期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 10, 期 7, 页码 1061-1067出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.9b00163
关键词
Parkinson's disease; antioxidant; anti-inflammatory; Nrf2/Keapl pathway; MPTP mouse model; vinyl sulfone
资金
- National Research Council of Science & Technology grant, South Korean government (MSIP) [CRC-15-04-KIST]
- National Research Foundation of Korea [NRF-2018M3A9C8016849]
- National Research Foundation of Korea [2018M3A9C8016849] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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 (1) 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, 3c exhibited 6.9- and 83.S-fold higher effects on Nrf2 activation than the corresponding vinyl sulfone (1) and vinyl sulfonamide (2c), respectively. Compound 3c was confirmed to induce expression of the Nrf2-dependent antioxidant enzymes at the protein level in cells. In addition, 3c mitigated PD-associated behavioral deficits by protecting DAergic neurons in the MPTP-induced mouse model of PD.
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