Esterase Activated Carbonyl Sulfide/Hydrogen Sulfide (H₂S) Donors

Abstract

Hydrogen sulfide (HS) is a mediator of a number of cellular processes, and modulating cellular levels of this gas has emerged as an important therapeutic area. Localized generation of HS is thus very useful but highly challenging. Here, we report pivaloyloxymethyl-based carbonothioates and carbamothioates that are activated by the enzyme, esterase, to generate carbonyl sulfide (COS), which is hydrolyzed to HS.

Kinetic Insights into Hydrogen Sulfide Delivery from Caged-Carbonyl Sulfide Isomeric Donor Platforms

“…We note that Chakrapani and co-workers recently reported esterase-cleavable S -alkyl thiocarbonate and thiocarbamate COS donor motifs, but their activities were not compared with O -alkyl donor analogues. 75 Our expectation was that the S- alkyl isomer should have a greater ground state stability due to enhanced resonance stabilization in the amide moiety of the thiocarbamate by comparison to the thioamide moiety in the O -alkyl derivative. Although SA - PeroxyTCM-1 is more thermodynamically stable than the corresponding O -alkyl isomer, it is less stable in solution, likely due to the better leaving group ability of the benzyl thiol versus benzyl alcohol.…”

“…In addition to H 2 O 2 activation, our group as well as other researchers have expanded the COS-releasing landscape to include donors activated by nucleophilic attack, 72 light, 73 click chemistry, 53 and cellular esterases. 74–75 Because such donors function by the intermediate release of COS en-route to H 2 S generation, it is possible that such donors could also reveal activities associated with COS directly, although the CA-mediated conversion of COS to H 2 S is fast. Despite the rapid expansion of this research area, the structural motifs comprising the caged COS core structures have remained somewhat limited.…”

Inhibition of Mitochondrial Bioenergetics by Esterase-Triggered COS/H2S Donors

“…31 Similarly, during the preparation of this manuscript an esterase-activated S -alkyl thiocarbamate COS/H 2 S donor was reported, but detailed biological applications were not investigated. 32 Here, we report the design, evaluation, and application of esterase-activated COS/H 2 S donors and provide the first insights into the influence of COS donors on cellular toxicology and mitochondrial bioenergetics.…”

Colorimetric Carbonyl Sulfide (COS)/Hydrogen Sulfide (H2S) Donation from γ‐Ketothiocarbamate Donor Motifs

“…[10] To meet the demand for new donor strategies,werecently reported H 2 Sd elivery from caged-carbonyl sulfide (COS) molecules. [12] Following our initial report, we,a sw ell as others,h ave expanded this strategy to include COS-based H 2 Sdonors that are activated by different triggers,s uch as reactive oxygen species (ROS), [13] esterases, [14] glycine, [15] click chemistry, [16] light, [17] and cysteine. [12] Following our initial report, we,a sw ell as others,h ave expanded this strategy to include COS-based H 2 Sdonors that are activated by different triggers,s uch as reactive oxygen species (ROS), [13] esterases, [14] glycine, [15] click chemistry, [16] light, [17] and cysteine.…”

“…[11] In this approach, we utilized self-immolative thiocarbamates that undergo cascade reactions to release COS,w hich is quickly converted into H 2 Sb yt he ubiquitous enzyme carbonic anhydrase (CA) (Scheme 1a). [12] Following our initial report, we,a sw ell as others,h ave expanded this strategy to include COS-based H 2 Sdonors that are activated by different triggers,s uch as reactive oxygen species (ROS), [13] esterases, [14] glycine, [15] click chemistry, [16] light, [17] and cysteine. [18] Although these molecules exhibit promising H 2 S-related functions,m ost of these donor scaffolds require a1 ,6-elimination system, which has limited the expansion of this platform.…”