Small molecule persulfides (R–SSH) have recently been recognized as key players in redox balance and cell signaling, but the extent of their biological roles remains unclear. Early research into small molecule persulfides (R–SSH) has been hampered by a lack of donor molecules, as the few examples of persulfide donors in the literature suffer from limited benchtop stability, poorly understood release mechanisms, and/or ill-defined persulfide species. In addition, the persulfide donors that are currently available have half-lives (t1/2 &lt; 1 h) that make them unsuitable for the treatment chronic disease conditions. To mitigate the issues of persulfide stability, ill-defined persulfide species being released, and short release half-life we report the synthesis of a family of tunable protected N-acetyl cysteine (NAC) persulfide prodrugs. Communicated here is the synthesis and characterization of an esterase responsive persulfide-releasing prodrug, termed EDP-NAC, and its polymeric counterpart poly(EDP-NAC). The prodrugs display excellent benchtop stability and release the desired NAC persulfide with half-lives ranging from 1.7 ± 0.3 h – 37 ± 1.5 h, as determined by 1H NMR spectroscopy and LCMS. Additionally, the persulfide prodrugs were found to be nontoxic in the presence of H9c2 myoblasts at concentrations nearing 1 mM. EDP-NAC was shown to exhibit strong ROS-quenching effects, allowing cells to retain 80% cell viability in the presence of H2O2. Poly(EDP-NAC), with its extended half-life, exhibited sustained anti-inflammatory effects, rescuing cells from equimolar 5-fluorouracil exposure and retaining 100% cell viability.

Persulfide prodrugs with extended release kinetics

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.