细胞周期调控因子CDC25A、B抑制剂F09ZB-860H的研究  

Studies on F09ZB-860H,the inhibitor of regulator CDC25A and B in cell cycle

作　　者：吴晓燕[1] 任晓[2] 郑海洲[2] 李业英[2] 范玉玲[2] 郑智慧[2] 张振亮[1] 路新华[2] 赵宝华[1] 

机构地区：[1]河北师范大学生命科学学院,石家庄050024 [2]微生物药物国家工程研究中心,河北省工业微生物代谢工程技术研究中心,华北制药集团新药研究开发有限责任公司,石家庄050015

出　　处：《中国抗生素杂志》2014年第8期571-573,589,共4页Chinese Journal of Antibiotics

基　　金：国家"重大新药创制"科技重大专项(2012ZX09301002-003);河北省科技支撑计划重点项目(13272607D)

摘　　要：目的从真菌的代谢产物中筛选出对细胞周期调控因子CDC25A、CDC25B具有抑制活性的化合物,为研发新抗癌药物提供了先导化合物。方法利用基于重组表达的CDC25A和CDC25B建立的高通量筛选模型进行体外酶抑制活性测定,筛选获得活性菌株;筛选得到的阳性菌株,其发酵液溶剂提取物经硅胶柱层析及HPLC制备分离,得到活性化合物并通过综合波谱解析确定了活性化合物结构;利用肿瘤细胞株进行活性化合物体外抗肿瘤细胞增殖活性评价。结果从真菌F09ZB-860的代谢产物中分离得到活性化合物F09ZB-860H,其结构与脱氢弯孢菌素相同。该化合物对CDC25A和CDC25B的IC50值分别为4.0和14.9μg/mL。抗癌细胞增殖结果表明该化合物具有强肿瘤细胞增殖抑制活性,对人宫颈癌细胞株HeLa和人乳腺癌细胞株MDA-MB-231的IC50值分别为0.7和2.8μg/mL。结论 F09ZB-860H是一个新的CDC25A和CDC25B双抑制剂,并具有强抗癌细胞增殖活性。Objective To discover cell division cycle 25A and B （CDC25A and CDC25B） inhibitors from fungal metabolites and provide lead compounds for new anticancer drugs. Methods Using a recombinant enzymebased high throughput screening method to discover positive strain with CDC25A and CDC25B inhibition. The culture broth of the strain was processed by solvent extraction, silica column chromatography and HPLC preparation to obtain an active compound. Its structure was elucidated on the basis of comprehensive spectral data analysis. The in vitro anticancer effects of the compound were assayed by measuring their inhibitory activity against cancer cell lines proliferation. Results An active compound coded as F09ZB-860H was isolated from the metabolites of fungus strain F09ZB-860, and it was identified as α,β-dehydrocurvularin. The compound showed a strong inhibitory activity against CDC25A and CDC25B with IC50 values of 4.1 and 15.6μg/mL. It inhibits the proliferation of human cervical cancer cell HeLa and human breast cancer cell MDA-MB-231 with ICs0 values of 2.0 and 3. 1μg/mL, respectively. Conclusion F09ZB-860H was a new inhibitor against CDC25 A and B with significant anticancer activity.

关 键 词：CDC25A CDC25B 抑制剂 脱氢弯孢菌素 抗癌 

分 类 号：R979.1[医药卫生—药品]