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Mechanistic differences in S/Se chemistry enable direct H₂Se release from selenocarbamates. 

Hydrogen selenide (H2Se) is an emerging bioregulator and precursor to essential selenium-containing biomolecules. We show that aryl isoselenocyanates (ISeC-R) release H2Se upon activation by cysteine, and that electronic substitution can modulate release profiles. We also demonstrate applications to live cell imaging, expanding available tools for investigating H2Se chemical biology. 

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 (H 2 Se/HSe − ) formation. Despite this importance, well-characterized chemistry that enables H 2 Se release under controlled conditions remains lacking. Motivated by this need, we report here the development of a hydrolysis-based H 2 Se donor (TDN1042). Utilizing 31 P and 77 Se NMR experiments, we demonstrate the pH dependence of H 2 Se release and characterize observed reaction intermediates during the hydrolysis mechanism. Finally, we confirm H 2 Se release using electrophilic trapping reagents, which not only demonstrates the fidelity of this donor platform but also provides an efficient method for investigating future H 2 Se donor motifs. Taken together, this work provides an early example of an H 2 Se donor that functions through a well-defined and characterized mechanism. 

Dithioesters have a rich history in polymer chemistry for RAFT polymerizations and are readily accessible through different synthetic methods. Here we demonstrate that the dithioester functional group is a tunable motif that releases H 2 S upon reaction with cysteine and that structural and electronic modifications enable the rate of cysteine-mediated H 2 S release to be modified. In addition, we use (bis)phenyl dithioester to carry out kinetic and mechanistic investigations, which demonstrate that the initial attack by cysteine is the rate-limiting step of the reaction. These insights are further supported by complementary DFT calculations. We anticipate that the results from these investigations will allow for the further development of dithioesters as important chemical motifs for studying H 2 S chemical biology.