Fluorogenic Probe Using a Mislow-Evans Rearrangement for Real-Time Imaging of Hydrogen Peroxide
Hydrogen peroxide (H2O2) is a second messenger that mediates the biology of wound healing, apoptosis, inflammation, aging, neurodegenerative diseases, and more. Its presence has been fluorometrically imaged with protein- or small molecule-based sensors. However, only protein-based sensors have afforded temporal insights with the resolution of seconds. Small molecule-based fluorogenic probes are preferred for various reasons; however, current electrophilic chemosensors react with H2O2 slowly, requiring >20 minutes for a sufficient response. Here, we report a fluorogenic probe that selectively reacts with H2O2 and undergoes a [2,3]-sigmatropic rearrangement (seleno-Mislow-Evans rearrangement) followed by an acetal hydrolysis to produce a green fluorescent molecule in seconds. The mode of reaction is based on the umpolung of previously developed sensors; the probe acts as a nucleophile rather than an electrophile. The fast kinetics outcompete the reaction between thiols and H2O2, enabling real-time imaging of H2O2 produced inside the subcellular compartments of cells in 8 seconds. Further, the probe was able to recapitulate data previously observed only with a genetically encoded protein-based sensor. The present probe design provides a platform that can match the temporal resolution of protein-based H2O2 detection.
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in Angewandte Chemie International Edition