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

Abstract

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 B2 (12), and cyathin Q (13) showed significant nitric oxide production inhibition in Lipopolysaccharide (LPS)-activated BV-2 microglial cells with IC50 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.

A Mechanistic Review on Medicinal Mushrooms-Derived Bioactive Compounds: Potential Mycotherapy Candidates for Alleviating Neurological Disorders

“…In their continuing search of neuroprotrophic compounds from the Cynathus genus, two new cyathane diterpenoids named neocyathin S (22) and neocyathin T (23), along with three drimane sesquiterpenoids isolated from the solid culture of Cyathus africanus H. J. Brodie, including one known 3β,6β-dihydroxycinnamolide (24) and two new ones 3β,6α-dihydroxycinnamolide (25) and 2-keto-3β,6β-dihydroxycinnamolide (26), showed neurite outgrowth-promoting activity in PC12 cells [40]. From the liquid culture of Cyathus hookeri Berk., six new cyathane diterpenes, cyahookerins A-F (27-32), and nine known analogs were isolated, with cyahookerin C (29) showing significant neurotrophic activity amongst the nine screened cyathane diterpenoids [41]. ▶ Fig.…”

“…Known as birdʼs nest fungi, several Cyathus species produce novel compounds with biological activities such as antibiotic, antifungal, anti-neurodegenerative, antioxidative, and anti-inflammatory activities [38], and some cyathanes are specific to this genus. Gao et al isolated several cyathane diterpenoids with a contiguous 5/6/7 tricyclic skeleton from Cyathus species with neurotrophic activity [39][40][41]. Six highly oxygenated polycyclic cyathanexylosides, designated striatoids A-F (16)(17)(18)(19)(20)(21), were shown to be isolated from the liquid cultures of Cyathus striatus (Huds.)…”

“…Orally ingested ergothioneine promoted neuronal differentiation and readily permeated the BBB, thus alleviating the symptoms of depression in mice [60]. The structures of uridine (41) and ergothioneine (42) are shown in ▶ Fig. 7.…”

“…Ganodermasides A-D (43)(44)(45)(46), the biologically active compounds obtained from different parts of G. lucidum, increase life span and show antiaging properties [64][65][66]. Other bioactive triterpenoid compounds such as lucidenic acids, 7-oxo-ganoderic acid-Z (47), (41) in PC12 cells via the MEK/ERK or PI3K/AKT pathway. Uridine, an isolated P. giganteus mushroom compound, activates nucleotide metabotropic receptor P2Y.…”

“…▶ Fig. 7 Structures of uridine (41) and ergothioneine (42) isolated from P. giganteus. 4,4,1,4α-trimethyl-5α-chol-7,9 (11)-diene-3-oxo-24-oic acid (48), ganoderic acid-S1 (49), ganolucidic acid-A (50), methyl ganoderic acid-A (51), and methyl ganoderic acid-B (52) from G. lucidum are capable of inducing neurite outgrowth [64][65][66].…”