An Innovative Hydrogen Peroxide‐Sensing Scaffold and Insight Towards its Potential as an ROS‐Activated Persulfide Donor

Abstract

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.

Convenient and flexible syntheses of gem-dimethyl carboxylic triggers via mono-selective β-C(sp3)–H arylation of pivalic acid with ortho-substituted aryl iodides

“…The total yield over 2-steps can reach 47% (Scheme 2a). In recent years, the biochemical properties of aryl boronic acids and boronate esters have been exploited in some important applications, such as ROS-responsive prodrugs and probes, 11,25 dynamic covalent chemistry, and protein modification. 26…”

“…Recently, Lukesh and coworkers 11 utilized a gem-dimethyl carboxylic moiety mimicking the TML to develop a reactiveoxygen-species (ROS) sensing platform (Fig. 1b).…”

“…Further research indicated that the gem-dimethyl group is crucial to promote cyclization and keep stability of the adjacent ester linkage versus (enzymatic) hydrolyzation. 11,12 Besides this ROSactivated pattern, (bio)reductive 7a-c,8e,9a-c,10,12 and esterasesensitive 7d,8a-c,9d,13 mechanisms are the most popular triggers used based on TML lactonization or lactamization. However, methods for their syntheses largely rely on traditional approaches.…”

Leveraging an enzyme/artificial substrate system to enhance cellular persulfides and mitigate neuroinflammation

“…Other strategies for generating persulfides in cells have relied on installing the persulfide/ polysulfide functional group in the donor. 5,6,41,[43][44][45][46][47][48][49][50][51][52][53] These strategies work very well but have limitations in the ease of synthesis, poor shelf-life due to susceptibility towards decomposition, and heterogeneity of the persulfide source due to the ambiguity in the number of sulfurs in the donor. The protocol developed here involves the synthesis of a thioacetate, which is easy to prepare with high reproducibility and is stable for extended periods.…”