论文部分内容阅读
目的筛选次黄嘌呤核苷酸脱氢酶(IMPDH)的抑制剂,为新的抗癌药物和免疫抑制剂研发提供先导化合物。方法利用IMPDH抑制剂的高通量筛选方法,筛选放线菌次级代谢产物,发现阳性菌株;对阳性菌株的发酵提取物进行分离纯化获得活性化合物并通过综合波谱解析确定其结构;然后利用多种相关细胞对活性化合物进行活性评价。结果筛选得到两个活性化合物N01WB-352A、B;它们对IMPDH的IC_(50)分别为6.01μmol/L和1.40μmol/L。在细胞毒活性测定中,它们对多种相关细胞的增殖有抑制作用,IC_(50)值如下:对一系列人源癌细胞在11.6～556nmol/L之间;对人脐静脉内皮细胞ECV--304分别为185nmol/1L,和147nmol/L:对小鼠T淋巴细胞分别为546nmol/L和425nmol/L。另外,它们对人正常胎肝细胞L02在100μmol/L浓度下未显示出增殖抑制。结论 N01WB-352A、B为特异性的IMPDH抑制剂,国内外未见报道。在细胞水平上的活性评价显示它们具有一定的开发成抗癌药物和免疫抑制药物的潜力。
Objective To screen inhibitors of inosine dehydrogenase (IMPDH) and provide lead compounds for the development of new anticancer drugs and immunosuppressants. Methods The high-throughput screening method of IMPDH inhibitor was used to screen the secondary metabolites of actinomycetes and found positive strains. The fermented extracts of positive strains were isolated and purified to obtain active compounds and their structures were determined by comprehensive spectral analysis. The related cells are used to evaluate the activity of the active compounds. As a result, two active compounds N01WB-352A, B were screened out and their IC50 values for IMPDH were 6.01μmol / L and 1.40μmol / L, respectively. In the determination of cytotoxic activity, they inhibit the proliferation of a variety of related cells, IC 50 values ?? are as follows: a series of human cancer cells between 11.6 ~ 556nmol / L; on human umbilical vein endothelial cells ECV- -304 were 185 nmol / L and 147 nmol / L respectively: 546 nmol / L and 425 nmol / L for mouse T lymphocytes, respectively. In addition, they showed no inhibitory effect on human normal fetal hepatocyte L02 at a concentration of 100 μmol / L. Conclusion N01WB-352A, B is a specific inhibitor of IMPDH, no reports at home and abroad. The activity evaluation at the cellular level shows that they have a certain potential for developing anticancer drugs and immunosuppressive drugs.