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用小分子准NFE2L1信号,以保护其免受ferroptosis的侵害

Lucie Svobodová¹, Jindřich Sedláček², Zuzana Šmahelová²

¹Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, 16610 Prague, Czech Republic; Department of Organic Chemistry, Charles University, Hlavova 2030/8, Prague 2 12843, Czech Republic.

Bioorganic & medicinal chemistry letters

|October 5, 2025

概括

新化合物激活NFE2L1 (核因子红色素2相关因子1),这是细胞应激的关键调节者. 这些药物保护细胞免受铁亡,这是一种涉及神经退行和癌症的细胞死亡途径.

科学领域:

生物化学生物化学
细胞生物学细胞生物学
药用化学医学化学

背景情况:

铁亡是一种受调节的细胞死亡过程,与铁失调,氧化应激有关,并与神经退行和癌症等疾病有关.
核因子红色素2相关因子1 (NFE2L1) 是维持细胞平衡和减轻压力的关键转录因子.
调节铁亡是一种有希望的治疗途径,用于各种病理.

研究的目的:

设计和合成激活NFE2L1通路的新化合物.
在细胞模型中评估这些化合物对铁亡的细胞保护作用.

主要方法:

一系列 bis ((dimethoxybenzylidene) oxocyclohexylsulfonamides 和 sulfamides 的合成.
通过合成的化合物对NFE2L1激活的评估.
试验化合物在保护SH-SY5Y神经母细胞瘤细胞免受ferroptosis诱导剂 (erastin,RSL3,FAC) 的有效性.

主要成果:

成功设计和合成了新的硫胺和硫胺衍生物.
通过低微分子度的合成化合物证明了NFE2L1的强有力的激活.
观察到人类神经母细胞瘤细胞对多个ferroptosis诱导物的显著保护.

结论:

开发的化合物是强大的NFE2L1激活剂.
这些药物表现出对铁亡的显著细胞保护作用.
这些发现凸显了NFE2L1向剂对铁亡相关疾病的治疗潜力.

关键词:

铁化是铁化的一种.在NRF1 (NFE2L1) 中.氧化症是一种氧化症.具有保护作用的保护作用.

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