Photochemical Release of Hydropersulfides.

Hydropersulfides (RSSH) have received significant interest in the field of redox biology because of their intriguing biochemical properties. However, because RSSH are inherently unstable, their study is challenging, and as a result, the details of their physiological roles remain ill-defined. Herein, we report strategies to release RSSH utilizing photoremovable protecting groups. RSSH protection with the well-established p-hydroxyphenacyl (pHP) photoprotecting group resulted in inefficient RSSH photorelease along with complex chemistry. Therefore, an alternative precursor was examined in which a self-immolative linker was inserted between the pHP group and RSSH, providing nearly quantitative RSSH release following photolysis at 365 nm. Inspired by these results, we also synthesized an analogous precursor derivatized with 7-diethylaminocoumarin (DEACM), a visible light-cleavable photoprotecting group. Photolysis of this precursor at 420 nm led to efficient RSSH release, and in vitro experiments demonstrated intracellular RSSH delivery in breast cancer MCF-7 cells.

Development of Hydropersulfide Donors to Study Their Chemical Biology.

Significance: Hydropersulfides (RSSH) are ubiquitous in prokaryotes, eukaryotic cells, and mammalian tissues. The unique chemical properties and prevalent nature of these species suggest a crucial role of RSSH in cell regulatory processes, yet little is known about their physiological functions. Recent Advances: Examining the biological roles of RSSH species is challenging because of their inherent instability. In recent years, researchers have developed a number of small-molecule donors that efficiently release RSSH in response to various stimuli, including pH, thiols, reactive oxygen species, enzymes, and light. These RSSH donors have provided researchers with chemical tools to uncover the potential function and role of RSSH as physiological signaling and/or protecting agents. Critical Issues: Because RSSH, hydrogen sulfide (H2S), and higher order polysulfides are related to each other and can be present simultaneously in biological systems, distinguishing among the activities due to each of these species is difficult. Discerning this activity is critical to elucidate the chemical biology and physiology of RSSH. Moreover, although RSSH donors have been shown to confer cytoprotection against oxidative and electrophilic stress, their biological targets remain to be elucidated. Future Directions: The development of RSSH donors with optimal drug-like properties and selectivity toward specific tissues/pathologies represents a promising approach. Further investigation of releasing efficiencies in vivo and a clear understanding of RSSH biological responses remain targets for future investigation. Antioxid. Redox Signal. 36, 309-326.

Alkylsulfenyl thiocarbonates: precursors to hydropersulfides potently attenuate oxidative stress.

The recent discovery of the prevalence of hydropersulfides (RSSH) species in biological systems suggests their potential roles in cell regulatory processes. However, the reactive and transient nature of RSSH makes their study difficult, and dependent on the use of donor molecules. Herein, we report alkylsulfenyl thiocarbonates as a new class of RSSH precursors that efficiently release RSSH under physiologically relevant conditions. RSSH release kinetics from these precursors are tunable through electronic modification of the thiocarbonate carbonyl group's electrophilicity. In addition, these precursors also react with thiols to release RSSH with a minor amount of carbonyl sulfide (COS). Importantly, RSSH generation by these precursors protects against oxidative stress in H9c2 cardiac myoblasts. Furthermore, we demonstrate the ability of these precursors to increase intracellular RSSH levels.