Design, synthesis, and evaluation of novel ferrostatin derivatives for the prevention of HG-induced VEC ferroptosis

Ferroptosis is a nonapoptotic, iron-catalyzed form of regulated cell death. It has been shown that high glucose (HG) could induce ferroptosis in vascular endothelial cells (VECs), consequently contributing to the development of various diseases. This study synthesized and evaluated a series of novel...

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Published in:MedChemComm 2024-04, Vol.15 (4), p.1198-129
Main Authors: Wang, Xin-Xin, Wang, Run-Jie, Ji, Hua-Long, Liu, Xiao-Yu, Zhang, Nai-Yu, Wang, Kai-Ming, Chen, Kai, Liu, Ping-Ping, Meng, Ning, Jiang, Cheng-Shi
Format: Article
Language:English
Subjects:
Cell death
Damage accumulation
Damage prevention
Endothelial cells
Ferroptosis
Ferrous ions
Glucose
Lead compounds
Mercury
Vascular diseases
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Summary:Ferroptosis is a nonapoptotic, iron-catalyzed form of regulated cell death. It has been shown that high glucose (HG) could induce ferroptosis in vascular endothelial cells (VECs), consequently contributing to the development of various diseases. This study synthesized and evaluated a series of novel ferrostatin-1 (Fer-1) derivatives fused with a benzohydrazide moiety to prevent HG-induced VEC ferroptosis. Several promising compounds showed similar or improved inhibitory effects compared to positive control Fer-1. The most effective candidate 12 exhibited better protection against erastin-induced ferroptosis and high glucose-induced ferroptosis in VECs. Mechanistic studies revealed that compound 12 prevented mitochondrial damage, reduced intracellular ROS accumulation, upregulated the expression of GPX4, and decreased the amounts of ferrous ion, LPO and MDA in VECs. However, compound 12 still exhibited undesirable microsomal stability like Fer-1, suggesting the need for further optimization. Overall, the present findings highlight ferroptosis inhibitor 12 as a potential lead compound for treating ferroptosis-associated vascular diseases. This work designed and synthesized novel ferrostatin analogs with a benzohydrazide moiety, and identified compound 12 as a promising lead for preventing HG-induced VEC ferroptosis.
ISSN:2632-8682
2040-2503
2632-8682
2040-2511
DOI:10.1039/d4md00038b