Hydrogen Peroxide-Responsive Triggers Based on Borinic Acids: Molecular Insights into the Control of Oxidative Rearrangement.

Arylborinic acids represent new, efficient, and underexplored hydrogen peroxide-responsive triggers. In contrast to boronic acids, two concomitant oxidative rearrangements are involved in the complete oxidation of these species, which might represent a major limitation for an efficient effector (drug or fluorophore) release. Herein, a comprehensive study of H2 O2 -mediated unsymmetrical arylborinic acid oxidation to investigate the factors that could selectively guide their oxidative rearrangement is described. The o-CF3 substituent was found to be an excellent directing group allowing a complete regioselectivity on borinic acid models. This result was successfully applied to synthesizing new borinic acid-based fluorogenic probes, which exclusively release the fluorescent moiety upon H2 O2 treatment. These compounds maintained their superior kinetic properties compared to boronic acids, thus further enhancing the potential of arylborinic acids as valuable new H2 O2 -sensitive triggers.

Evaluation of borinic acids as new, fast hydrogen peroxide-responsive triggers.

Hydrogen peroxide (H2O2) is responsible for numerous damages when overproduced, and its detection is crucial for a better understanding of H2O2-mediated signaling in physiological and pathological processes. For this purpose, various "off-on" small fluorescent probes relying on a boronate trigger have been prepared, and this design has also been involved in the development of H2O2-activated prodrugs or theranostic tools. However, this design suffers from slow kinetics, preventing activation by H2O2 with a short response time. Therefore, faster H2O2-reactive groups are awaited. To address this issue, we have successfully developed and characterized a prototypic borinic-based fluorescent probe containing a coumarin scaffold. We determined its in vitro kinetic constants toward H2O2-promoted oxidation. We measured 1.9 × 104 m-1⋅s-1 as a second-order rate constant, which is 10,000-fold faster than its well-established boronic counterpart (1.8 m-1⋅s-1). This improved reactivity was also effective in a cellular context, rendering borinic acids an advantageous trigger for H2O2-mediated release of effectors such as fluorescent moieties.