Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea.
Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul, 02792, Republic of Korea.
Eur J Med Chem. 2021 Feb 15;212:113103. doi: 10.1016/j.ejmech.2020.113103. Epub 2020 Dec 25.
The Kelch-like ECH-associated protein 1 (Keap1)-Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway plays a pivotal role in the cellular defense system against oxidative stress by inducing antioxidant and anti-inflammatory effects. We previously developed Nrf2 activators that potentially protect the death of dopaminergic (DAergic) neuronal cells against oxidative stress in Parkinson's disease (PD). In this study, we designed and synthesized a class of halogenated vinyl sulfones by inserting halogens and pyridine to maximize Nrf2 activation efficacy. Among the synthesized compounds, (E)-3-chloro-2-(2-((2-chlorophenyl)sulfonyl)vinyl)pyridine (9d) significantly exhibited potent Nrf2 activating efficacy (9d: EC = 26 nM) at least 10-fold compared with the previous developed compounds (1 and 2). Furthermore, treating with 9d remarkably increased Nrf2 nuclear translocation and Nrf2 protein levels in microglial BV-2 cells. 9d was shown to induce the expression of antioxidant response genes HO-1, GCLC, GCLM, and SOD-1 at both the mRNA and protein levels and suppress proinflammatory cytokines and enzymes. Also, 9d remarkably protected DAergic neurons and restored the PD-associated motor dysfunction in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model.
Kelch 样 ECH 相关蛋白 1（Keap1）-核因子红细胞 2 相关因子 2（Nrf2）信号通路通过诱导抗氧化和抗炎作用，在细胞对抗氧化应激的防御系统中发挥关键作用。我们之前开发了 Nrf2 激活剂，它们有可能保护帕金森病（PD）中多巴胺能（DAergic）神经元细胞免受氧化应激的死亡。在这项研究中，我们通过插入卤素和吡啶设计并合成了一类卤代乙烯砜，以最大限度地提高 Nrf2 的激活功效。在所合成的化合物中，（E）-3-氯-2-（2-（（2-氯苯基）磺酰基）乙烯基）吡啶（9d）在 Nrf2 激活功效方面表现出显著的效力（9d：EC = 26 nM），至少比以前开发的化合物（1 和 2）高出 10 倍。此外，用 9d 处理可显著增加小胶质细胞 BV-2 细胞中 Nrf2 的核易位和 Nrf2 蛋白水平。9d 可诱导 HO-1、GCLC、GCLM 和 SOD-1 的抗氧化反应基因在 mRNA 和蛋白水平上的表达，并抑制促炎细胞因子和酶。此外，9d 可显著保护 DAergic 神经元并恢复 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的小鼠模型中的 PD 相关运动功能障碍。
