学成分研究发现了大量结构非常新颖的细胞松弛素类化合物，其中部分化合物具有很好的HK-II抑制活性。黄柄曲霉发酵产物的HPLC分析显示其次级代谢产物非常丰富且大部分为细胞松弛素类化合物。本项目首先拟通过优化发酵培养基对发酵产物中的活性成分进行进一步分离；再通过添加酶抑制剂干预，对发酵产物进行系统的分离纯化和对比。对各种发酵条件下所得化合物HK-II抑制活性进行筛选，并探讨活性化合物抑制HK-II活性从而产生抗肿瘤作用的机制。该研究项目的实施对进一步开发HK-II抑制剂类药物具有很重要的意义。

申请者在前期实验中发现黄柄曲霉能够代谢产生丰富的新颖细胞松弛素类化合物。本项目对多种来源的黄柄曲霉进行了多种方式的培养，进而对其次生代谢产物进行了研究，共分离得到化合物184个，新化合物88个，新骨架化合物23个，并对多种不同种类化合物进行了相应活性研究。研究表明，黄柄曲霉能够产生一系列结构复杂新颖的细胞松弛素。相关研究发表SCI论文8篇，其中影响因子大于10的论文3篇，影响因子大于5的论文2篇，申请并获授权专利2项。