微生物来源抗肿瘤先导化合物的靶向筛选研究

目的寻找具有抗肿瘤活性的雷帕霉素结构类似物。方法以雷帕霉素细胞内结合蛋白RBP为靶标,运用营养依赖重组微生物工程菌筛选方法,从微生物的的次级代谢产物中筛选活性化合物;通过16SrDNA序列分析鉴定活性化合物产生菌;深层发酵制备活性物培养液并分离、纯化目标物;根据波谱检测及数据解析进行化合物结构鉴定并进行活性评价。结果筛选获得1株活性菌株CY-365,经鉴定为放线菌链霉菌属,其代谢活性产物CY-365结构解析为15(S)-O-乙基雷帕霉素,与雷帕霉素具有相似的体外抗肿瘤活性。结论链霉菌CY-365经深层培养,主要代谢产物为具有抗肿瘤活性的15(S)-O-乙基雷帕霉素。

Targeting screening for antitumor precursor compounds from microorganisms

Objective To search for structural analogues of rapamycin with anti-tumor activity. Methods Targeting the intracellular rapamycin binding protein (RBP), active compounds were screened from secondary metabolites of microorganisms by using recombinant microbial engineering strains with nutrition dependence; the active compound producing strain was taxonomically identified through sequence analysis of 16 rDNA; the active constituent was obtained by submerged fermentation, isolation, and purification; the chemical structure of the active compound was elucidated on the basis of comprehensive spectral data analysis and its anti-tumor activity was evaluated. Results One active strain CY-365 was obtained and identified as Streptomyces sp. The structure of active compound was elucidated to be 15(S)-O-ethyl-rapamycin and the anti-tumor activity of 15(S)-O-ethyl-rapamycin was similar to rapamycin in vitro. Conclusion After submerged fermentation, Streptomyces strain CY-365 mainly produced 15(S)-O-ethyl-rapamycin which has anti-tumor