Hypecotumines A-D, new isoquinoline alkaloids with potential PCSK9 inhibition activity from Hypecoum erectum L.

IF 4.8 3区化学 Q1 CHEMISTRY, MEDICINAL Natural Products and Bioprospecting Pub Date : 2024-10-15 DOI:10.1007/s13659-024-00479-3

Yinling Wei, Hongyan Wen, Lian Yang, Bodou Zhang, Xiaoyu Li, Sheng Li, Jing Dong, Zhenzhen Liang, Yu Zhang

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Abstract

Four new isoquinoline alkaloids, hypecotumines A-D (1–4), were isolated and identified from the whole herbs of Hypecoum erectum L. Their structures were determined by a combination of HRESIMS, NMR, and X-ray diffraction analysis methods. Compounds 1–4 were characterized by a terminal double bond at C-9 and their plausible biosynthetic pathway was hypothesized. Since PCSK9 plays a key role in the development of cardiovascular disease (CVD), exploration of PCSK inhibitors from natural products are beneficial for drug discovery of CVD treatment. SPR and Western blot assays showed compound 4 had PCSK9 inhibition activity with K_D value of 59.9 µM and thus elevated the LDLR level. Further molecular docking studies demonstrated that 4 and PCSK9 could form stable interactions via key hydrogen bonds.

Graphical Abstract

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具有潜在 PCSK9 抑制活性的新异喹啉生物碱 Hypecotumines A-D from Hypecoum erectum L.

结合 HRESIMS、核磁共振和 X 射线衍射分析方法确定了它们的结构。化合物 1-4 的特征是 C-9 上有一个末端双键，并假设了其合理的生物合成途径。由于 PCSK9 在心血管疾病（CVD）的发生发展中起着关键作用，因此从天然产物中探索 PCSK 抑制剂有利于发现治疗心血管疾病的药物。SPR 和 Western 印迹分析表明，化合物 4 具有 PCSK9 抑制活性，KD 值为 59.9 µM，从而提高了 LDLR 水平。进一步的分子对接研究表明，化合物 4 与 PCSK9 可通过关键氢键形成稳定的相互作用。

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