Design, Synthesis, and Biological Evaluation of New Improved Ferrostatin-1 Derived Ferroptosis Inhibitors

  • Chem Biodivers. 2024 Oct 4:e202402141. doi: 10.1002/cbdv.202402141.
Nai-Yu Zhang  1 ,  Jun-Yu Liu  1 ,  Hui Zheng  2 ,  Kai-Ming Wang  1 ,  Juan Zhang  1 ,  Ning Meng  1  3 ,  Cheng-Shi Jiang  1  3
Affiliations
  • 1. School of Biological Science and Technology, University of Jinan, Jinan, 250022, China.
  • 2. Jinan University Hospital, University of Jinan, Jinan, 250022, China.
  • 3. Jinan Engineering Research Center of Plant-Microbial Interaction, Jinan, 250022, China.
PMID: 39367646 DOI: 10.1002/cbdv.202402141
Abstract

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-NH2 of Fer-1 with benzenesulfonyl groups, resulting in analogs 9-25. Biological evaluation revealed that compound 18, with an EC50 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.

Keywords
Fer-1 analogs; Ferroptosis inhibitor; Glutathione peroxidase 4; Plasma stability; Solubility.
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