Design, synthesis and evaluation of NBP/borneol hybrids as neuroprotective agents for the treatment of ischemic stroke.

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2025-09-30 DOI:10.1016/j.bioorg.2025.109056

Xiaolin Wang, Guangyu Li, Haoyue Shen, Chenwei Zuo, Qing Wu, Hai Shang, Yu Tian

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引用次数: 0

Abstract

The pathogenesis of cerebral ischemia is a highly complex biochemical process, mainly caused by cerebral vascular occlusion or rupture, which results in the interruption of blood flow and ischemic injury to brain tissue. Based on 3-n-Butylphthalide (NBP), a listed drug with approved neuroprotective properties, a series of NBP/Borneol hybrids were designed, synthesized and evaluated for their biological activities in vitro. Most of these compounds exhibited potent neuroprotection with low cytotoxicity, among all derivatives, L-NRB and S6b exhibited significantly improved cell viabilities compared to NBP in OGD/R model and glutamate induced model using HT22 cells. Further biological activity studies revealed that compounds L-NRB, S6b inhibit LDH release and may exert anti-cerebral ischemia activities by resisting oxidative stress and reducing apoptosis. In addition, L-NRB, S6b could regulate the levels of apoptosis pathway-related proteins Caspase 3, Bcl-2 and Bax. Notably, S6b reduced cerebral thrombosis in the ponatinib-induced zebrafish model. In conclusion, this work designed, synthesized and evaluated a novel series of NBP derivatives with neuroprotective activity and provides a reference for the design of other potential compounds for the treatment of ischemic stroke.

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NBP/冰片复合物治疗缺血性脑卒中神经保护剂的设计、合成和评价。

脑缺血的发病机制是一个高度复杂的生化过程，主要是由于脑血管闭塞或破裂导致血流中断，对脑组织造成缺血性损伤。以具有神经保护作用的上市药物3-n-丁基苯酞（NBP）为基础，设计、合成了一系列NBP/冰片杂合体，并对其体外生物活性进行了评价。其中，L-NRB和S6b在HT22细胞OGD/R模型和谷氨酸诱导模型中均表现出较NBP显著提高的细胞活力。进一步的生物活性研究表明，化合物L-NRB、S6b抑制LDH释放，可能通过抗氧化应激、减少细胞凋亡发挥抗脑缺血作用。此外，L-NRB、S6b可调控凋亡通路相关蛋白Caspase 3、Bcl-2、Bax的表达水平。值得注意的是，S6b在波纳替尼诱导的斑马鱼模型中减少了脑血栓形成。综上所述，本工作设计、合成并评价了一系列具有神经保护作用的NBP衍生物，为设计其他潜在的缺血性脑卒中治疗化合物提供了参考。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.