2. Academic Validation
  3. Design, synthesis, and biological evaluation of 2-amino-6-methyl-phenol derivatives targeting lipid peroxidation with potent anti-ferroptotic activities

Design, synthesis, and biological evaluation of 2-amino-6-methyl-phenol derivatives targeting lipid peroxidation with potent anti-ferroptotic activities

  • Eur J Med Chem. 2023 Nov 28:264:115997. doi: 10.1016/j.ejmech.2023.115997.
Xie-Huang Sheng 1,  Li-Cong Han 1,  Xiao-Jie Ma 2,  Ao Gong 3,  Meng-Zhu Hao 1,  Hao Zhu 1,  Xiang-Shuai Meng 1,  Ting Wang 4,  Chang-Hua Sun 5,  Jian-Ping Ma 6,  Lei Zhang 7
Affiliations

Affiliations

  • 1 College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Shandong Provincial Key Laboratory of Clean Production of Fine Chemicals, Shandong Normal University, Jinan, 250014, China.
  • 2 Department of Rheumatology and Immunology, Shandong University of Traditional Chinese Medicine, Jinan, 250011, China.
  • 3 Second Clinical Medical College of Shandong University of Traditional Chinese Medicine, Jinan, 250001, China.
  • 4 Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250014, China.
  • 5 Shandong Center for Disease Control and Prevention, Jinan, 250014, China.
  • 6 College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Shandong Provincial Key Laboratory of Clean Production of Fine Chemicals, Shandong Normal University, Jinan, 250014, China. Electronic address: [email protected].
  • 7 Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Shandong Provincial Qianfoshan Hospital, Tissue Engineering Laboratory, Department of Radiology, Shandong First Medical University, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, 250014, China. Electronic address: [email protected].
PMID: 38056303 DOI: 10.1016/j.ejmech.2023.115997
Abstract

The suppression of Ferroptosis is emerging as a promising therapeutic strategy for effectively treating a wide range of diseases, including neurodegenerative disorders, organ ischemia-reperfusion injury, and inflammatory conditions. However, the clinical utility of Ferroptosis inhibitors is significantly impeded by the limited availability of rational drug designs. In our previous study, we successfully unraveled the efficacy of ferrostatin-1 (Fer-1) attributed to the synergistic effect of its ortho-diamine (-NH) moiety. In this study, we present the discovery of the ortho-hydroxyl-amino moiety as a novel scaffold for Ferroptosis inhibitors, employing quantum chemistry as well as in vitro and in vivo assays. 2-amino-6-methylphenol derivatives demonstrated remarkable inhibition of RSL3-induced Ferroptosis, exhibiting EC50 values ranging from 25 nM to 207 nM. These compounds do not appear to modulate iron homeostasis or lipid Reactive Oxygen Species (ROS) generation pathways. Nevertheless, they effectively prevent the accumulation of lipid peroxides in living cells. Furthermore, compound 13 exhibits good in vivo activities as it effectively protect mice from kidney ischemia-reperfusion injury. In summary, compound 13 has been identified as a potent Ferroptosis inhibitor, warranting further investigation as a promising lead compound.

Keywords

2-Amino-6-Methyl-phenol; Ferroptosis inhibitors; Ferrostatin-1; Kidney ischemia-reperfusion; Lipid peroxidation.

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