Cysteine-Activated Small-Molecule H₂Se Donors Inspired by Synthetic H₂S Donors

Abstract

The importance of selenium (Se) in biology and health has become increasingly clear. Hydrogen selenide (H₂Se), the biologically available and active form of Se, is suggested to be an emerging nitric oxide (NO)-like signaling molecule<b>.</b> Nevertheless, the research on H₂Se chemical biology has technique difficulties due to the lack of well-characterized and controllable H₂Se donors under physiological conditions, as well as a robust assay for direct H₂Se quantification. Motivated by these needs, here, we demonstrate that selenocyclopropenones and selenoamides are tunable donor motifs that release H₂Se upon reaction with cysteine (Cys) at pH 7.4 and that structural modifications enable the rate of Cys-mediated H₂Se release to be tuned. We monitored the reaction pathways for the H₂Se release and confirmed H₂Se generation qualitatively using different methods. We further developed a quantitative assay for direct H₂Se trapping and quantitation in an aqueous solution, which should also be operative for investigating future H₂Se donor motifs. In addition, we demonstrate that arylselenoamide has the capability of Cys-mediated H₂Se release in cellular environments. Importantly, mechanistic investigations and density functional theory (DFT) calculations illustrate the plausible pathways of Cys-activated H₂Se release from arylselenoamides in detail, which may help understand the mechanistic issues of the H₂S release from pharmacologically important arylthioamides. We anticipate that the well-defined chemistries of Cys-activated H₂Se donor motifs will be useful for studying Se biology and for development of new H₂Se donors and bioconjugate techniques.