CO Sense and Release Flavonols: Progress toward the Development of an Analyte Replacement PhotoCORM for Use in Living Cells

Abstract

Carbon monoxide (CO) is a signaling molecule in humans. Prior research suggests that therapeutic levels of CO can have beneficial effects in treating a variety of physiological and pathological conditions. To facilitate understanding of the role of CO in biology, molecules that enable fluorescence detection of CO in living systems have emerged as an important class of chemical tools. A key unmet challenge in this field is the development of fluorescent analyte replacement probes that replenish the CO that is consumed during detection. Herein, we report the first examples of CO sense and release molecules that involve combining a common CO-sensing motif with a light-triggered CO-releasing flavonol scaffold. A notable advantage of the flavonol-based CO sense and release motif is that it is trackable via fluorescence in both its pre- and postsensing (pre-CO release) forms. In vitro studies revealed that the PdCl2 and Ru­(II)-containing CORM-2 used in the CO sensing step can result in metal coordination to the flavonol, which minimizes the subsequent CO release reactivity. However, CO detection followed by CO release is demonstrated in living cells, indicating that a cellular environment mitigates the flavonol/metal interactions.

Visible-to-NIR-Light Activated Release: From Small Molecules to Nanomaterials

“… 1111 When combined with PdCl 2 , the allyl-protected flavonol derivative 211 was shown to act as an OFF-ON fluorescent CO sensor that replenishes the CO consumed during detection. 1113 A similar approach was used by Tang and co-workers, who designed the hydrogen peroxide-sensitive compound 212 . 1114 Oxidation of this compound’s pinacol boronate ester by hydrogen peroxide liberates free 205 , which can subsequently photorelease CO.…”

“…1111 When combined with PdCl 2 , the allyl-protected flavonol derivative 211 was shown to act as an OFF-ON fluorescent CO sensor that replenishes the CO consumed during detection. 1113 A similar approach was used 1115,1116 Flavonol derivatives substituted with polar groups such as triphenylphosphonium (214) were found to target mitochondria and affect cellular bioenergetics. 1117 However, the sulfonated analog 215 did not penetrate through the cell membrane and thus enabled extracellular CO release.…”

“…An acryloyl-protected derivative 209 , was activated by thiols including cysteine, while the cyanate-substituted compound 210 proved suitable for intracellular H 2 S sensing . When combined with PdCl 2 , the allyl-protected flavonol derivative 211 was shown to act as an OFF-ON fluorescent CO sensor that replenishes the CO consumed during detection . A similar approach was used by Tang and co-workers, who designed the hydrogen peroxide-sensitive compound 212 .…”

Recent Advances in Fluorescence Light‐Up Endogenous and Exogenous Carbon Monoxide Detection in Biology

“…Further, 1 is the first imageable analyte replacement photoCORM reported for the use in living cells. [66]…”

“…Thus, subsequent reaction with O 2 in the presence of light makes the cell image non‐emissive (Figure ). Further, 1 is the first imageable analyte replacement photoCORM reported for the use in living cells …”