000000bd_一株真菌产生的强抗癌活性新的山酮类化合物西西作用机制研析.docVIP

一株真菌产生的强抗癌活性新的山酮类化合物及其作用机制的研究 路新华，郑智慧，可爱兵，马瑛，范玉玲，朱京童，林洁，李业英，崔晓兰，张华, 贺建功 （华北制药集团新药研究开发公司，微生物药物国家研究工程中心，石家庄050015 ） 目的：发现新的抗肿瘤先导化合物，并对其进行深入的抗癌机制研究。方法：利用MTT抗肿瘤细胞增殖筛选方法从微生物次生代谢产物中筛选具有抗肿瘤化合物，利用各种色谱手段分离活性化合物,通过化合物理化性质及波谱数据分析进行结构鉴定；并利用细胞形态、流式细胞仪、caspase 3/7的活性在细胞周期、凋亡诱导效应、凋亡诱导机制等方面对其进行了的抗肿瘤机制研究。结果：从一株真菌F02Z-1593的固体发酵产物得到5个山酮类化合物F02Z-1593 I、J、T、U和V，其中1593 I、T、U分别鉴定为Austocystin D、H、F， 1593 J和V为新化合物；5个化合物均表现出很好的体外抗肿瘤和抑制血管内皮细胞的增殖活性，而且对正常细胞人胚肝细胞表现出较低的细胞毒作用。新化合物1593 J将肿瘤细胞周期阻滞在G1期，并引起细胞明显的变圆、皱缩和核固缩等凋亡现象。1593 J能剂量和时间依赖地增加细胞中的caspase 3/7活性。结论：分离得到两个新的F02Z-1593J和V和三个已知的山酮类化合物，该类化合物通过caspase 3/7途径诱导肿瘤细胞和血管内皮细胞的凋亡起抗癌作用。 关键词: Austocystin；细胞凋亡；山酮；caspase ABSTRACT Objective: To discover new anticancer compounds and study their active mechanism. Methods: Screening anticancer compounds from microbial metabolites by measuring the antiproliferation effects on MCF-7 cell line by MTT method. The active compounds were isolated and purified by various chromatographic techniques and their structures were elucidated based on analysis of physicochemical properties and spectroscopic data. Results: Five active xanthones named F02Z-1593 I, J, T, U, V were isolated from the solid fermentate of fungus F02-1593. F02Z-1593 I, T, U were identified as known compounds Austocystin D, H and F respectively and F02Z-1593 J and V were two novel ones. All of the five compounds showed strong inhibitory activity against human cancer cell lines and vascular endothelial cell ECV304, while had low toxity to normal human embryo hepatocyte L02 in vitro. F02Z-1593 J could arrest the cell cycle at phase G1, and induce the activities of caspase 3/7 in human cancer cells in dose and time dependent manner. Conclusion: Five anticancer xanthones were obtained . Among them two were novel and the other three were known. They play anticancer effect by induction apoptosis of tumor and vascular endothelial cell lines through activation of caspase 3/7 pathway. KEY WORDS：Xanthones；Austocystin；anticancer；caspase；apoptosis 癌症是人类最严重的致死