Filicinic acid based meroterpenoids from Hypericum elodeoides and their anti-Alzheimer’s disease effects

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2024-09-02 DOI:10.1016/j.bioorg.2024.107787

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Abstract

(±)-Elodeoidileons A-L (1–12), 12 pairs of previously undescribed filicinic acid based meroterpenoids were isolated from Hypericum elodeoides with unique linear or angular 6/6/6 ring core. Modern spectroscopic techniques, modified Mosher’s method and quantum chemical calculations were used to identify the planner structures and configurations of 1–12. Additionally, the potential biosynthetic pathways for 1–12 were anticipated. Moreover, biological activity assessments suggested that 1a, 5a, and 11b could activate Retinoid X receptor-α (RXRα) transcription and enhance the ATP-binding cassette transporter A1 (ABCA1) protein’s expression. Fluorescence titration assay suggested that 1a might have a direct interaction with the RXRα-LBD protein, with an estimated K_d value of 5.85 μM. Moreover, molecular docking study confirmed the binding of 1a to RXRα and further validated by cellular thermal shift assay (CETSA). Thus, compound 1a may promote β-amyloid (Aβ) clearance by targeting RXRα and upregulating the expression of the ABCA1 protein, showing promise as anti-Alzheimer’s agent.

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来自金丝桃的基于丝胶酸的 meroterpenoids 及其抗老年痴呆症的作用。

(±)-Elodeoidileons A-L (1-12)，是从金丝桃中分离出的 12 对以前未曾描述过的以丝氨酸为基础的 meroterpenoids，具有独特的线性或角性 6/6/6 环核心。研究人员利用现代光谱技术、改进的莫舍尔法和量子化学计算，确定了 1-12 的平面结构和构型。此外，还预测了 1-12 的潜在生物合成途径。此外，生物活性评估表明，1a、5a 和 11b 可以激活视黄醇 X 受体-α（RXRα）的转录，并增强 ATP 结合盒转运体 A1（ABCA1）蛋白的表达。荧光滴定分析表明，1a 可能与 RXRα-LBD 蛋白有直接相互作用，其 Kd 值估计为 5.85 μM。此外，分子对接研究证实了 1a 与 RXRα 的结合，细胞热转移试验（CETSA）也进一步验证了这一点。因此，化合物 1a 可通过靶向 RXRα 和上调 ABCA1 蛋白的表达来促进 β 淀粉样蛋白（Aβ）的清除，有望成为抗老年痴呆症的药物。

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来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.