Generation of potent Nrf2 activators via tuning the electrophilicity and steric hindrance of vinyl sulfones for neuroprotection
Generation of potent Nrf2 activators via tuning the electrophilicity and steric hindrance of vinyl sulfones for neuroprotection
复制标题
通过调节乙烯基砜的亲电性和空间位阻生成有效的 Nrf2 激活剂以保护神经
DOI：
10.1016/j.bioorg.2020.104520
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发表时间：
2021
影响因子：
5.1
通讯作者：
Fang Jianguo
中科院分区：
文献类型：
--
作者：
Song Zi-Long;Hou Yanan;Bai Feifei;Fang Jianguo
氧化应激一直参与越来越广泛的神经退行性疾病的发病机制。因此，将细胞氧化应激有效抑制至氧化还原稳态条件是治疗或至少延缓此类病症进展的有前景且可行的策略。Nrf2是细胞抗氧化反应机制的主要协调者，通过转录激活多种抗氧化生物分子，负责解毒和补偿有害的氧化应激。在我们持续关注的框架内，公开了干扰细胞氧化还原调节机制的小分子，我们在此报告了47种乙烯砜支架小分子的合成、优化和生物学评估，其中大多数对H2O2介导的PC12细胞损伤表现出强大的神经保护作用。经过初步筛选，选择最有效的神经保护化合物9和9 c进行后续研究。我们的研究结果表明，它们的神经保护作用归因于一组抗氧化基因和相应的基因产物的上调。进一步的机制研究表明，Nrf2是必不可少的细胞性能的9band9c，所产生的事实，Nrf2基因的沉默大大抵消了他们的保护作用。总而言之，本工作中发现的9 band 9 c值得进一步开发，作为治疗氧化应激介导的病理状况的神经保护候选药物。
Oxidative stress is constantly involved in the etiopathogenesis of an ever-widening range of neurodegenerative diseases. As a consequence, effective repression of cellular oxidative stress to a redox homeostatic condition is a promising and feasible strategy to treat, or at least retard the progression of, such disorders. Nrf2, a primary orchestrator of cellular antioxidant response machine, is responsible for detoxifying and compensating for deleterious oxidative stressviatranscriptional activation of a diverse array of antioxidant biomolecules. In the framework of our persistent interest in disclosing small molecules that interfere with cellular redox-regulating machinery, we report herein the synthesis, optimization, and biological assessment of 47 vinyl sulfone scaffold-bearing small molecules, most of which exhibit robust neuroprotective effect against H2O2-mediated lesions to PC12 cells. After initial screening, the most potent neuroprotective compounds9band9cwith marginal cytotoxicity were selected for the follow-up studies. Our results demonstrate that their neuroprotective effects are attributed to the up-regulation of a panel of antioxidant genes and corresponding gene products. Further mechanistic studies indicate that Nrf2 is indispensable for the cellular performances of9band9c, arising from the fact that silence of Nrf2 gene drastically nullifies their protective action. Taken together,9band9cdiscovered in this work merit further development as neuroprotective candidates for the treatment of oxidative stress-mediated pathological conditions.