Use of Dithiasuccinoyl‐Caged Amines Enables COS/H₂S Release Lacking Electrophilic Byproducts

Abstract

The enzymatic conversion of carbonyl sulfide (COS) to hydrogen sulfide (H2S) by carbonic anhydrase has been used to develop self‐immolating thiocarbamates as COS‐based H2S donors to further elucidate the impact of reactive sulfur species in biology. The high modularity of this approach has provided a library of COS‐based H2S donors that can be activated by specific stimuli. A common limitation, however, is that many such donors result in the formation of an electrophilic quinone methide byproduct during donor activation. As a mild alternative, we demonstrate here that dithiasuccinoyl groups can function as COS/H2S donor motifs, and that these groups release two equivalents of COS/H2S and uncage an amine payload under physiologically relevant conditions. Additionally, we demonstrate that COS/H2S release from this donor motif can be altered by electronic modulation and alkyl substitution. These insights are further supported by DFT investigations, which reveal that aryl and alkyl thiocarbamates release COS with significantly different activation energies.

Progress and perspective on hydrogen sulfide donors and their biomedical applications

“…230 More recently, Pluth et al reported a suite of DTS-based compounds (donor 30, Figure 4P) that could be stimulated to produce COS/H 2 S by various nucleophiles such as cysteine, N-acetyl-L-cysteine (NAC), homocysteine, GSH, lysine but not serine, while lysine activated donor 30 through a pathway different from thiols-dependent one. 114 Similarly, S-methyl cysteine also gives rise to a slow but considerable H 2 S release, indicating a less preferred amino-dependent activation mechanism involved by lysine and S-methyl cysteine. 231 The experimental results that 25 μM of donor 30 could liberate ~40 μM H 2 S in the presence of 500 μM cysteine not only highlight the excellent H 2 S-releasing efficiency up to ~80% but also underpins the activation mechanism that two equivalents of COS were produced by per donor 30.…”

N-Methylation of Self-Immolative Thiocarbamates Provides Insights into the Mechanism of Carbonyl Sulfide Release

“…Alternatively, other approaches have utilized the intermediate release of carbonyl sulfide (COS), which is rapidly converted to H 2 S by the enzyme carbonic anhydrase (CA) (Figure a). , One common platform within this approach is the use of self-immolative thiocarbamates that can be triggered by specific stimuli to release COS. Moreover, these donor motifs provide access to critical control compounds, including triggerless control compounds and sulfur-depleted control compounds that release CO 2 rather than COS. Highlighting the diversity of this platform, prior donors have been developed that respond to both external and internal stimuli, including endogenous levels of peroxide, , bio-orthogonal chemistry, enzymes, , thiols, − acid, nucleophiles, , and light. − …”

Enzyme‐Triggered Chemodynamic Therapy via a Peptide‐H2S Donor Conjugate with Complexed Fe2+

“…A wide variety of H 2 S donors have been designed over the past decade, [26–29] with several generating COS and relying on its CA‐mediated conversion into H 2 S [30–33] . Here we designed and synthesized a legumain‐responsive, COS‐releasing PHDC termed AAN ‐ PTC (Scheme 1; AAN represents the peptide component, and PTC represents the phenyl thionocarbonate).…”

“…A wide variety of H 2 S donors have been designed over the past decade, [26][27][28][29] with several generating COS and relying on its CA-mediated conversion into H 2 S. [30][31][32][33] Here we designed and synthesized a legumain-responsive, COSreleasing PHDC termed AAN-PTC (Scheme 1; AAN represents the peptide component, and PTC represents the phenyl thionocarbonate). The peptide component included the hexapeptide Ac-Glu-Glu-Phe-Ala-Ala-Asn (EEFAAN, Figure S1), where the EEF segment provided amphiphilicity and the AAN segment was the legumain-responsive epitope.…”