Reactive sulfur species,s uch as hydrogen sulfide, persulfides,a nd polysulfides,h ave recently emerged as key signaling molecules and important physiological mediators within mammalian systems.T ob etter assess the therapeutic potential of their exogenous administration, we report on the development of au nique hydrogen peroxide (H 2 O 2)-sensing motif and its capacity for providing cellular protection against oxidative stress while serving as ar eactive oxygen species (ROS)-activated persulfide donor.W ith the strategic implementation of ag em-dimethyl group to promote both stability and cyclization, we found the initial rate of payloadr elease from this newly derived scaffold to be directly proportional to the concentration of H 2 O 2 and to proceed via an unprecedented pathway that avoids the production of electrophilic byproducts, asevere limitation that has plagued the physiological application of previous designs.
Similar to hydrogen sulfide (H2S), its chalcogen congener, Hydrogen selenide (H2Se), is an emerging molecule of interest given its endogenous expression and purported biological activity. However, unlike H2S, detailed investigations...
Arylthioamides have been frequently employed to assess the chemical biology and pharmacology of hydrogen sulfide (H2S). From this class of donors, however, extremely low H2S releasing efficiencies have been reported and proper mechanistic studies have been omitted. Consequently, millimolar concentrations of arylthioamides are required to liberate just trace amounts of H2S, and via an unidentified mechanistic pathway, which obfuscates the interpretation of any biological activity that stems from their use. Herein, we report that H2S release from this valuable class of donors can be markedly enhanced through intramolecular nucleophilic assistance. Specifically, we demonstrate that both disulfide‐ and diselenide‐linked thioamides are responsive to biologically relevant concentrations of glutathione and release two molar equivalents of H2S via an intramolecular cyclization that significantly augments their rate and efficiency of sulfide delivery in both buffer and live human cells.
Reactive sulfur species,s uch as hydrogen sulfide, persulfides,a nd polysulfides,have recently emerged as key signaling molecules and important physiological mediators within mammalian systems.T ob etter assess the therapeutic potential of their exogenous administration, we report on the development of au nique hydrogen peroxide (H 2 O 2)-sensing motif and its capacity for providing cellular protection against oxidative stress while serving as ar eactive oxygen species (ROS)-activated persulfide donor.W ith the strategic implementation of ag em-dimethyl group to promote both stability and cyclization, we found the initial rate of payloadr elease from this newly derived scaffold to be directly proportional to the concentration of H 2 O 2 and to proceed via an unprecedented pathway that avoids the production of electrophilic byproducts, asevere limitation that has plagued the physiological application of previous designs.
Arylthioamides have been frequently employed to assess the chemical biology and pharmacology of hydrogen sulfide (H 2 S). From this class of donors, however, extremely low H 2 S releasing efficiencies have been reported and proper mechanistic studies have been omitted. Consequently, millimolar concentrations of arylthioamides are required to liberate just trace amounts of H 2 S, and via an unidentified mechanistic pathway, which obfuscates the interpretation of any biological activity that stems from their use. Herein, we report that H 2 S release from this valuable class of donors can be markedly enhanced through intramolecular nucleophilic assistance. Specifically, we demonstrate that both disulfide-and diselenide-linked thioamides are responsive to biologically relevant concentrations of glutathione and release two molar equivalents of H 2 S via an intramolecular cyclization that significantly augments their rate and efficiency of sulfide delivery in both buffer and live human cells.
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