Asperterpenes A and B, two unprecedented meroterpenoids from Aspergillus terreus with BACE1 inhibitory activities.
Asperterpenes A and B, two unprecedented meroterpenoids from Aspergillus terreus with BACE1 inhibitory activities.
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Asperterpenes A 和 B，两种前所未有的来自土曲霉的类萜，具有 BACE1 抑制活性
DOI：
10.1039/c6sc02464e
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发表时间：
2016-10-19
期刊：
影响因子：
8.4
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Qi C;Bao J;Wang J;Zhu H;Xue Y;Wang X;Li H;Sun W;Gao W;Lai Y;Chen JG;Zhang Y
曲霉烯A和B是从土曲霉中分离出来的两种具有前所未有的碳骨架的BACE1抑制剂，具有强大的抗阿尔茨海默病活性。从土曲霉中分离得到两个3，5-二甲基亚硒酸基单萜类化合物A(1)和B(2)，它们含有一种独特的具有前所未有的1，2，5-trimethyl-4，9-dioxobicyclo[3.3.1]non-2-ene-3-carboxylic酸含量的面向β的Me-21。用X-射线衍射法测定了1的绝对结构。由于1的产率较低，在电子靶标确认(ISTC)的指导下，通过分子生物学、细胞和动物研究完成了对1的BACE1抑制活性的全面表征。ISTC分析表明，化合物1和2可能是BACE1抑制剂。在细胞实验中，天冬青A和B作为天然产物对BACE1具有良好的抑制活性，IC50值分别为78和59 nM。临床上最有效的BACE1抑制剂之一LY2811376(阳性对照)的IC50值为260 nM。在体内，化合物1在3xTg AD小鼠中显示出与LY2811376相似的抗阿尔茨海默病(AD)的活性。综上所述，这些发现表明，含有一个新的碳骨架的半萜烯A是第一个表现出有效的BACE1抑制活性的萜类化合物。此外，1代表了一种潜在的先导化合物和开发治疗阿尔茨海默病药物的多功能支架。
Asperterpenes A and B, two BACE1 inhibitors with unprecedented carbon skeletons isolated from Aspergillus terreus, exhibit potent anti-Alzheimer's disease activity. Asperterpenes A (1) and B (2), two 3,5-dimethylorsellinic acid-based meroterpenoids that contain a unique β-oriented Me-21 with an unprecedented 1,2,5-trimethyl-4,9-dioxobicyclo[3.3.1]non-2-ene-3-carboxylic acid moiety, were obtained from Aspergillus terreus in very limited amounts of 3.6 mg and 1.8 mg, respectively. The absolute structure of 1 was determined using X-ray diffraction. Because of the low yield of 1, a comprehensive characterization of the BACE1 inhibitory activities of 1 was completed via molecular biological, cell and animal studies guided by in silico target confirmation (ISTC). ISTC assays suggested that compounds 1 and 2 might be BACE1 inhibitors. In cell-based tests, asperterpenes A and B, as natural products, exhibited promising inhibitory activities against BACE1, with IC50 values of 78 and 59 nM, respectively. LY2811376 (the positive control), one of the most potent clinical BACE1 inhibitors, has shown an IC50 value of 260 nM. In vivo, compound 1 exhibited activity similar to that of LY2811376 against Alzheimer's disease (AD) in 3xTg AD mice. Taken together, these findings demonstrate that asperterpene A, which contains a novel carbon skeleton, is the first terpenoid to exhibit effective BACE1 inhibitory activity. Moreover, 1 represents a potential lead compound and a versatile scaffold for the development of drugs for the treatment of AD.
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影响因子：
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