Discovery of Vinyl Sulfones as a Novel Class of Neuroprotective Agents toward Parkinson's Disease Therapy

Title
Discovery of Vinyl Sulfones as a Novel Class of Neuroprotective Agents toward Parkinson's Disease Therapy
Authors
우서연김지현문미경한세희연슬기최지원장보고송효정강용구김진우이재익김동진황온유박기덕
Keywords
Parkinson's Disease; Nrf2 activation; Keap1/Nrf2 pathway; vinyl sulfone compound; MPTP mouse model; anti-oxidant activity
Issue Date
2014-02
Publisher
Journal of medicinal chemistry
Citation
VOL 57, 1473-1487
Abstract
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.
URI
http://pubs.kist.re.kr/handle/201004/47331
ISSN
00222623
Appears in Collections:
KIST Publication > Article
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