Ent-eudesmane sesquiterpenoids with anti-neuroinflammatory activity from the marine-derived fungus Eutypella sp. F0219

• Published in: Phytochemistry (Oxford) 2024-07, Vol.223, p.114121-114121, Article 114121
• Main Authors: Jiang, Zhong-Ping, Su, Rui, Chen, Meng-Ting, Li, Jun-Yi, Chen, Han-Yu, Yang, Lu, Liu, Fei-Fei, Liu, Jin, Xu, Cong-Jun, Li, Wan-Shan, Rao, Yong, Huang, Ling
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - isolation & purification; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - isolation & purification; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-neuroinflammatory activity; Dose-Response Relationship, Drug; Ent-eudesmane sesquiterpenoids; Eutypella sp. F0219; Lipopolysaccharides - antagonists & inhibitors; Lipopolysaccharides - pharmacology; Marine-derived fungus; Mice; Microglia; Microglia - drug effects; Molecular Structure; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; Nitric oxide; Nitric Oxide - antagonists & inhibitors; Nitric Oxide - biosynthesis; Sesquiterpenes - chemistry; Sesquiterpenes - isolation & purification; Sesquiterpenes - pharmacology; Sesquiterpenes, Eudesmane - chemistry; Sesquiterpenes, Eudesmane - isolation & purification; Sesquiterpenes, Eudesmane - pharmacology; Structure-Activity Relationship
• ISSN: 0031-9422; 1873-3700
• DOI: 10.1016/j.phytochem.2024.114121

In this study, twenty-three ent-eudesmane sesquiterpenoids (1–23) including fifteen previously undescribed ones, named eutypelides A–O (1–15) were isolated from the marine-derived fungus Eutypella sp. F0219. Their planar structures and relative configurations were established by HR-ESIMS and extensive 1D and 2D NMR investigations. The absolute configurations of the previously undescribed compounds were determined by single-crystal X-ray diffraction analyses, modified Mosher's method, and ECD calculations. Structurally, eutypelide A (1) is a rare 1,10-seco-ent-eudesmane, whereas 2–15 are typically ent-eudesmanes with 6/6/-fused bicyclic carbon nucleus. The anti-neuroinflammatory activity of all isolated compounds (1−23) was accessed based on their ability to NO production in LPS-stimulated BV2 microglia cells. Compound 16 emerged as the most potent inhibitor. Further mechanistic investigation revealed that compound 16 modulated the inflammatory response by decreasing the protein levels of iNOS and increasing ARG 1 levels, thereby altering the iNOS/ARG 1 ratio and inhibiting macrophage polarization. qRT-PCR analysis showed that compound 16 reversed the LPS-induced upregulation of pro-inflammatory cytokines, including iNOS, TNF-α, IL-6, and IL-1β, at both the transcriptional and translational levels. These effects were linked to the inhibition of the NF-κB pathway, a key regulator of inflammation. Our findings suggest that compound 16 may be a potential structure basis for developing neuroinflammation-related disease therapeutic agents. Fifteen previously undescribed ent-eudesmane sesquiterpenoids (1–15) were isolated from the marine-derived fungus Eutypella sp. F0219. Compound 16 inhibited LPS stimulation induced macrophage polarization alongside canonical inflammatory-regulated pathway NF-κB suppression. [Display omitted] •15 previously undescribed ent-eudesmane sesquiterpenoids were isolated.•Compound 16 displayed potent anti-neuroinflammatory activity.•Compound 16 inhibited LPS stimulation induced macrophage polarization.•Compound 16 suppressed the NF-κB pathway.