Design, Synthesis, and Biological Evaluation of New Improved Ferrostatin‐1 Derived Ferroptosis Inhibitors
Ferrostatin-1 (Fer-1), a first potent ferroptosis inhibitor, faces limitations in clinical use due to its low potency and metabolic instability. This study introduces a series of novel Ferrostatin-1 analogs designed to enhance plasm stability. Our design strategy focused on the modification of the 3-NH<sub>2</sub> of Fer-1 with benzenesulfonyl groups, resulting in analogs 9-25. Biological evaluation revealed that compound 18, with an EC<sub>50</sub> value of 0.57 μM, outperformed Fer-1 in inhibiting ferroptosis. It reduced intracellular ferrous ion accumulation, lipid peroxidation, and restored glutathione (GSH) and glutathione peroxidase 4 (GPX4) levels effectively. Moreover, compound 18 exhibited favorable solubility and remarkable metabolic stability in rat plasma. These results position compound 18 as a promising candidate for developing therapeutics against ferroptosis-related diseases.
Authors
- Cheng‐Shi Jiang (ORCID: https://orcid.org/0000-0002-2760-7596)
- Jun-Yu Liu
- Hui Zheng (ORCID: https://orcid.org/0000-0003-3085-4560)
- Nai-Yu Zhang
- Juan Zhang (ORCID: https://orcid.org/0009-0002-0374-5385)
- Kaiming Wang (ORCID: https://orcid.org/0000-0002-7574-064X)
- Ning Meng (ORCID: https://orcid.org/0000-0002-0481-9916)
Institutions
- University of Jinan (CN)
Publication Details
- Journal
- Chemistry & Biodiversity
- Published
- 2024-10-05
- DOI
- https://doi.org/10.1002/cbdv.202402141
- Citations
- 4
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 1.68
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Shandong Province