Chlorocyclinones A-D, chlorinated angucyclinones from Streptomyces sp strongly antagonizing rosiglitazone-induced PPAR-γ activation
Chlorocyclinones A-D, chlorinated angucyclinones from Streptomyces sp strongly antagonizing rosiglitazone-induced PPAR-γ activation
复制标题
DOI：
10.1021/np070498j
复制
发表时间：
2007-12-01
影响因子：
5.1
通讯作者：
Kauschke, Stefan G.
中科院分区：
文献类型：
--
作者：
Potterat, Olivier;Puder, Carsten;Kauschke, Stefan G.
在我们筛选以鉴定用于2型糖尿病的潜在治疗的新的PPAR-gamma调节剂的过程中，从链霉菌属菌株DSM 17045的菌丝体中分离出四种新的氯化angucyclinone，氯环素A-D（1-4）。它们的结构经波谱方法确证。使用AlphaScreen测定，氯环素酮在体外拮抗罗格列酮诱导的过氧化物酶体增殖物激活受体γ（PPAR-gamma）激活，IC 50 < 0.4 μ M，并且能够在闪烁接近测定（SPA）中从PPAR-gamma配体结合结构域（LBD）置换罗西阿立酮。化合物在基于细胞的报告基因测定中也被证明是活性的，拮抗罗格列酮诱导的PPAR-gamma活性，IC 50值在0.60和7.0 μ M之间。在所有试验中，氯环素C（3）表现出最强的活性。
In the course of our screening to identify novel PPAR-gamma modulators for the potential treatment of type 2 diabetes, four new chlorinated angucyclinones, chlorocyclinones A-D (1-4), were isolated from the mycelium of Streptomyces sp. strain DSM 17045. Their structures were established by spectroscopic methods. Chlorocyclinones antagonize rosiglitazone-induced peroxisome proliferator-activated receptor gamma (PPAR-gamma) activation with IC50's < 0.4 mu M in vitro using an AlphaScreen assay and are able to displace rosialitazone from the PPAR-gamma ligand-binding domain (LBD) in a scintillation proximity assay (SPA). The compounds proved to be active in a cell-based reporter gene assay as well, antagonizing rosiglitazone-induced PPAR-gamma activity with IC50 values between 0.60 and 7.0 mu M. Chlorocyclinone C (3) exhibited the most potent activity in all assays.