Novel small molecule 11β-HSD1 inhibitor from the endophytic fungus Penicillium commune.
Novel small molecule 11β-HSD1 inhibitor from the endophytic fungus Penicillium commune.
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DOI：
10.1038/srep26418
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发表时间：
2016-05-19
影响因子：
4.6
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Sun W;Chen X;Tong Q;Zhu H;He Y;Lei L;Xue Y;Yao G;Luo Z;Wang J;Li H;Zhang Y
从葡萄属内生真菌Penicillium commune的培养液中分离得到两个新的苯酮衍生物戊二酮A（1）和B（2），一个新的环四肽戊二肽A（3），以及五个已知化合物。化合物1 - 3通过1D和2D NMR和HRESIMS等波谱分析进行了结构鉴定。1和3的绝对构型分别通过与相关分子的ECD比较和改进的Marveland分析确定。青霉苯酮A（1）具有一个罕见的苯环化的6，6-螺缩酮结构，是以青霉苯酮A为代表的一类罕见结构的新成员。化合物3在体外对11 β-羟基类固醇脱氢酶1（11 β-HSD1）表现出显著的抑制活性，并显示出与11 β-HSD1的强结合亲和力。此外，化合物3处理降低了与分化诱导的3T3-L1前脂肪细胞中11 β-HSD1表达的抑制相关的脂滴积累。分子对接结果表明，化合物3配位在11 β-HSD1的活性中心，对11 β-HSD1的酶活性有抑制作用。
Two new phenone derivatives penicophenones A (1) and B (2), a new cyclic tetrapeptide penicopeptide A (3), and five known compounds were isolated from the culture broth of Penicillium commune, an endophytic fungus derived from Vitis vinifera. Compounds 1–3 were elucidated by extensive spectroscopic analyses including 1D and 2D NMR and HRESIMS. The absolute configurations of 1 and 3 were determined by comparing its ECD with related molecules and modified Marfey’s analysis, respectively. Penicophenone A (1) possesses a rare benzannulated 6,6-spiroketal moiety, which is a new member of the unusual structural class with peniphenone A as the representative. Compound 3 exhibited significant inhibition activities against 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in vitro and showed strong binding affinity to 11β-HSD1. Moreover, compound 3 treatments decreased the lipid droplet accumulation associate with the inhibition of 11β-HSD1 expression in differentiate-induced 3T3-L1 preadipocytes. Furthermore, the molecular docking demonstrated that compound 3 coordinated in the active site of 11β-HSD1 is essential for the ability of diminishing the enzyme activity.