Stimulus-Responsive Perselenide, Thioselenide, and Selenosulfide Donors for Reactive Selenium Species Chemical Biology

Reactive selenium species (RSeS), including perselenides (RSeSeH), thioselenides (RSSeH), and selenosulfides (RSeSH), have long been proposed as fleeting yet biologically important intermediates in hydrogen selenide (H₂Se) signaling and cellular redox regulation. However, their inherent instability and the absence of suitable small-molecule precursors have precluded direct experimental access under physiologically relevant conditions. Here, we report the first synthesis, isolation, and comprehensive characterization of a stimulus-responsive donor platform capable of controlled RSeS generation in biological environments. These donors employ a modular 1,6-elimination architecture that enables precisely triggered release of discrete RSeS, exemplified here by esterase activation, with tunable stability and release kinetics achieved through systematic electronic and steric modification of the dichalcogenide framework and supported by computational analysis. Importantly, studies under thiol-rich conditions reveal that thioselenide and perselenide donors converge to generate common RSeS, providing mechanistic insights into their behavior in cellular settings. Consistent with this finding, biological evaluation demonstrates that thioselenide and perselenide donors exhibit exceptionally potent antioxidative activity─effective at concentrations up to 100-fold lower than those of sulfur analogs (RSSH)─and pronounced antiproliferative effects in cancer cells. Collectively, this work establishes an entirely new and tunable class of RSeS donors and introduces the first general platform for the controlled generation of RSeSeH, RSSeH, and RSeSH, enabling systematic investigation of their reactivity, redox signaling, and therapeutic potential in both simplified buffer systems and living cells.