Amino acid-based H2S donors: N-thiocarboxyanhydrides that release H2S with innocuous byproducts.

A library of N-thiocarboxyanhydrides (NTAs) derived from natural amino acids with benign byproducts and controlled H2S-release kinetics is reported. Minimal acute in vitro toxicity was observed in multiple cell lines, while longer-term toxicity in cancer cells was observed, with slow-releasing donors exhibiting the greatest cytotoxic effects.

Targeted Delivery of Persulfides to the Gut: Effects on the Microbiome.

Persulfides (R-SSH) have been hypothesized as potent redox modulators and signaling compounds. Reported herein is the synthesis, characterization, and in vivo evaluation of a persulfide donor that releases N-acetyl cysteine persulfide (NAC-SSH) in response to the prokaryote-specific enzyme nitroreductase. The donor, termed NDP-NAC, decomposed in response to E. coli nitroreductase, resulting in release of NAC-SSH. NDP-NAC elicited gastroprotective effects in mice that were not observed in animals treated with control compounds incapable of persulfide release or in animals treated with Na2 S. NDP-NAC induced these effects by the upregulation of beneficial small- and medium-chain fatty acids and through increasing growth of Turicibacter sanguinis, a beneficial gut bacterium. It also decreased the populations of Synergistales bacteria, opportunistic pathogens implicated in gastrointestinal infections. This study reveals the possibility of maintaining gut health or treating microbiome-related diseases by the targeted delivery of reactive sulfur species.

Polymeric persulfide prodrugs: Mitigating oxidative stress through controlled delivery of reactive sulfur species.

Related biologically to the known gasotransmitter hydrogen sulfide (H2S), persulfides (R-SSH) have recently been recognized as native signaling compounds and redox regulators in their own right. Reported here is the synthesis, characterization, and in vitro evaluation of a small molecule persulfide donor and its polymeric counterpart, both of which release N-acetyl cysteine persulfide (NAC-SSH) in response to esterases. The donors, termed EDP-NAC and poly(EDP-NAC), underwent controlled decomposition in response to porcine liver esterase, resulting in pseudo-first-order release half-lives of 1.6 h ± 0.3 h and 36.0 h ± 0.6 h, respectively. In cell experiments, slow-releasing poly(EDP-NAC) rescued H9C2 cardiomyocytes more effectively than EDP-NAC when cells were treated with 5-fluorouricil (5-FU), which induces sustained production of ROS. Neither EDP-NAC nor poly(EDP-NAC) rescued MCF-7 breast cancer cells from 5-FU-induced oxidative stress, suggesting that polymeric persulfide donors could be used as adjuvants to reduce the deleterious cardiotoxic effects of many chemotherapeutics.

Self-Amplified Depolymerization of Oligo(thiourethanes) for the Release of COS/H2S.

Herein we report the self-amplified depolymerization of an aryl oligo(thiourethane) (OTU) for the release of COS/H2S. The OTU was synthesized via polyaddition of 4-isothiocyanatobenzyl alcohol and end-capped with an aryl azide. The aryl azide chain-end was reduced by tris(2-carboxyethyl)phosphine or H2S to the corresponding aniline, resulting in depolymerization (i.e., self-immolation) and the release of COS/H2S. Depolymerization was monitored by 1H NMR and UV-Vis spectroscopy, and the released COS was converted into H2S by the ubiquitous enzyme carbonic anhydrase in aqueous media.

Self-Immolative Prodrugs: Effective Tools for the Controlled Release of Sulfur Signaling Species.

H2S, persulfides (R-SSH), and related sulfur species have recently received attention due to the pronounced physiological effects they elicit. Delivering sulfur signaling molecules in a controlled manner presents many challenges, as many available donors have short half-lives, lack water solubility, and exhibit poor trigger specificity. Self-immolative prodrugs provide a unique ability to impart stability to H2S precursors and persulfides while allowing for trigger specificity by tuning the functional group installed on the self-immolative linker. This strategy has proven successful in delivering sulfur signaling species under specific conditions and may lead to the further elucidation of persulfide interactions within biological systems, affording effective therapeutics.

Functional N-Substituted N-Thiocarboxyanhydrides as Modular Tools for Constructing H2S Donor Conjugates.

We report a synthetic route toward a family of functional COS/H2S-releasing N-substituted N-thiocarboxyanhydrides (NTAs) with functionalities to accommodate popular conjugation reactions, including olefin cross metathesis, thiol-ene, and copper-catalyzed azide-alkyne cycloaddition. The N-substituted NTAs were attached to small molecules, polymers, and a protein to synthesize novel H2S donors convergently. All conjugates showed sustained H2S release kinetics.

A Persulfide Donor Responsive to Reactive Oxygen Species: Insights into Reactivity and Therapeutic Potential.

Persulfides (RSSH) have been hypothesized as critical components in sulfur-mediated redox cycles and as potential signaling compounds, similar to hydrogen sulfide (H2 S). Hindering the study of persulfides is a lack of persulfide-donor compounds with selective triggers that release discrete persulfide species. Reported here is the synthesis and characterization of a ROS-responsive (ROS=reactive oxygen species), self-immolative persulfide donor. The donor, termed BDP-NAC, showed selectivity towards H2 O2 over other potential oxidative or nucleophilic triggers, resulting in the sustained release of the persulfide of N-acetyl cysteine (NAC) over the course of 2 h, as measured by LCMS. Exposure of H9C2 cardiomyocytes to H2 O2 revealed that BDP-NAC mitigated the effects of a highly oxidative environment in a dose-dependent manner over relevant controls and to a greater degree than common H2 S donors sodium sulfide (Na2 S) and GYY4137. BDP-NAC also rescued cells more effectively than a non-persulfide-releasing control compound in concert with common H2 S donors and thiols.

A review of hydrogen sulfide (H2S) donors: Chemistry and potential therapeutic applications.

Hydrogen sulfide (H2S) is a ubiquitous small gaseous signaling molecule, playing an important role in many physiological processes and joining nitric oxide and carbon monoxide in the group of signaling agents termed gasotransmitters. Endogenous concentrations of H2S are generally low, making it difficult to discern precise biological functions. As such, probing the physiological roles of H2S is aided by exogenous delivery of the gas in cell and animal studies. This need for an exogenous source of H2S provides a unique challenge for chemists to develop chemical tools that facilitate the study of H2S under biological conditions. Compounds that degrade in response to a specific trigger to release H2S, termed H2S donors, include a wide variety of functional groups and delivery systems, some of which mimic the tightly controlled endogenous production in response to specific, biologically relevant conditions. This review examines a variety of H2S donor systems classified by their H2S-releasing trigger as well as their H2S release profiles, byproducts, and potential therapeutic applications.

Therapeutic Delivery of H2S via COS: Small Molecule and Polymeric Donors with Benign Byproducts.

Carbonyl sulfide (COS) is a gas that may play important roles in mammalian and bacterial biology, but its study is limited by a lack of suitable donor molecules. We report here the use of N-thiocarboxyanhydrides (NTAs) as COS donors that release the gas in a sustained manner under biologically relevant conditions with innocuous peptide byproducts. Carbonic anhydrase converts COS into H2S, allowing NTAs to serve as either COS or H2S donors, depending on the availability of the enzyme. Analysis of the pseudo-first-order H2S release rate under biologically relevant conditions revealed a release half-life of 75 min for the small molecule NTA under investigation. A polynorbornene bearing pendant NTAs made by ring-opening metathesis polymerization was also synthesized to generate a polymeric COS/H2S donor. A half-life of 280 min was measured for the polymeric donor. Endothelial cell proliferation studies revealed an enhanced rate of proliferation for cells treated with the NTA over untreated controls.

S-aroylthiooximes: a facile route to hydrogen sulfide releasing compounds with structure-dependent release kinetics.

We report the facile preparation of a family of S-aroylthiooxime (SATO) H2S donors, which are synthesized via a click reaction analogous to oxime formation between S-aroylthiohydroxylamines (SATHAs) and aldehydes or ketones. Analysis of cysteine-triggered H2S release revealed structure-dependent release kinetics with half-lives from 8-82 min by substitution of the SATHA ring. The pseudo-first-order rate constants of substituted SATOs fit standard linear free energy relationships (ρ = 1.05), demonstrating a significant sensitivity to electronic effects.