Development of Hydropersulfide Donors to Study Their Chemical Biology

Hydropersulfides Inhibit Lipid Peroxidation and Protect Cells from Ferroptosis

“…Given the instability of RSSH in aqueous solution, we considered whether in situ formation could improve RTA efficiency. ,, The Toscano group has developed RSSH precursors characterized by various release rates under physiological conditions; deprotonation at pH 7.4 initiates RSSH formation by elimination from S -alkylsulfenyl isothioureas ( 4 ) and intramolecular substitution on N -alkylamine perthiocarbamates ( 5 ), while S -alkylsulfenyl thiocarbonates ( 6 ) undergo hydrolysis to afford RSSH (Figure A). We selected examples of each of these precursors to probe the impact of both half-life and polarity on their ability to suppress (phospho)­lipid peroxidation.…”

“…Due to the intrinsic instability of RSSH in aqueous solutions, model studies of their reactivity have benefitted from small molecules that are able to slowly and steadily release them, minimizing their decomposition under relevant conditions. ,, The reactivity of the three types of precursors studied above depended significantly on the polarity of the initiator of (phospho)­lipid peroxidation. When DTUN, the lipophilic hyponitrite typically used in the FENIX assay, was used, only the N -alkylamine perthiocarbamates displayed significant activity.…”

“…Sulfhydration of protein cysteine thiols has emerged as a ubiquitous physiologic post-translation modification. − Reactions of the resultant hydropersulfides (RSSH)and the polysulfides (RSS n R) derived therefromare widely believed to exert the biological effects attributed to H 2 S. − Numerous reports suggest that RSSH derived from cysteine and glutathione are omnipresent in mammalian cells, tissue, and plasma, prompting intensive investigations of their role. , Given the substantially enhanced nucleophilicity of RSSH relative to thiols (RSH), , they are often invoked as intermediates in cellular signaling pathways that respond to electrophile and/or oxidant stress ,− (Figure A, top). Importantly, while protein thiol modification/oxidation is generally irreversible, protein hydropersulfides can be reduced to restore protein thiols once the stress is resolved. ,,, Alternativelyor in addition to a signaling functionsulfhydration may have evolved as a direct protective mechanism against electrophilic/oxidative stress.…”

Photochemical Release of Hydropersulfides

“…Small molecules that can efficiently generate RSSH under physiological conditions are important research tools for investigating their roles in cellular processes. , Several donor molecules have been developed that release RSSH in the presence of specific stimuli such as cellular thiols, reactive oxygen species (ROS), − pH, − and enzymes. − Interestingly, several recent studies show that pharmacological application of RSSH species can inhibit/prevent cellular damage resulting from oxidative/electrophilic stress. ,, However, many RSSH precursors suffer from limitations, including a lack of controllable release kinetics and electrophilic byproduct formation. The photochemical release of biomolecules from light-sensitive precursors has been a longstanding strategy in biological research as it offers both spatial and temporal control over the administration of effector species.…”

“…Small molecules that can efficiently generate RSSH under physiological conditions are important research tools for investigating their roles in cellular processes. 14,15 Several donor molecules have been developed that release RSSH in the presence of specific stimuli such as cellular thiols, 16 reactive oxygen species (ROS), 17−19 pH, 20−22 and enzymes. 23−26 Interestingly, several recent studies show that pharmacological application of RSSH species can inhibit/prevent cellular damage resulting from oxidative/electrophilic stress.…”