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Discovery of a Redox-Activatable Chemical Probe for Detection of Cyclooxygenase-2 in Cells and Animals


Uddin MJMd Jashim , Lo JHJustin Han-Je , Oltman CGConnor G , Crews BCBrenda C , Huda TTamanna , Liu JJustin , Kingsley PJPhilip J , Lin SShuyang , Milad MMathew , Aleem AMAnsari M , Asaduzzaman AAbu , McIntyre JOJ Oliver , Duvall CLCraig L , Marnett LJLawrence J . ACS chemical biology. 2022 7 5; 17(7). 1714-1722


Cyclooxygenase-2 (COX-2) expression is up-regulated in inflammatory tissues and many premalignant and malignant tumors. Assessment of COX-2 protein in vivo, therefore, promises to be a powerful strategy to distinguish pathologic cells from normal cells in a complex disease setting. Herein, we report the first redox-activatable COX-2 probe, fluorocoxib Q (FQ), for in vivo molecular imaging of pathogenesis. FQ inhibits COX-2 selectively in purified enzyme and cell-based assays. FQ exhibits extremely low fluorescence and displays time- and concentration-dependent fluorescence enhancement upon exposure to a redox environment. FQ enters the cells freely and binds to the COX-2 enzyme. FQ exhibits high circulation half-life and metabolic stability sufficient for target site accumulation and demonstrates COX-2-targeted uptake and retention in cancer cells and pathologic tissues. Once taken up, it undergoes redox-mediated transformation into a fluorescent compound fluorocoxib Q-H that results in high signal-to-noise contrast and differentiates pathologic tissues from non-pathologic tissues for real-time in vivo imaging.