Exploring the large-scale regulation of hydrogen selenide release rate by selenoanhydride structures and their cytotoxic effects toward 4T1 cells

Abstract

Hydrogen selenide (H₂Se) serves as a critical metabolic intermediate in the biosynthesis of selenoproteins. However, its investigation has been impeded by the scarcity of controllable H₂Se donors. This study introduces cyclic selenoanhydride derivatives as innovative H₂Se donors. Nine compounds featuring diverse substituents were synthesized, and their hydrolysis in phosphate-buffered saline (PBS) released H₂Se at rates dictated by their structural characteristics. Their release half-lives have a wide range from 2.76 hours to 385.08 hours. Specifically, aliphatic ring strain accelerates ring-opening hydrolysis, whereas aromatic ring substituents modulate reactivity: electron-donating groups stabilize the selenoanhydrides (thereby reducing hydrolysis), while electron-withdrawing groups enhance reactivity. In 4T1 cell assays, these donors exhibited concentration-dependent growth inhibition with varying efficacies, which was attributed to differences in their half-lives and molecular structures. This work elucidates that fine-tuning the ring size and substituents enables precise regulation of H₂Se release, thus providing a promising strategy for the rational design of H₂Se donors.