European Journal of Medicinal Chemistry, volume 264, pages 115997
Design, synthesis, and biological evaluation of 2-amino-6-methyl-phenol derivatives targeting lipid peroxidation with potent anti-ferroptotic activities
Xiong Sheng
1
,
Lu Han
1
,
Xiaojie Ma
2
,
Ao Gong
3
,
Meng-Zhu Hao
1
,
Hui Zhu
1
,
Xiang-Shuai Meng
1
,
Ting Wang
4
,
Chun Yan Sun
5
,
Jie Ma
1
,
Lei Zhang
6
5
Shandong Center for Disease Control and Prevention, Jinan, 250014, China
|
Publication type: Journal Article
Publication date: 2024-01-01
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 6.7
ISSN: 02235234, 17683254
Organic Chemistry
Drug Discovery
General Medicine
Pharmacology
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 RSL-3-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.
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Drug Discovery Today
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Elsevier
1 publication, 100%
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Sheng X. et al. Design, synthesis, and biological evaluation of 2-amino-6-methyl-phenol derivatives targeting lipid peroxidation with potent anti-ferroptotic activities // European Journal of Medicinal Chemistry. 2024. Vol. 264. p. 115997.
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Sheng X., Han L., Ma X., Gong A., Hao M., Zhu H., Meng X., Wang T., Sun C. Y., Ma J., Zhang L. Design, synthesis, and biological evaluation of 2-amino-6-methyl-phenol derivatives targeting lipid peroxidation with potent anti-ferroptotic activities // European Journal of Medicinal Chemistry. 2024. Vol. 264. p. 115997.
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TY - JOUR
DO - 10.1016/j.ejmech.2023.115997
UR - https://doi.org/10.1016/j.ejmech.2023.115997
TI - Design, synthesis, and biological evaluation of 2-amino-6-methyl-phenol derivatives targeting lipid peroxidation with potent anti-ferroptotic activities
T2 - European Journal of Medicinal Chemistry
AU - Sheng, Xiong
AU - Han, Lu
AU - Ma, Xiaojie
AU - Gong, Ao
AU - Hao, Meng-Zhu
AU - Zhu, Hui
AU - Meng, Xiang-Shuai
AU - Wang, Ting
AU - Sun, Chun Yan
AU - Ma, Jie
AU - Zhang, Lei
PY - 2024
DA - 2024/01/01 00:00:00
PB - Elsevier
SP - 115997
VL - 264
SN - 0223-5234
SN - 1768-3254
ER -
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@article{2024_Sheng,
author = {Xiong Sheng and Lu Han and Xiaojie Ma and Ao Gong and Meng-Zhu Hao and Hui Zhu and Xiang-Shuai Meng and Ting Wang and Chun Yan Sun and Jie Ma and Lei Zhang},
title = {Design, synthesis, and biological evaluation of 2-amino-6-methyl-phenol derivatives targeting lipid peroxidation with potent anti-ferroptotic activities},
journal = {European Journal of Medicinal Chemistry},
year = {2024},
volume = {264},
publisher = {Elsevier},
month = {jan},
url = {https://doi.org/10.1016/j.ejmech.2023.115997},
pages = {115997},
doi = {10.1016/j.ejmech.2023.115997}
}