Development of <i>S</i>-Substituted Thioisothioureas as Efficient Hydropersulfide Precursors

Khodade, Vinayak S.; Toscano, John P.

doi:10.1021/jacs.8b08469

Cited by 33 publications

(30 citation statements)

References 38 publications

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“…Due to their inherent instability, persulfides are difficult to detect directly by high resolution mass spectrometry (HRMS), so electrophilic trapping reagents such as N ‐ethylmaleimide (NEM), iodoacetamide (IAM), [20] or dinitrofluorobenzene (DNFB) [9a] are commonly used. The reaction of a persulfide with these trapping agents forms a disulfide that typically can withstand MS ionization conditions, whereas the persulfide itself mostly disproportionates into H 2 S and a thiol or forms trisulfides when directly analyzed [9e] . We attempted to trap the persulfide using NEM, IAM, and DNFB, and we found that DNFB worked best in this system.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2021

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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 Na2S. 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.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2021

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“…As a competing process, the HAT from thiol (R-SH) to R ∙ will lead to the formation of the alkane side product (R-H) 51 , 52 , which can be suppressed by a rapid trapping of R ∙ with active thiolating agents via Path I or II. In the end, the desired thiol is produced after the elimination of one molecule of ArCN 68 , 69 , which could be a relatively slow step, and a slow release of free thiols can decrease the formation of the undesired alkane product. The nitrile byproduct formation was confirmed by gas chromatography-mass spectrometry (GC-MS) analysis, and it can also be isolated by column chromatography.…”

Section: Resultsmentioning

confidence: 99%

Decarboxylative thiolation of redox-active esters to free thiols and further diversification

Cao

et al. 2020

Nat Commun

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Thiols are important precursors for the synthesis of a variety of pharmaceutically important sulfur-containing compounds. In view of the versatile reactivity of free thiols, here we report the development of a visible light-mediated direct decarboxylative thiolation reaction of alkyl redox-active esters to free thiols based on the abundant carboxylic acid feedstock. This transformation is applicable to various carboxylic acids, including primary, secondary, and tertiary acids as well as natural products and drugs, forging a general and facile access to free thiols with diverse structures. Moreover, the direct access to free thiols affords an advantage of rapid in situ diversification with high efficiency to other important thiol derivatives such as sulfide, disulfide, thiocyanide, thioselenide, etc.

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“…Protein persulfidation is ac haracteristic post translational modification associated with H 2 S. [23] Protein persulfides, thus assume importance in sulfur mediated signaling and therapeutics. 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.…”

Section: Resultsmentioning

confidence: 99%

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

Chauhan

Gupta

Ravikumar

et al. 2019

Chemistry An Asian Journal

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The emergence of hydrogen sulfide (H 2 S) as an important signallingm olecule in redox biology with therapeutic potentialh as triggered interesti ng enerating this molecule within cells. One strategy that has been proposed is to use carbonyl sulfide (COS) as as urrogate for hydrogen sulfide. Small molecules that generate COS have been shown to produce hydrogen sulfide in the presenceo fc arbonic anhydrase, aw idely prevalent enzyme. However,o ther studies have indicated that COS may have biological effects which are distinct from H 2 S. Thus, it would be useful to develop tools to compare (and contrast) effects of COS and H 2 S. Here we report enzyme-activated COS donors that are capable of inducing protein persulfidation, which is symptomatic of generation of hydrogen sulfide. The COS donors are also capable of mitigating stress induced by elevated reactive oxygen species. To gether,o ur data suggests that the effects of COS parallel that of hydrogen sulfide,l aying the foundation for further development of these donors as possible therapeutic agents.

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Development of S-Substituted Thioisothioureas as Efficient Hydropersulfide Precursors

Cited by 33 publications

References 38 publications

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

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

Decarboxylative thiolation of redox-active esters to free thiols and further diversification

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

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