2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of New Improved Ferrostatin-1 Derived Ferroptosis Inhibitors

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

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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