摘要
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 5＇-monophosphate dehydrogenase （IMPDH）, for contributing leads of new anticancer agents and immunity inhibitors. Methods A high throughput screening method for IMPDH inhibitors from the secondary metabolites of actinomycetes was carried out, the extract of the fermentation broth from the positive strain was purified to get active compounds and the chemical structures were elucidated on the basis of comprehensive spectral data analysis. Furthermore, the antiproliferative effects of the compounds on varieties of related cells were evaluated. Results Two active compounds were obtained and named as NO 1WB-352A,B, which inhibited IMPDH at the IC50 of 6.01μmol/L and 1.40μmol/L. Meanwhile, they exhibited cytotoxicity on related cells, the IC50 values of them were as follows： in the range from 11.6nmol/L to 556nmol/L against a panel of human cancer cell lines, 185nmol/L and 147nmol/L against human umbilical vein endothelial cell line ECV-304, 546nmol/L and 425nmol/L against mouse T lymphocytes, respectively. On the other hand, the compounds did not show cytotoxicity to human fetus liver cell line L02 at 100μmol/L. Conclusion N01WB-352A,B are reported as specific IMPDH inhibitors for the first time and the cell based evaluations indicated that they have the potential to be developed as anticancer agents and immunosupressants..
出处
《中国抗生素杂志》
CAS
CSCD
北大核心
2012年第5期362-365,共4页
Chinese Journal of Antibiotics
基金
国家重点基础研究发展项目(2009CB526513)
国家重大新药创制项目(2008ZX09401-05
2010ZX09401-403)资助
关键词
IMPDH抑制剂
结构解析
活性评价
IMPDH inhibitors
Structural determination
Activity evaluation
