Asperterpenes A and B, two unprecedented meroterpenoids from with BACE1 inhibitory activities.

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.