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

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• 作者：Seo Yeon Woo ; Ji Hyun Kim ; Mi Kyeong Moon ; Se-Hee Han ; Seul Ki Yeon ; Ji Won Choi ; Bo Ko Jang ; Hyo Jung Song ; Yong Gu Kang ; Jin Woo Kim ; Jaeick Lee ; Dong Jin Kim ; Onyou Hwang ; Ki Duk Park
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：February 27, 2014
• 年：2014
• 卷：57
• 期：4
• 页码：1473-1487
• 全文大小：543K
• 年卷期：v.57,no.4(February 27, 2014)
• ISSN：1520-4804

文摘

Although the etiology of Parkinson鈥檚 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.