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

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.