Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 57, Issue 4, Pages 1473-1487Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm401788m
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Funding
- Korea Institute of Science and Technology (KIST) [2E23870, 2E22520]
- Korea Health Technology RD Project
- Ministry of Health and Welfare [HI12C1022]
- National Agenda Project from Korea Research Council of Fundamental Science and Technology
- National Research Foundation of Korea [NRF-2009-0081674, NRF-2009-0081675]
- Korea Health Promotion Institute [HI12C1022020014] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- National Research Council of Science & Technology (NST), Republic of Korea [2E24670, 2E23870] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Although the etiology of Parkinson's disease (PD) remains elusive, recent studies suggest that oxidative stress contributes to the cascade leading to dopaminergic (DAergic) neurodegeneration. The Nrf2, signaling is the main pathway responsible for cellular defense system against oxidative stress. Nrf2 is a transcription factor that regulates environmental stress response by inducing expression of antioxidant enzyme genes. We have synthesized novel vinyl sulfone derivatives. They exhibited a broad range of activities in inducing HO-1, whose gene expression is under the control of Nrf2. Among them, compound 12g was confirmed to activate Nrf2 and induce expression of the Nrf2-dependent antioxidant enzymes NQO1, GCLC, GLCM, and HO-1, at both mRNA and protein levels in DAergic neuronal cells. This was accompanied by protection of DAergic neurons in both in vitro and MPTP-induced in vivo models of PD. In addition, compound 12g effectively resulted in attenuation of the PD-associated behavioral deficits in the mouse model.
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