Computational Study of H₂S Release in Reactions of Diallyl Polysulfides with Thiols

Abstract

Hydrogen sulfide (HS) is a gasotransmitter molecule recognized for its role in cell signaling. Garlic-derived polysulfides including diallyl disulfide (DADS) and diallyl trisulfide (DATS) have been shown to release HS. We investigated the mechanism of the reaction of DADS and DATS with biological thiols, including cysteine (Cys) and glutathione (GSH), using density functional theory. We propose that Cys and GSH react with DADS and DATS in their anionic forms. Thiol anions are much more likely to attack the sulfur atoms of DADS and DATS than the α-carbon of allyl groups. We found that nucleophilic attack of thiol anions on the peripheral sulfur of DATS is kinetically and thermodynamically more favorable than that on the central sulfur atom, resulting in the formation of allyl perthiol anion (ASS). In the presence of Cys or GSH, HS is released by proton-shuffle from the thiol to ASS, followed by another nucleophilic attack by thiol anion on ASSH. Our computed potential energy surfaces revealed that GSH and Cys are capable of releasing HS from DATS and that DADS is a much poorer HS donor than DATS.

Hydrogen Sulfide Reduces Myeloid-Derived Suppressor Cell-Mediated Inflammatory Response in a Model of Helicobacter hepaticus-Induced Colitis

“…It has to be noted that the mechanisms by which H 2 S is released from DATS have in depth analyzed by several research groups ( 22 , 39 – 42 ). In particular, it has been shown that H 2 S is liberated from DATS in presence of GSH and l -cys ( 43 ). However, sulfane sulfur (polysulfides), rather than H 2 S, are considered the active agent in physiological signaling ( 44 – 47 ).…”

Antimicrobial garlic-derived diallyl polysulfanes: Interactions with biological thiols in Bacillus subtilis

“…ASH can be generated by nucleophilic attack of the cellular thiol at the central S-atom of DAS3 (Scheme 2, path-a), whereas reaction at either of the peripheral S-atoms would generate AS2H (Scheme 2, path-b). Previous computational calculations predict that thiol-polysulfane exchange reactions at the peripheral S-atoms of DAS3 are kinetically more favourable [38]. However, only ASH production is observed in B. subtilis when exposed to DAS3.…”

Hydrogen Sulfide in Pharmacotherapy, Beyond the Hydrogen Sulfide-Donors

“…These effects are believed to be mediated by physiological concentrations of H 2 S. Therefore, H 2 S is now regarded as a third gaseous signaling molecule, next to nitric oxide (NO) and carbon monoxide (CO). In order to develop H 2 S-releasing donors, researchers started to modify chemical structures of well-described sulfide releasing agents, obtaining several H 2 S donors including Lawesson's reagent and analogues [8], DTT (1,2-dithiole-3-thiones) derivatives like ADT-OH, ACS 5, ACS 48 and ACS 50 [9][10][11], diallyl disulfide (DADS) derivatives like ACS 81 [12], arylthioamides (TBZ) [13], aryl isothiocyanates [14] and thiourea derivatives [15] (Figure 1). Interestingly, there are numerous well-established medicines which contain sulfur moieties.…”