title: Asperterpenes A and B, two unprecedented meroterpenoids fromAspergillus terreuswith BACE1 inhibitory activities.
abstract: 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 fromAspergillus terreusin very limited amounts of 3.6 mg and 1.8 mg, respectively. The absolute structure of1was determined using X-ray diffraction. Because of the low yield of1, a comprehensive characterization of the BACE1 inhibitory activities of1was completedviamolecular biological, cell and animal studies guided byin silicotarget confirmation (ISTC). ISTC assays suggested that compounds1and2might be BACE1 inhibitors. In cell-based tests, asperterpenes A and B, as natural products, exhibited promising inhibitory activities against BACE1, with IC50values of 78 and 59 nM, respectively. LY2811376 (the positive control), one of the most potent clinical BACE1 inhibitors, has shown an IC50value of 260 nM.In vivo, compound1exhibited 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,1represents a potential lead compound and a versatile scaffold for the development of drugs for the treatment of AD.
authors.affiliation: 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: zhangyh@mails.tjmu.edu.cn.
authors.forename: Changxing
authors.initials: C
authors.lastname: Qi
authors.affiliation: School of Basic Medicine , Tongji Medical College , Huazhong University of Science and Technology , Wuhan 430030 , China.
authors.forename: Jian
authors.initials: J
authors.lastname: Bao
authors.affiliation: 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: zhangyh@mails.tjmu.edu.cn.
authors.forename: Jianping
authors.initials: J
authors.lastname: Wang
authors.affiliation: 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: zhangyh@mails.tjmu.edu.cn.
authors.forename: Hucheng
authors.initials: H
authors.lastname: Zhu
authors.affiliation: 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: zhangyh@mails.tjmu.edu.cn.
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Xue
authors.affiliation: School of Basic Medicine , Tongji Medical College , Huazhong University of Science and Technology , Wuhan 430030 , China.
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Wang
authors.affiliation: 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: zhangyh@mails.tjmu.edu.cn.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: 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: zhangyh@mails.tjmu.edu.cn.
authors.forename: Weiguang
authors.initials: W
authors.lastname: Sun
authors.affiliation: 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: zhangyh@mails.tjmu.edu.cn.
authors.forename: Weixi
authors.initials: W
authors.lastname: Gao
authors.affiliation: 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: zhangyh@mails.tjmu.edu.cn.
authors.forename: Yongji
authors.initials: Y
authors.lastname: Lai
authors.affiliation: School of Basic Medicine , Tongji Medical College , Huazhong University of Science and Technology , Wuhan 430030 , China.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Chen
authors.affiliation: 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: zhangyh@mails.tjmu.edu.cn.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Zhang