Cys fluorescent probe precisely modified by fluorine revealing oxidative stress mechanism in Parkinson's disease

Abstract

Oxidative stress is considered the fundamental pathophysiological mechanism of neurodegenerative diseases such as Parkinson's. Nuclear factor erythroid 2-related factor 2 (Nrf2), as a critical transcription factor for antioxidant response, activating its regulation of biothiol level is deemed an essential pathway for disease mitigation. Cysteine (Cys), an abundant and active biothiol, is a crucial molecule in this antioxidant pathway. To further elucidate these regulatory mechanisms, a specific, rapid, blood-brain barrier-crossing Cys fluorescent probe was demanded. Therefore, we selected isophorone as the parent compound, with bromoacetyl ester as the site responsive to Cys. By introducing fluorine only at the ortho position of bromoacetyl ester, utilizing fluorine's strong electron-withdrawing ability to activate the electrophilicity of methylene and carbonyl groups, probe WSX-F achieved specific and rapid response to Cys. Meanwhile, fluorine lengthened the probe's fluorescence emission wavelength and improved lipophilicity. In situ probe imaging revealed that the activated antioxidant mechanism for Nrf2 will up-regulate the level of Cys cells and the brain in Parkinson's disease, and the differential distribution of Cys in the Parkinson's brain region. The research provided theoretical guidance for preventing and treating Parkinson's disease.