Polyoxygenated cyathane diterpenoids from the mushroom Cyathus africanus, and their neurotrophic and anti-neuroinflammatory activities

Jing Wei,Marcin Górecki,Jin-Ming Gao,Gennaro Pescitelli,Rong-Wei Kou,Wan-Hui Guo,Chen-Yu Cao,Yuan-Zhen Xu,Lorenzo Di Bari

doi:10.1038/s41598-018-20472-4

Abstract

In a previous study, we reported ten new polyoxygenated cyathane diterpenoids, neocyathins A–J, and their anti-neuroinflammatory effects from the liquid culture of the medicinal Basidiomycete Cyathus africanus. In the present study, eight new highly polyoxygenated cyathane diterpenoids, named neocyathins K–R (1–8), were isolated from the solid culture of C. africanus cultivated on cooked rice, together with three known congeners (9–11). The structures and the absolute configurations of the new compounds were elucidated through comprehensive NMR and HRESIMS spectroscopic data, electronic circular dichroism (ECD) data, and chemical conversion. Compounds 1 and 2 represent the first reported naturally occurring compounds with 4,9-seco-cyathane carbon skeleton incorporating an unprecedented medium-sized 9/7 fused ring system, while the 3,4-seco-cyathane derivative (3) was isolated from Cyathus species for the first time. All compounds were evaluated for their neurotrophic and anti-neuroinflammatory activity. All the isolates at 1–25 μM displayed differential nerve growth factor (NGF)-induced neurite outgrowth-promoting activity in PC-12 cells, while one of the compounds, allocyathin B2 (11), inhibited NO production in lipopolysaccharide (LPS)-stimulated microglia BV-2 cells. In addition, molecular docking studies showed that compound 11 generated interactions with the inducible nitric oxide synthase (iNOS) protein.

Highlights

The prevalence of neurodegenerative diseases such as Alzheimer’s disease (AD) will continue to rise steadily
The fungus C. africanus was grown in the solid-substrate medium in static condition, and further detailed chemical investigation led to the isolation of eight new cyathane diterpenoids (Fig. 1), namely, neocyathins K–R [1,2,3,4,5,6,7,8], along with three known congeners [9,10,11], different from compounds isolated from the liquid culture18, further demonstrating that using different media may produce different metabolites
The NMR spectroscopic data of carbons (C-10 to C-15) of 1 were similar to those of 10 (Fig. 1), a known cyathane diterpene obtained from Strobilurus tenacellus23, later isolated from Cyathus gansuensis25

Summary

Introduction

The prevalence of neurodegenerative diseases such as Alzheimer’s disease (AD) will continue to rise steadily. It is vital to explore novel bioactive natural products to mitigate neurodegenerative disorders Neurotrophic factors such as nerve growth factor (NGF) have generated much excitement over the past decade due to their therapeutic potential in regulating the proliferation, survival, migration, and differentiation of cells in the nervous system. The fungus C. africanus was grown in the solid-substrate medium in static condition, and further detailed chemical investigation led to the isolation of eight new cyathane diterpenoids (Fig. 1), namely, neocyathins K–R [1,2,3,4,5,6,7,8], along with three known congeners [9,10,11], different from compounds isolated from the liquid culture, further demonstrating that using different media may produce different metabolites. The isolation, structure elucidation, and biological activities of these compounds from C. africanus growing on cooked rice are described

Methods

Results

Conclusion