Effects of sulfane sulfur content in benzyl polysulfides on thiol-triggered H2S release and cell proliferation

Abstract

Investigations into hydrogen sulfide (H 2 S) signaling pathways have demonstrated both the generation and importance of persulfides, which are reactive sulfur species that contain both reduced and oxidized sulfur. These observations have led researchers to suggest that oxidized sulfur species, including sulfane sulfur (S 0), are responsible for many of the physiological phenomena initially attributed to H 2 S. A common method of introducing S 0 to biological systems is the administration of organic polysulfides, such as diallyl trisulfide (DATS). However, prior reports have demonstrated that commercially-available DATS often contains a mixture of polysulfides, and furthermore a lack of structure-activity relationships for organic polysulfides has limited our overall understanding of different polysulfides and their function in biological systems. Advancing our interests in the chemical biology of reactive sulfur species including H 2 S and S 0 , we report our investigations into the rates and quantities of H 2 S release from a series of synthetic, pure benzyl polysulfides, ranging from monosulfide to tetrasulfide. We demonstrate that H 2 S is only released from the trisulfide and tetrasulfide, and that this release requires thiol-mediated reduction in the presence of cysteine or reduced glutathione. Additionally, we demonstrate the different effects of trisulfides and tetrasulfides on cell proliferation in murine epithelial bEnd.3 cells.

Modified cyclodextrins solubilize elemental sulfur in water and enable biological sulfane sulfur delivery

“…Although prior studies have investigated how different functional groups on polysulde motifs impacts H 2 S release, one limitation of these systems is that all of these compounds also generate organic byproducts upon H 2 S release. 12,37 As expected, a higher S 0 content in organic polysuldes leads to greater H 2 S release, although tetrasuldes appear to be the largest synthetically-accessible and consistently-stable polysuldes. Using a similar logic of trying to maximize the S 0 content per donor motif, we envisioned that the solubilized 2HPb/S 8 complex could also function as an entirely new approach to deliver S 0 and/or H 2 S. Importantly, since S 8 is comprised entirely of S 0 it should be an effective donor, with the only byproduct being 2HPb.…”

“…These systems present divergent reactivity based on the polysulde chain length and pendant alkyl group. 12 Inorganic polysuldes in particular are unstable in aqueous conditions and quickly equilibrate to different polysulde mixtures. 13 Despite these fundamental challenges, available S 0 sources demonstrate signicant promise in different systems, ranging from anticancer properties in several human cell lines [14][15][16][17] to enhanced antioxidative activity.…”

SG1002 and Catenated Divalent Organic Sulfur Compounds as Promising Hydrogen Sulfide Prodrugs

“…Remarkably, Xu et al (280) found that DBTS-which they used as a reference standard in their anticancer assaysconsistently displayed the highest anticancer activity. As already mentioned, toxicity against normal cells may increase on increasing the number of tethering sulfur atoms, as shown by Pluth et al (35) for DBTS and DBTTS, and by Schneider et al (213) for DAS, DADS, and DATTS.…”

Glutathione–Allylsulfur Conjugates as Mesenchymal Stem Cells Stimulating Agents for Potential Applications in Tissue Repair

“…The cytotoxicity of OSCs and H 2 S-donors in general likely depends on their concentration per cell and on their metabolic rate in the cells, which in turn depends on the cell type. The exogenous H 2 S can have pro- [15][16][17][18] or anti-apoptotic effects [19][20][21][22], depending on the individual cell phenotype and on the experimental settings used, such as the concentration of H 2 S. Previous studies suggest that garlic-derived OSCs selectively induce programmed cell death in neoplastic cells but not in their physiological counterparts or adult stem cells [23][24][25][26][27][28][29][30]. H 2 S is able, in fact, to improve cell survival in a cell-specific manner by activation of molecular signalling [31].…”