Esterase-Activated Perthiocarbonate Persulfide Donors Provide Insights into Persulfide Persistence and Stability

Abstract

Persulfides (RSSH) are important reactive sulfur species (RSS) that are intertwined with the biological functions of hydrogen sulfide (H 2 S). The direct study of persulfides is difficult, however, due to their both nucleophilic and electrophilic character, which leads to the generation of an equilibrium of different RSS. To investigate the effects of persulfides directly, especially in biological systems, persulfide donors are needed to generate persulfides in situ.Here, we report the synthesis of esterase-activated perthiocarbonate persulfide donors and investigate the effects of structural modifications on persulfide release. Although steric bulk of the ester did not significantly alter persulfide release kinetics, increased steric bulk of the thiol increased the persulfide release rate. In addition, we found that the steric bulk and identity of the thiol significantly impact persulfide persistence. Further mechanistic investigations into different competing reaction pathways from perthiocarbonates revealed that multiple RSS can be delivered (i.e., H 2 S, COS, or RSSH) depending on the persulfide donor structure and activator identity.

Hydropersulfides (RSSH) attenuate doxorubicin-induced cardiotoxicity while boosting its anticancer action

“…Similarly, N -acetyl penicillamine ( NAP ), a thiol control that lacks the sulfane sulfur of NAP-SSH also shows mild protection, indicating that AST cytoprotective assets stem from RSSH generation. Although both CysS 3 and AST produce RSSH, the better cytoprotection observed with AST is presumably attributed to its ability to generate a t -alkyl hydropersulfide, which is more persistent than the primary alkyl hydropersulfide generated from CysS 3 [ 58 ]. For comparison with a more traditional antioxidant and cytoprotectant, N -acetyl cysteine ( NAC ) [ 59 , 60 ], shows only mild protection against DOX under our experimental conditions.…”

Thiobenzophenones: tunable hydrolysis-based donors for intracellular H2S delivery

“…S2, ESI†). 8 Meanwhile, thiomichler's ketone can release H 2 S in aqueous solution (Fig. 2), and the H 2 S release was a slow process with the efficiency up to about 10% at 4 h incubation in PBS.…”

“…In recent years, significant progress has been made in the development of synthetic H 2 S donors. 5–11 There are three primary strategies for H 2 S donation, including (1) spontaneous H 2 S release via hydrolysis reaction; 6 (2) H 2 S release triggered by endogenous species ( e.g. , biothiols or enzymes) or external bioorthogonal stimuli ( e.g.…”

“…, light or chemoselective reactions); 7 (3) H 2 S generated from the released carbonyl sulfide (COS) by endogenous carbonic anhydrase (CA). 8 In addition, plenty of H 2 S donors have been reported for further exploring their biological functions and biomedicine applications. 9 For instance, arylthioamides possess unique pharmacological activities and have been used to conjugate to nonsteroidal anti-inflammatory drugs (NSAIDS) for clinical development.…”

A modular scaffold for triggerable and tunable nitroxyl (HNO) generation with a fluorescence reporter

“…9 Together, the sulfane sulfur pool is implicated in numerous cellular stress responses, including protective effects against reactive oxygen species (ROS) and inflammation. 10,11 Hence, platforms for reliable generation of HNO are essential for a better understanding of the chemical biology of this short-lived species.…”