Clonostachys rogersoniana发酵改性香青藤的化学机制及抗肿瘤活性物质基础研究

申请人前期研究发现根际土壤真菌Clonostachys rogersoniana能定量的将荷包牡丹碱转化成抗肿瘤活性相当而水溶性更高的4R-羟基荷包牡丹碱。采用该菌发酵壮族民间药香青藤时，发现该菌同样能定量的将香青藤中的放线瑞香宁转化成高水溶性的4R-羟基放线瑞香宁。最有趣的是在发酵香青藤中还发现了一个具有较强抗肿瘤细胞活性的新颖二萜rogernine，初步研究表明该化合物由微生物和植物共同产生。本项目拟深入研究C. rogersoniana对香青藤的发酵改性，分离更多的4R-羟基阿朴菲生物碱及rogernine类似物，发现（高水溶性）抗肿瘤活性化合物，并通过系统发酵研究探讨rogernine产生的化学机制。该研究有望实现抗肿瘤活性先导化合物4R-羟基阿朴菲生物碱和rogernine的发现和量产，阐明发酵过程中C. rogersoniana与香青藤的关系，为发酵药材研究提供新思路。

Our previous study revealed that rhizosphere soil fungi Clonostachys rogersoniana could facilitate the biotransformation of (R)-dicentrine to (4R,6aR)-4-hydroxyldicentrine, which exhibits the same level of cytotoxicity as (R)-dicentrine, but possesses much higher water solubility than (R)-dicentrine. Fermentation of Illigera aromatic (folk medicine of the Zhuang nationality) with C. rogersoniana also led to the biotransformation of actinodaphnine to 4R-hydroxylactinodaphnine, whose water solubility was significantly increased. Interestingly, a novel diterpene named rogernine, which exhibited significant cytotoxicity, was isolated from fermented I. aromatic. Previous studies suggested that rogernine was derived from the co-effect of fungus and plant materials. In this project, fermentation of I. aromatic with C. rogersoniana will be studied carefully. It is hopeful to find more 4R-aporphine alkaloids and rogernine analogues and develop (high water-soluble) antitumor lead compounds. According to systematic fermentation research, the chemical mechanism of the production of rogernine will be investigated. This study will facilitate the discovery and mass production of 4R-hydroxylaporphine alkaloids and rogernine, clarify the relationship between I. aromatic and C. rogersoniana during fermentation process. This project will offer a new thought for the study of fermented traditional Chinese medicine.