Choi Ji Won, Shin Su Jeong, Kim Hyeon Ji, Park Jong-Hyun, Kim Hyeon Jeong, Lee Elijah Hwejin, Pae Ae Nim, Bahn Yong Sun, Park Ki Duk
Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
Department of Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.
ACS Med Chem Lett. 2019 Jun 3;10(7):1061-1067. doi: 10.1021/acsmedchemlett.9b00163. eCollection 2019 Jul 11.
The main pathway responsible for cellular regulation against oxidative stress is nuclear factor E2-related factor-2 (Nrf2) signaling. We previously synthesized and reported a novel vinyl sulfone () as an Nrf2 activator with therapeutic potential for Parkinson's disease (PD). In this study, we changed the vinyl sulfone to vinyl sulfonamide or vinyl sulfonate to improve Nrf2 activating efficacy. We observed that the introduction of vinyl sulfonamide led to a reduction of the effects on Nrf2 activation, whereas vinyl sulfonate compounds exhibited superior activity compared to the vinyl sulfone compounds. Among the vinyl sulfonates, exhibited 6.9- and 83.5-fold higher effects on Nrf2 activation than the corresponding vinyl sulfone () and vinyl sulfonamide (), respectively. Compound was confirmed to induce expression of the Nrf2-dependent antioxidant enzymes at the protein level in cells. In addition, mitigated PD-associated behavioral deficits by protecting DAergic neurons in the MPTP-induced mouse model of PD.
负责细胞对抗氧化应激调节的主要途径是核因子E2相关因子2（Nrf2）信号通路。我们之前合成并报道了一种新型乙烯基砜（）作为Nrf2激活剂，对帕金森病（PD）具有治疗潜力。在本研究中，我们将乙烯基砜改为乙烯基磺酰胺或乙烯基磺酸盐，以提高Nrf2激活功效。我们观察到，引入乙烯基磺酰胺会导致对Nrf2激活的作用降低，而乙烯基磺酸盐化合物与乙烯基砜化合物相比表现出更高的活性。在乙烯基磺酸盐中，对Nrf2激活的作用分别比相应的乙烯基砜（）和乙烯基磺酰胺（）高6.9倍和83.5倍。化合物被证实在细胞中蛋白质水平上诱导Nrf2依赖性抗氧化酶的表达。此外，在MPTP诱导的PD小鼠模型中，通过保护多巴胺能神经元减轻了PD相关的行为缺陷。
