Design, Synthesis and Evaluation of Novel 1,4-Disubstituted Piperazine-2,5-dione Derivatives as Antioxidants against H<sub>2</sub>O<sub>2</sub>-Induced Oxidative Injury via the IL-6/Nrf2 Loop Pathway
Excessive reactive oxygen species (ROS) production leads to oxidative stress in cells, impairing the function of mitochondria and finally inducing cell apoptosis. Considering the essential role of oxidative stress in the pathogenesis of various neurodegenerative diseases and psychiatric disorders, t...
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| Format: | Article |
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MDPI AG
2022-10-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/11/10/2014 |
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| author | Liang Xiong Hongshan Wu Ting Zhong Fang Luo Qing Li Mei Li Yanhua Fan |
| author_facet | Liang Xiong Hongshan Wu Ting Zhong Fang Luo Qing Li Mei Li Yanhua Fan |
| author_sort | Liang Xiong |
| collection | DOAJ |
| description | Excessive reactive oxygen species (ROS) production leads to oxidative stress in cells, impairing the function of mitochondria and finally inducing cell apoptosis. Considering the essential role of oxidative stress in the pathogenesis of various neurodegenerative diseases and psychiatric disorders, the discovery of novel antioxidants has attracted increasing attention. Herein, a series of novel 1,4-disubstituted piperazine-2,5-dione derivatives were designed, synthesized and evaluated for their antioxidative activity. The results of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay indicated that none of the tested compounds showed significant toxicity to SH-SY5Y cells at concentrations up to 80 μM. Cell counting via flow cytometry revealed that most of the tested compounds could effectively protect SH-SY5Y cells from H<sub>2</sub>O<sub>2</sub>-induced oxidative damage at 20 μM. Among these compounds, compound <b>9r</b> exhibited the best antioxidative activity. Further mechanistic investigation indicated that <b>9r</b> decreased ROS production and stabilized the mitochondrial membrane potential to restrain cell apoptosis, and promoted cell survival via an IL-6/Nrf2 positive-feedback loop. These results suggested the potential of compound <b>9r</b> as a novel antioxidative candidate for the treatment of diseases caused by oxidative stress. |
| first_indexed | 2024-03-09T20:48:43Z |
| format | Article |
| id | doaj.art-87962f49ea0a413f89748841c85dd8b5 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-09T20:48:43Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-87962f49ea0a413f89748841c85dd8b52023-11-23T22:39:22ZengMDPI AGAntioxidants2076-39212022-10-011110201410.3390/antiox11102014Design, Synthesis and Evaluation of Novel 1,4-Disubstituted Piperazine-2,5-dione Derivatives as Antioxidants against H<sub>2</sub>O<sub>2</sub>-Induced Oxidative Injury via the IL-6/Nrf2 Loop PathwayLiang Xiong0Hongshan Wu1Ting Zhong2Fang Luo3Qing Li4Mei Li5Yanhua Fan6State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, ChinaState Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, ChinaState Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, ChinaState Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, ChinaState Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, ChinaState Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, ChinaState Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, ChinaExcessive reactive oxygen species (ROS) production leads to oxidative stress in cells, impairing the function of mitochondria and finally inducing cell apoptosis. Considering the essential role of oxidative stress in the pathogenesis of various neurodegenerative diseases and psychiatric disorders, the discovery of novel antioxidants has attracted increasing attention. Herein, a series of novel 1,4-disubstituted piperazine-2,5-dione derivatives were designed, synthesized and evaluated for their antioxidative activity. The results of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay indicated that none of the tested compounds showed significant toxicity to SH-SY5Y cells at concentrations up to 80 μM. Cell counting via flow cytometry revealed that most of the tested compounds could effectively protect SH-SY5Y cells from H<sub>2</sub>O<sub>2</sub>-induced oxidative damage at 20 μM. Among these compounds, compound <b>9r</b> exhibited the best antioxidative activity. Further mechanistic investigation indicated that <b>9r</b> decreased ROS production and stabilized the mitochondrial membrane potential to restrain cell apoptosis, and promoted cell survival via an IL-6/Nrf2 positive-feedback loop. These results suggested the potential of compound <b>9r</b> as a novel antioxidative candidate for the treatment of diseases caused by oxidative stress.https://www.mdpi.com/2076-3921/11/10/20141,4-disubstituted piperazine-2,5-dionesoxidative stresscell apoptosiscell survivalIL-6/Nrf2 positive-feedback loop |
| spellingShingle | Liang Xiong Hongshan Wu Ting Zhong Fang Luo Qing Li Mei Li Yanhua Fan Design, Synthesis and Evaluation of Novel 1,4-Disubstituted Piperazine-2,5-dione Derivatives as Antioxidants against H<sub>2</sub>O<sub>2</sub>-Induced Oxidative Injury via the IL-6/Nrf2 Loop Pathway Antioxidants 1,4-disubstituted piperazine-2,5-diones oxidative stress cell apoptosis cell survival IL-6/Nrf2 positive-feedback loop |
| title | Design, Synthesis and Evaluation of Novel 1,4-Disubstituted Piperazine-2,5-dione Derivatives as Antioxidants against H<sub>2</sub>O<sub>2</sub>-Induced Oxidative Injury via the IL-6/Nrf2 Loop Pathway |
| title_full | Design, Synthesis and Evaluation of Novel 1,4-Disubstituted Piperazine-2,5-dione Derivatives as Antioxidants against H<sub>2</sub>O<sub>2</sub>-Induced Oxidative Injury via the IL-6/Nrf2 Loop Pathway |
| title_fullStr | Design, Synthesis and Evaluation of Novel 1,4-Disubstituted Piperazine-2,5-dione Derivatives as Antioxidants against H<sub>2</sub>O<sub>2</sub>-Induced Oxidative Injury via the IL-6/Nrf2 Loop Pathway |
| title_full_unstemmed | Design, Synthesis and Evaluation of Novel 1,4-Disubstituted Piperazine-2,5-dione Derivatives as Antioxidants against H<sub>2</sub>O<sub>2</sub>-Induced Oxidative Injury via the IL-6/Nrf2 Loop Pathway |
| title_short | Design, Synthesis and Evaluation of Novel 1,4-Disubstituted Piperazine-2,5-dione Derivatives as Antioxidants against H<sub>2</sub>O<sub>2</sub>-Induced Oxidative Injury via the IL-6/Nrf2 Loop Pathway |
| title_sort | design synthesis and evaluation of novel 1 4 disubstituted piperazine 2 5 dione derivatives as antioxidants against h sub 2 sub o sub 2 sub induced oxidative injury via the il 6 nrf2 loop pathway |
| topic | 1,4-disubstituted piperazine-2,5-diones oxidative stress cell apoptosis cell survival IL-6/Nrf2 positive-feedback loop |
| url | https://www.mdpi.com/2076-3921/11/10/2014 |
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