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

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. Nrf...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2014-02, Vol.57 (4), p.1473-1487
Main Authors: Woo, Seo Yeon, Kim, Ji Hyun, Moon, Mi Kyeong, Han, Se-Hee, Yeon, Seul Ki, Choi, Ji Won, Jang, Bo Ko, Song, Hyo Jung, Kang, Yong Gu, Kim, Jin Woo, Lee, Jaeick, Kim, Dong Jin, Hwang, Onyou, Park, Ki Duk
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Cell Line
Disease Models, Animal
DNA Primers
Heme Oxygenase-1 - genetics
Humans
Magnetic Resonance Spectroscopy
Neuroprotective Agents - chemistry
Neuroprotective Agents - therapeutic use
Oxidative Stress
Parkinson Disease - drug therapy
Parkinson Disease - metabolism
Reverse Transcriptase Polymerase Chain Reaction
Spectrometry, Mass, Electrospray Ionization
Sulfones - chemistry
Sulfones - therapeutic use
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm401788m