O→S Relay Deprotection: A General Approach to Controllable Donors of Reactive Sulfur Species

Abstract

Reactive sulfur species (RSS) are biologically important molecules. Among them, H S, hydrogen polysulfides (H S n>1), persulfides (RSSH), and HSNO are believed to play regulatory roles in sulfur-related redox biology. However, these molecules are unstable and difficult to handle. Having access to their reliable and controllable precursors (or donors) is the prerequisite for the study of these sulfur species. Reported in this work is the preparation and evaluation of a series of O-silyl-mercaptan-based sulfur-containing molecules which undergo pH- or F -mediated desilylation to release the corresponding H S, H S , RSSH, and HSNO in a controlled fashion. This O→S relay deprotection serves as a general strategy for the design of pH- or F -triggered RSS donors. Moreover, we have demonstrated that the O-silyl groups in the donors could be changed into other protecting groups like esters. This work should allow the development of RSS donors with other activation mechanisms (such as esterase-activated donors).

Carbonyl Sulfide (COS) Donor Induced Protein Persulfidation Protects against Oxidative Stress

“…Protein persulfides, thus assume importance in sulfur mediated signaling and therapeutics. Strategies to release small molecule persulfides have been developed which include—spontaneous persulfide donors, enzyme activated donors, oxidative stress induced persulfide release, pH or F − dependent persulfide release . These donors provide testament to therapeutic utility of enhancing persulfidation levels within cells.…”

“…Strategies to releases mall molecule persulfides have been developed which include-spontaneous persulfide donors, [24] enzymea ctivated donors, [25] oxidative stress induced persulfide release, [19b, 26] pH or F À dependent persulfide release. [27] These donors provide testament to therapeutic utility of enhancing persulfidation levels within cells. Therefore, we investigated if the donors reported herein get activated by NQO1 present within cells to release H 2 Sa nd furtheri nduce protein persulfidation.T he persulfides can be trapped and detected using improvedt ag switcht echnique which is widely accepted for detectiono fp ersulfides in cells.…”

Strategies for the Design of Donors and Precursors of Reactive Sulfur Species

“…With this idea in mind, we recentlyd eveloped as eries of O-protected geminal hydroxyl-mercaptans( 39,S cheme21). [59] We expected O-deprotection of 39 should produce intermediate 40,w hich should spontaneously decompose to form RSS. So far,w eh ave prepared four types of precursors 41, 42, 43,a nd 44,w hich acted as the precursors of H 2 S, H 2 S n ,R SSH, and HSNO,r espectively.Silyl groups (TMS or TES) were used in these compounds so the releaseo ft hese RSS could be triggeredb yapH or fluoride.…”

“…If O‐protection/deprotection could be relayed to sulfur atoms, it would significantly enhance our ability to develop RSS precursors. With this idea in mind, we recently developed a series of O‐protected geminal hydroxyl‐mercaptans ( 39 , Scheme ) . We expected O‐deprotection of 39 should produce intermediate 40 , which should spontaneously decompose to form RSS.…”

Data‐Driven Identification of Hydrogen Sulfide Scavengers

“…Briefly, 200 μ m H 2 S solution was prepared in cell culture medium with 10 % fetal bovine serum (FBS) and treated with the scavengers (200 μ m ). After incubation for 1 h, the remaining H 2 S was measured by H 2 S‐gas trapping followed by a methylene blue assay . As shown in Figure , SS15–20 and SS22 effectively reduced H 2 S content, while the scavenging ability of SS2, SS3, SS10, and SS13 was somewhat diminished.…”