Molecular Diversity and Potential Anti-neuroinflammatory Activities of Cyathane Diterpenoids from the Basidiomycete Cyathus africanus

Abstract

Ten new polyoxygenated cyathane diterpenoids, named neocyathins A–J (1–10), together with four known diterpenes (11–14), were isolated from the liquid culture of the medicinal basidiomycete fungus Cyathus africanus. The structures and configurations of these new compounds were elucidated through comprehensive spectroscopic analyses including 1D NMR, 2D NMR (HSQC, HMBC, NOESY) and HRESIMS, and electronic circular dichroism (ECD) data. Neuroinflammation is implicated in the pathogenesis of various neurodegenerative diseases, such as Alzheimers’ disease (AD). All isolated compounds were evaluated for the potential anti-neuroinflammatory activities in BV2 microglia cells. Several compounds showed differential effects on the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in lipopolysaccharide (LPS)-stimulated and Aβ1–42-treated mouse microglia cell line BV-2. Molecular docking revealed that bioactive compounds (e.g., 11) could interact with iNOS protein other than COX-2 protein. Collectively, our results suggested that this class of cyathane diterpenoids might serve as important lead compounds for drug discovery against neuroinflammation in AD.

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

“…The 1 H and 13 C NMR data of 2 resembled those of 1 (Tables 1 and 2 ). The marked difference between the two compounds was that the isopropyl group[δ H /δ C :2.58(m)/34.0, 1.12 (d, J = 6.9 Hz)/21.7; 1.15 (d, J = 6.9 Hz)/21.5] at C-3 in 1 was changed into an isopropylidene group[δ C 143.9, δ H /δ C : 1.91 (s)/23.8; 1.98 (s)/22.8] containing an exocyclic olefin at Δ 3 , 18 in 2 , which caused significant upfield shifts of its C-2 and C-3 resonances (δ C 126.0 vs. 45.7 and 164.6 vs. 133.3, respectively) and downfield shifts of its C-18, C-19, and C-20 resonances (δ C 34.0 vs. 143.9, 21.7 vs. 23.8 and 21.5 vs. 22.8, respectively) compared with those in 1 , suggesting that these two compounds differ by a shifted double bond. In addition, analysis of the NMR data of 2 revealed the presence of an isopropylidene group with resonances corresponding to one tetrasubstituted double bond [δ C 133.3(C-3) and 143.9 (C-18)] and two olefinic methyl singlets [δ H 1.91 (H 3 -19) and 1.98 (H 3 -20); δ C 23.8 (C-19) and 22.8 (C-20)].…”

“…To gain access to this potential reservoir of bioactive compounds, the cryptic biosynthetic pathways have to be induced. Our previous phytochemical investigations of the medicinal mushroom C. africanus grown in liquid culture led to the discovery of 14 cyathane diterpenoids including ten new ones, neocyathins A–J, and they showed differential effects on the expression of iNOS and cyclooxygenase-2 (COX-2) in LPS-stimulated and Aβ 1–42 -treated BV-2 cells 18 . Many findings have proved that one of these strategies, OSMAC (one strain, many compounds) involving the alteration of cultivation parameters, is an effective strategy to explore the biosynthetic potential of the fungi 19 – 21 .…”

“…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 – 8 ), along with three known congeners ( 9 – 11 ), different from compounds isolated from the liquid culture 18 , further demonstrating that using different media may produce different metabolites. In this paper, the isolation, structure elucidation, and biological activities of these compounds from C. africanus growing on cooked rice are described.…”

Synthesis and Biological Evaluation of Diversified Hamigeran B Analogs as Neuroinflammatory Inhibitors and Neurite Outgrowth Stimulators

“…According to previously reported methods [30,31], we used rat pheochromocytoma PC12 cells as a model system of neuronal differentiation to measure the effects of the synthesized compounds hamigeran B (2), 9a-n and 9o-w on neurite outgrowth, with NGF (10 ng/mL) as positive control. Specifically, as shown in Figure 3, most of them in combination with NGF (10 ng/mL) showed NGF-mediated neurite-outgrowth promoting activities, and 9a, 9h, 9o, and 9q exhibited significant neuritogenic effects with the percentage of neurite-bearing PC12 cells of 15.94%, 14.99%, 24.23%, and 16.68%, respectively, compared to NGF control cells (9.35%) and the parent molecule 2 (11.34%).…”

A New Epi-neoverrucosane-type Diterpenoid from the Liverwort Pleurozia subinflata in Borneo

“…While, diterpenoids such as clerodanes, dolabellanes, fusicoccanes, kauranes, labdanes, pimaranes and others were found in numerous liverworts [6]. Recently several bioactive cyathane diterpenoids were discovered [7,8]. Cyathane is precursor structure for biosynthesis of the verrucosanetype diterpenoid, a fused 3,6,6,5-tetracyclic carbon skeleton [9].…”