Qi Changxing, Bao Jian, Wang Jianping, Zhu Hucheng, Xue Yongbo, Wang Xiaochuan, Li Hua, Sun Weiguang, Gao Weixi, Lai Yongji, Chen Jian-Guo, Zhang Yonghui
Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation , School of Pharmacy , Tongji Medical College , Huazhong University of Science and Technology , Wuhan 430030 , China . Email:
School of Basic Medicine , Tongji Medical College , Huazhong University of Science and Technology , Wuhan 430030 , China.
Chem Sci. 2016 Oct 19;7(10):6563-6572. doi: 10.1039/c6sc02464e. Epub 2016 Jun 27.
Asperterpenes A () and B (), 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 in very limited amounts of 3.6 mg and 1.8 mg, respectively. The absolute structure of was determined using X-ray diffraction. Because of the low yield of , a comprehensive characterization of the BACE1 inhibitory activities of was completed molecular biological, cell and animal studies guided by target confirmation (ISTC). ISTC assays suggested that compounds and might be BACE1 inhibitors. In cell-based tests, asperterpenes A and B, as natural products, exhibited promising inhibitory activities against BACE1, with IC values of 78 and 59 nM, respectively. LY2811376 (the positive control), one of the most potent clinical BACE1 inhibitors, has shown an IC value of 260 nM. , compound 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, represents a potential lead compound and a versatile scaffold for the development of drugs for the treatment of AD.
曲霉萜类化合物A（）和B（）是两种基于3,5-二甲基苔色酸的半萜类化合物，它们含有独特的β位取向的Me-21以及前所未有的1,2,5-三甲基-4,9-二氧代双环[3.3.1]壬-2-烯-3-羧酸部分，分别从[来源]中以非常少量的3.6毫克和1.8毫克获得。通过X射线衍射确定了[化合物名称未明确]的绝对结构。由于[化合物名称未明确]的产率较低，在目标确认（ISTC）的指导下，通过分子生物学、细胞和动物研究完成了对其BACE1抑制活性的全面表征。ISTC分析表明化合物[未明确指代]可能是BACE1抑制剂。在基于细胞的测试中，曲霉萜类化合物A和B作为天然产物，对BACE1表现出有前景的抑制活性，IC值分别为78和59 nM。LY2811376（阳性对照）是最有效的临床BACE1抑制剂之一，其IC值为260 nM。此外，化合物[未明确指代]在3xTg AD小鼠中表现出与LY2811376类似的抗阿尔茨海默病（AD）活性。综上所述，这些发现表明含有新型碳骨架的曲霉萜烯A是首个表现出有效BACE1抑制活性的萜类化合物。此外，[未明确指代]代表了一种潜在的先导化合物和用于开发治疗AD药物的通用支架。
