Cyathane Diterpenes from Cultures of the Bird’s Nest Fungus Cyathus hookeri and Their Neurotrophic and Anti-neuroinflammatory Activities

Six new cyathane diterpenoids, cyahookerins A–F ( 1 – 6 ), as well as nine known analogues ( 7 – 15 ), were isolated from the liquid culture of the basidiomycete Cyathus hookeri . Their structures were elucidated on the basis of extensive spectroscopic analyses (1D and 2D NMR, HRESIMS, and ECD), and the absolute configurations of compounds 1 and 4 were determined by single-crystal X-ray crystallography. Compounds 1 and 2 represent the first unusual cyathane acetals featuring a dioxolane ring. Compounds 1 – 6 displayed differential nerve growth factor-induced neurite outgrowth-promoting activity in PC-12 cells at concentrations of 10 μM. In addition, cyahookerin B ( 2 ), cyathin E ( 9 ), cyathin B 2 ( 12 ), and cyathin Q ( 13 ) showed significant nitric oxide production inhibition in Lipopolysaccharide (LPS)-activated BV-2 microglial cells with IC 50 values of 12.0, 6.9, 10.9, and 9.1 μM, respectively. Similar binding modes of the four compounds were indicated by molecular-docking studies, and structure–activity relationships are discussed.