An ROS-Responsive Donor That Self-Reports Its H2S Delivery by Forming a Benzoxazole-Based Fluorophore.

Abstract

Hydrogen sulfide (H2S), an endogenous signaling molecule, is known to play a pivotal role in neuroprotection, vasodilation, and hormonal regulation. To further explore the biological effects of H2S, refined donors that facilitate its biological delivery, especially under specific (patho) physiological conditions, are needed. In the present study, we demonstrate that ortho-substituted, aryl boronate esters provide two unique and distinct pathways for H2S release from thioamide-based donors: Lewis acid-facilitated hydrolysis and reactive oxygen species (ROS)-induced oxidation/cyclization. Through a detailed structure-activity relationship study, donors that resist hydrolysis and release H2S solely via the latter mechanism were identified, which have the added benefit of providing a potentially useful heterocycle as the lone byproduct of this novel chemistry. To highlight this, we developed an ROS-activated donor (QH642) that simultaneously synthesizes a benzoxazole-based fluorophore en route to its H2S delivery. A distinct advantage of this design over earlier self-reporting donors is that fluorophore formation is possible only if H2S has been discharged from the donor. This key feature eliminates the potential for false positives and provides a more accurate depiction of reaction progress and donor delivery of H2S, including in complex cellular environments.