Design, Synthesis and Evaluation of Novel 1,4-Disubstituted Piperazine-2,5-dione Derivatives as Antioxidants against H(2)O(2)-Induced Oxidative Injury via the IL-6/Nrf2 Loop Pathway.
Design, Synthesis and Evaluation of Novel 1,4-Disubstituted Piperazine-2,5-dione Derivatives as Antioxidants against H(2)O(2)-Induced Oxidative Injury via the IL-6/Nrf2 Loop Pathway.
复制标题
DOI：
10.3390/antiox11102014
复制
发表时间：
2022-10-12
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
过多的活性氧（ROS）产生导致细胞氧化应激，损害线粒体功能，最终诱导细胞凋亡。考虑到氧化应激在各种神经退行性疾病和精神疾病发病机制中的重要作用，新型抗氧化剂的发现越来越受到人们的关注。本文设计、合成了一系列新的1,4-二取代哌嗪-2,5-二酮衍生物，并对其抗氧化活性进行了评价。3-（4,5-二甲基噻唑-2-基）-2,5-二苯基- 2h -溴化四氮唑（MTT）试验结果表明，在80 μM浓度下，所有化合物对SH-SY5Y细胞均无明显毒性。流式细胞术细胞计数显示，大多数化合物能有效保护SH-SY5Y细胞免受20 μM h2o2诱导的氧化损伤。其中化合物9r的抗氧化活性最好。进一步的机制研究表明，9r通过抑制ROS的产生，稳定线粒体膜电位，抑制细胞凋亡，并通过IL-6/Nrf2正反馈回路促进细胞存活。这些结果表明，化合物9r作为一种新的抗氧化剂候选物，具有治疗氧化应激引起的疾病的潜力。
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 H2O2-induced oxidative damage at 20 μM. Among these compounds, compound 9r exhibited the best antioxidative activity. Further mechanistic investigation indicated that 9r 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 9r as a novel antioxidative candidate for the treatment of diseases caused by oxidative stress.
登录
查看更多内容
影响因子：
3.6
作者：
Liguori I;Russo G;Curcio F;Bulli G;Aran L;Della-Morte D;Gargiulo G;Testa G;Cacciatore F;Bonaduce D;Abete P
通讯作者：
Abete P
影响因子：
3.4
作者：
Wang, Andong;Fan, Yanhua;Xu, Yongnan
通讯作者：
Xu, Yongnan
DOI：
10.1007/s00018-016-2223-0
发表时间：
2016-09
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
Loboda A;Damulewicz M;Pyza E;Jozkowicz A;Dulak J
通讯作者：
Dulak J
影响因子：
--
作者：
Pizzino G;Irrera N;Cucinotta M;Pallio G;Mannino F;Arcoraci V;Squadrito F;Altavilla D;Bitto A
通讯作者：
Bitto A
影响因子：
2
作者：
Majumdar, K. C.;Ray, Krishanu;Ganai, Sintu
通讯作者：
Ganai, Sintu