Abstract：
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.
摘要：
在这项研究中,二十三种Eudesmane倍半萜（1-23），包括15种以前未描述的，从海洋真菌Eutypellasp.中分离出名为eutypelidesA-O（1-15）。F0219.通过HR-ESIMS和广泛的1D和2DNMR研究建立了它们的平面结构和相对构型。通过单晶X射线衍射分析确定先前未描述的化合物的绝对构型，修改了Mosher\的方法，和ECD计算。在结构上,EutypelideA(1)是一种罕见的1,10秒-Eudesmane，而2-15通常是具有6/6/-稠合双环碳核的ent-eudesmanes。所有分离的化合物(1-23)的抗神经炎活性是基于它们在LPS刺激的BV2小胶质细胞中产生NO的能力而获得的。化合物16作为最有效的抑制剂出现。进一步的机制研究表明，化合物16通过降低iNOS的蛋白质水平和增加ARG1水平来调节炎症反应，从而改变iNOS/ARG1比率并抑制巨噬细胞极化。qRT-PCR分析表明，化合物16逆转了LPS诱导的促炎细胞因子的上调，包括iNOS,TNF-α,IL-6和IL-1β，在转录和翻译水平。这些作用与NF-κB通路的抑制有关，炎症的关键调节剂。我们的发现表明，化合物16可能是开发神经炎症相关疾病治疗剂的潜在结构基础。
