Cysteine-Activated Small-Molecule H 2 Se Donors Inspired by Synthetic H 2 S Donors

• Published in: Journal of the American Chemical Society 2022-03, Vol.144 (9), p.3957-3967
• Main Authors: Kang, Xueying, Huang, Haojie, Jiang, Chenyang, Cheng, Longhuai, Sang, Yueqian, Cai, Xuekang, Dong, Yalun, Sun, Lu, Wen, Xin, Xi, Zhen, Yi, Long
• Format: Article
• Language: English
• Subjects: Cysteine; Hydrogen Sulfide - chemistry; Selenium; Water
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.1c12006

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