Development of a hydrolysis-based small-molecule hydrogen selenide (H₂Se) donor

Selenium is essential to human physiology and has recently shown potential in the treatment of common pathophysiological conditions ranging from arsenic poisoning to cancer. Although the precise metabolic and chemical pathways of selenium incorporation into biomolecules remain somewhat unclear, many such pathways proceed through hydrogen selenide (H₂Se/HSe^-) formation. Despite this importance, well-characterized chemistry that enables H₂Se release under controlled conditions remains lacking. Motivated by this need, we report here the development of a hydrolysis-based H₂Se donor (TDN1042). Utilizing ³¹P and ⁷⁷Se NMR experiments, we demonstrate the pH dependence of H₂Se release and characterize observed reaction intermediates during the hydrolysis mechanism. Finally, we confirm H₂Se release using electrophilic trapping reagents, which not only demonstrates the fidelity of this donor platform but also provides an efficient method for investigating future H₂Se donor motifs. Taken together, this work provides an early example of an H₂Se donor that functions through a well-defined and characterized mechanism.