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Sulfur‐centered electrophilic ‘warheads’ have emerged as key components for chemical proteomic probes through sulfur‐exchange chemistry (SuFEx) with protein nucleophiles. Among these functional groups, sulfonimidoyl fluorides (SIFs) stand out for their modifiable sites, tunable electrophilicities, and chiral sulfur‐center, presenting exciting possibilities for new covalent chemical probes. However, the synthetic access to chiral SIFs has been a challenge, limiting their exploration and applications. In this study, we describe a convenient route to obtain chiral SIFs from readily available sulfenamides via a series of one‐pot tandem reactions with high enantiomeric excess (ees). The resulting chiral SIFs were further converted into a diverse array of chiral S(VI) derivatives under mild conditions or in buffer solutions. Most significantly, the specificity of the chiral SIFs in protein ligation experiments underscored the critical role of sulfur‐center chirality in the design and screening of more‐selective covalent probes and therapeutics. [ABSTRACT FROM AUTHOR]

Sulfenamides are organosulfur compounds that contain a single bond between nitrogen and sulfur in their structures. Sulfur can react with nucleophiles to yield new compounds. The compounds having nitrogen–sulfur bonds are used in polymers for a variety of purposes, including medicines, agrochemicals, veterinary medications, and environmental studies. This review will examine several chemical reactions that lead to sulfenamide production as well as how they are used in cell biology and biochemical applications. [ABSTRACT FROM AUTHOR]

Dimedone and its derivates are used as selective probes for the nucleophilic detection of sulfenic acids in biological samples. Qualitative analyses suggested that dimedone also reacts with cyclic sulfenamides. Furthermore, under physiological conditions, dimedone must compete with the highly concentrated nucleophile glutathione. We therefore quantified the reaction kinetics for a cyclic sulfenamide model peptide and the sulfenic acids of glutathione and a model peroxiredoxin in the presence or absence of dimedone and glutathione. We show that the cyclic sulfenamide is stabilized at lower pH and that it reacts with dimedone. While reactions between dimedone and sulfenic acids or the cyclic sulfenamide have similar rate constants, glutathione kinetically outcompetes dimedone as a nucleophile by several orders of magnitude. Our comparative in vitro and intracellular analyses challenge the selectivity of dimedone. Consequently, the dimedone labeling of cysteinyl residues inside living cells points towards unidentified reaction pathways or unknown, kinetically competitive redox species. Sulfenic acids in biological samples are indirectly detected by nucleophilic probes. Whether dimedone probes also detect cyclic sulfenamides is controversial and depends on kinetic competitions. Furthermore, dimedone probes have to compete with the highly abundant physiological nucleophile glutathione (GSH). Kinetic assays in vitro and in yeast challenge the specificity of dimedone and highlight the benefits of GSH competition assays. [Display omitted] • Glutathione kinetically outcompetes dimedone as a nucleophile. • Dimedone cannot discriminate between peptide sulfenic acids and cyclic sulfenamides. • The presence and detectability of cyclic sulfenamides could be highly pH-dependent. • Origin and relevance of dimedone-labeled peptides often remain to be analyzed. • Glutathione competition assays are recommended for nucleophilic probe development. [ABSTRACT FROM AUTHOR]

Purification by silica gel chromatography (10% EtOAc in hexanes, then 33% EtOAc in hexanes) afforded the product B 3k b as an off-white solid; yield: 167 mg (73%); mp 108-112 °C; [ ] SB D sb SP 20 sp +54.38 ( I c i 0.1, CHCl SB 3 sb ); I R SB f sb i = 0.14 (silica gel, 20% EtOAc/hexanes, UV). Purification by silica gel chromatography (20% EtOAc in hexanes, then 50% EtOAc in hexanes) afforded the product B 3c b as a white solid; yield: 304 mg (90%); mp 49-54 °C; I R SB f sb i = 0.48 (silica gel, 50% EtOAc/hexanes, UV). Keywords: sulfenamide; amide; thiosuccinimide; thiophthalimide; thiol; asymmetric catalysis EN sulfenamide amide thiosuccinimide thiophthalimide thiol asymmetric catalysis 2353 2360 8 07/14/23 20230801 NES 230801 Graph Sulfenamides, which incorporate a divalent sulfur bonded to nitrogen and carbon substituents, have enjoyed numerous uses ranging from industrial application for the vulcanization of rubber to prodrug synthesis. Purification by silica gel chromatography (10% EtOAc in hexanes) afforded the product B 3h b as a white solid; yield: 201 mg (89%); mp 65-67 °C; I R SB f sb i = 0.53 (20% EtOAc/hexanes, UV). [Extracted from the article]

Catalytic dehydrogenative coupling of thiols with amines to produce sulfenamides and disulfides is an important reaction in the industry. Classical synthesis of sulfenamides involves the reaction between amine nucleophiles and sulfonyl chlorides, which are not widely available, toxic and unstable, and the reaction requires a combination of oxidizing and chlorinating reagents. Here we decribe an environmentally benign protocol for the efficient electrochemical dehydrogenative coupling of thiols with amines or thiols to form compounds possessing S–N or S–S bonds. We used potassium iodide as electrocatalyst in methanol for a greener reaction. The reaction operates under ambient conditions in the absence of oxidants, acids/bases or toxic/explosive electrolytes. Results show that most produced sulfenamides and disulfides are generated in yields up to 99%. [ABSTRACT FROM AUTHOR]

An efficient and practical construction of S−N bond from aryl thioureas and amines under mild and metal‐free conditions is reported. A series of sulfenamides was obtained smoothly from aryl thioureas and amines (mainly secondary amines) through cross dehydrogenation coupling reaction (CDC) in the presence of phenyliodine(III) diacetate. The protocol features easily available starting materials, easy and odorless performance, mild reaction conditions, good yields, and a broad substrate scope, illustrating its synthetic value for the synthesis of diverse biologically or pharmaceutically relevant compounds. [ABSTRACT FROM AUTHOR]

The asymmetric rearrangement of allylic sulfilimines is an effective route to synthetic attractive targets such as allylic sulfenamides and others. The current methods are limited to chirality transfer from chiral allylic sulfilimine precursors. Herein, we report a general and fundamentally new rearrangement route accessing optically enriched allylic sulfenamides and their derivatives. The process involves a S-alkylation and an unusual S-to-N rearrangement step. The chiral nickel complex enables the transformation of a broad scope of sulfenamides and vinyl α-diazo pyrazoleamides under mild conditions. Various allylic sulfenamides have been synthesized with excellent γ-regioselectivity and enantioselectivity, which can be efficiently converted to sulfinamide and 4-aminobutenoic acid derivatives. In addition, DFT calculations demonstrate the connection between the spin state and conformation of nickel vinyl carbenoid, as well as an unknown rearrangement process., (© 2024 Wiley‐VCH GmbH.)

An efficient iodine‐mediated construction of S−N bond was developed. Such a cross‐dehydrogenative coupling of heterocyclic thiols with amines proceeded smoothly under metal‐free and base‐free conditions, and afforded a series of sulfenamides in good to excellent yields. The easily available substrates and convenient synthetic procedure illustrate potential synthetic value of this protocol for the preparation of sulfenamide related biologically or pharmaceutically active compounds. [ABSTRACT FROM AUTHOR]

A synthetic method is presented for S−N bond formation starting from cheap and affordable materials. We show that (un)substituted N‐protected cyclic eight‐membered C2‐symmetric sulfenamides have been prepared in a few steps using this procedure. The synthetic utility of these ambipolar derivatives was demonstrated in a variety of synthetic transformations affording different S,N‐heterocyles of pharmaceutical relevance in one or two steps from simple starting materials. [ABSTRACT FROM AUTHOR]

Cysteine oxidation is important in cellular redox regulation, signaling, and biocatalysis. To understand the biological relevance of cysteine oxidation, it is desirable to identify the proteins involved, the site of the oxidized cysteine, and the relevant oxidation states. Because the thiol of cysteine can be converted to a wide range of oxidation states, mapping these oxidative modifications is challenging. The dynamic and reversible nature of many cysteine oxidation states compounds the difficulty in such proteomic analyses. In this review, we examine methods to detect cysteine sulfenic acid — a particularly challenging functional group to analyze because of its reactive nature. We focus on the selectivity of recently reported probes and discuss some challenges and opportunities in this field. Image 1 • Probes for detecting cysteine sulfenic acid are important for understanding signaling, enzyme catalysis, and responses to oxidative stress. • Probes such as dimedone and related nucleophiles may react with off-target groups such the cyclic sulfenamide form of cysteine. • Strained alkenes and alkynes can react with cysteine sulfenic acid, but off-target reactions with cysteine are known. • There is substantial opportunity for the development of new probes that are selective for specific oxidation states of cysteine. [ABSTRACT FROM AUTHOR]

S−H activation reaction of thiols employing dibenzyl azodicarboxylate (DBAD) has been developed for the preparation of sulfenamides. The dehydrogenation of thiols and amines under these reaction conditions involved the formation of dibenzyl hydrazine‐1,2‐dicarboxylate (5 a), which led to the S−N bond formation reaction. The reaction proceeds efficiently with the release of 5 a and affords various sulfenamides in good to excellent yields. [ABSTRACT FROM AUTHOR]

Sulfenylation of electron-rich arenes was carried out with N-unsubstituted sulfenamides in the presence of Brønsted or Lewis acids. α-Methylstyrene as an olefin was also sulfenylated with acidic sulfenamides, and a sulfur substituent was introduced on the methyl group. Intramolecular sulfenylation proceeded for allyl 2-sulfenamoylbenzoate derivatives, and sulfur containing seven-membered heterocycles were obtained. [ABSTRACT FROM AUTHOR]

Sulfenamide based radical generators that contain a nitrogen-sulfur (N -S) core, can alone provide flame retardancy in polypropylene (PP), polyethylene and polystyrene, as we have earlier demonstrated. Herein, sulfenamides potential as synergists with conventional halogen free flame retardants has been explored. Thus, five different sulfenamides were individually combined with selected eco-friendly, phosphorus based flame retardants or aluminium trihydroxide (ATH), and their effect on polypropylene flammability was assessed by limiting oxygen index (LOI), vertical flammability (UL 94 V) and cone calorimeter tests. Thermogravimetric analysis (TGA) and nuclear magnetic resonance (NMR) studies were carried out to detect changes in thermal behaviour when such two component FR systems were mixed together at different ratios. TGA-FTIR (thermogravimetric analysis-Fourier transform infrared spectroscopy) was used to investigate the differences in decomposition products of non-flame retarded versus flame retarded PP. Strong synergistic effects were observed, and the UL 94 V-0 rating was reached for PP with a total FR loading of 10 wt% using 8 wt% of phosphonate ester AFLAMMIT ® PCO 900 together with 2 wt% of sulfenamide flame retardant. In a ternary mixture of an additional phosphazene additive (SPB-100), the needed total concentration for V-0 rating was further reduced to 9 wt%. In addition, the combination of 4 wt% of aluminum hypophosphite (AHP) with 0.5 wt% of sulfenamide offered a unique halogen free solution for achieving UL 94 V-2 rating in PP. Cone calorimeter studies of an ammonium polyphosphate-pentaerythritol based intumescent system in combination with 0.5 wt% of sulfenamide also showed encouraging results. The char stability was enhanced, the peak of heat release rate (HRR), CO and CO 2 production and total smoke generation were all reduced compared to the reference sample without sulfenamide. • Sulfenamide based radical generators were combined with eco-friendly halogen-free flame retardants in polypropylene. • Strong synergistic effects were observed; UL 94 V-0 rating for PP was reached at the total FR concentration of 9 wt%. • Aluminum hypophosphite (4 wt%) together with sulfenamide (0.5 wt%) offers a unique solution for achieving UL 94 V-2 rating. • Enhanced char stability and lower heat release rate were found for an intumescent system when 0.5 wt% sulfenamide was added. [ABSTRACT FROM AUTHOR]

• The multifunctional mono-component flame retardants comprising of sulfenamide and phosphate moieties exhibit inherently an exceptionally high synergistic fire retarding effect. • Polypropylene films containing any of the different multifunctional flame retardants at the low loading of 0.5 wt% passed the DIN4102 B2 fire test. • The multifunctional flame retardants denoted NS2 and NS3 passed the UL94 V2 criteria as standalone flame retardants at the low loading of 4 w%. A strategy to enhance flame retardant properties of polypropylene (PP) has been investigated by the design of six multifunctional mono-component flame retardants denoted from NS1 to NS6, where sulfenamide and phosphate moieties have been integrated into a single molecule. Herein, the synthesis and characterization of six different mono-component flame retardants are presented. Thermal decomposition characteristics of the multifunctional flame retardants were studied by thermogravimetry analysis, and a 5% mass lose was recorded in the temperature range between 220 °C to 267 °C for the samples. Moreover, the flame retardant samples were oven aged up to 260 °C in the presence and absence of 9, 10-dihydroantracene and the formed decomposition products were analyzed using GC/MS, LC/MS, 13C NMR and 31P NMR. The results indicate that the sulfenamide bond dissociates before the phosphorus moiety for samples NS1, NS2, NS3 and NS6. Whereas the phosphorus moiety breaks first in case of NS4 and NS5. The prepared flame retardants were then admixed with polypropylene in a Haake Rheocord melt blender at loadings ranging from 0.5 to 4 wt%. Thereafter, polypropylene films and plaques were prepared by hot pressing and their flame retardant properties were evaluated according to DIN 4102-B2 and UL94V standards, respectively. All the PP film samples containing any of the different multifunctional flame retardants at the low loading of 0.5 wt% passed the DIN4102 B2 test and for NS1film sample no burning dripping nor ignition of paper were recorded. Noteworthy, is that NS2 and NS3 samples reached the UL94V2 classification as standalone flame retardants even at a loading of only 4 wt%. From this standpoint, it seems the multifunctional mono-component flame retardants may exhibit inherently an exceptionally high synergistic effect. [ABSTRACT FROM AUTHOR]

[Display omitted] Metformin has been used for ages to treat diabetes mellitus due to its safety profile and low cost. However, metformin has variable pharmacokinetics in patients, and due to its poor oral absorption, the therapeutic doses are relatively high, causing unpleasant gastrointestinal adverse effects. Therefore, novel derivatives of metformin have been synthesized during the past decades. Particularly, after the mid-2000 s, when organic cation transporters were identified as the main metformin carriers, metformin derivatives have been under intensive investigation. Nevertheless, due to the biguanide structure, derivatives of metformin have been challenging to synthesize. Moreover, the mechanisms of metformin's action are not fully understood to date, and since it has multifunctional properties, the interests have switched to re-purposing for other diseases. Indeed, metformin derivatives have been demonstrated in many cases to be more effective than metformin itself and have the potential to be used in different diseases, including several types of cancers and neurodegenerative diseases. On the other hand, the pleiotropic nature of metformin and its derivatives can also create challenges. Not all properties are fit for all diseases. In this review, the history of the development of metformin-like compounds is summarized, and insights into their potential for future drug discovery are discussed. [ABSTRACT FROM AUTHOR]

A wide variety of molecules containing S–N or S–N–S cores were synthesized, and their flame retardant properties in polypropylene (PP), low density polyethylene (LDPE) and polystyrene (PS) were investigated. In addition, polymers or oligomers bearing the sulfenamide functionality (SN) were also synthesized. It was shown that this radical generator family based on sulfenamides is very versatile in terms of structural modifications, and the thermal decomposition range can be easily adjusted by changing the R groups attached to the core. The thermal stabilities of the different sulfenamides were examined by thermogravimetric analysis (TGA). Radicals generated by the homolytic cleavage of the S–N or S–N–S bonds at an elevated temperature can effectively interact with the intermediate products of polymer thermolysis and provide excellent flame retardant properties. The choice of most suitable SN-structure varies depending on the polymer type. For polypropylene DIN 4102-1 B2 and UL94 VTM-2 classifications were achieved with only 0.5 to 1 wt % of sulfenamide, and, in some cases, no flaming dripping was observed. Also for LDPE thin films, sulfenamides offered the DIN 4102-1 B2 rating at low dosage. In the case of polystyrene, the very stringent UL94 V-0 classification was even achieved at a loading of 5 wt % of sulfenamide. [ABSTRACT FROM AUTHOR]

We have developed a convenient method for the synthesis of functionalized N-acylsulfenamides under mild conditions and in moderate to good yields. The designed method is based on the reaction of (5,5-dimethyl-2-thioxo-1,3,2-dioxaphosphorinan-2-yl)-disulfanyl derivatives with nitrogen nucleophiles generated from primary amides or imides and sodium hydride. The developed method allows for the preparation of N-acylsulfenamides bearing additional hydroxyl, carboxyl, or amino functionalities. [ABSTRACT FROM PUBLISHER]

In the reaction of N-methylbenzenesulfenamide (1) with thioanisole (4) in the presence of trifluoroacetic acid (TFA), the initial rate ÃÂ…0 of total appearance of 2- and 4-(methylthio)phenyl phenyl sulfides (5) is first and zero order with respect to the initial concentrations of 1 and 4, respectively: ÃÂ…0=kobs[1]0. The pseudo-first order rate constant kobs is evaluated as 5.2×10-4 sec-1 with varying concentrations of 4 (0.72 to 5.0 M) in a mixture of 4 and CH2Cl2 in the presence of TFA at 10 °C. This data supports the notion that a phenylsulfenium ion intermediate 3 interacting with both the counter ion and the unshared electron-pair of amine is generated by heterolytic N-S scission of the protonated sulfenamide 2, leading to the observed formation of 5.

Background Proton pump inhibitors (PPIs) are extensively used in clinical practice because of their effectiveness and safety. Omeprazole is one of the best-selling drugs worldwide and, with other PPIs, has been proposed to be potential drugs for the treatment of several diseases. We demonstrated that omeprazole shows cytotoxic effects in Giardia and concomitantly inactivates giardial triosephosphate isomerase (GlTIM). Therefore, we evaluated the efficiency of commercially available PPIs to inactivate this enzyme. Methods We assayed the effect of PPIs on the GlTIM WT, single Cys mutants, and the human counterpart, following enzyme activity, thermal stability, exposure of hydrophobic regions, and susceptibility to limited proteolysis. Results PPIs efficiently inactivated GlTIM; however, rabeprazole was the best inactivating drug and was nearly ten times more effective. The mechanism of inactivation by PPIs was through the modification of the Cys 222 residue. Moreover, there are important changes at the structural level, the thermal stability of inactivated-GlTIM was drastically diminished and the structural rigidity was lost, as observed by the exposure of hydrophobic regions and their susceptibility to limited proteolysis. Conclusions Our results demonstrate that rabeprazole is the most potent PPI for GlTIM inactivation and that all PPIs tested have substantial abilities to alter GITIM at the structural level, causing serious damage. General significance. This is the first report demonstrating the effectiveness of commercial PPIs on a glycolytic parasitic enzyme, with structural features well known. This study is a step forward in the use and understanding the implicated mechanisms of new antigiardiasic drugs safe in humans. [ABSTRACT FROM AUTHOR]

Lewis acid-catalyzed insertion of isocyanides 2 into nitrogen–sulfur bonds of sulfenamides 1 was developed. This method provided a convenient method for the synthesis of isothioureas 3 . Among Lewis acids examined, AlCl 3 brought about the best result. Acetic acid assisted one-pot preparation of unsymmetrical ureas was also described. [ABSTRACT FROM AUTHOR]

Abstract: A convenient microwave-assisted synthesis of lipophilic sulfenamide prodrugs of antidiabetic agent, metformin, is reported in this study. These acyclic prodrugs were synthesized directly from selected disulfides with basic metformin and silver nitrate by a one-pot reaction under microwave irradiation. The prepared prodrugs had significantly increased lipophilicity, which resulted in excellent permeability of the octylthio prodrug of metformin across a Caco-2 cell monolayer. According to our preliminary in vivo studies, the octylthio prodrug was also absorbed mostly intact after oral administration in rats. In conclusion, this study shows that these types of more lipophilic sulfenamide prodrugs can be promising candidates to improve permeability and passive absorption of highly water-soluble metformin. [Copyright &y& Elsevier]

Abstract: A total of 29 novel sulfenamide compounds were synthesized, spectroscopically characterized and evaluated in vitro for antimicrobial activity against various infectious pathogens. Compounds 1b and 2c exhibited potent inhibition against clinical Methicillin-resistant Staphylococcus aureus (MRSA) strains with minimum inhibitory concentration (MIC) values of 1.56μg/mL. [Copyright &y& Elsevier]

Abstract: Two efficient syntheses of 1,4-benzothiazepines, substituted in the positions 2 and 5, have been achieved either by a ring expansion reaction of cyclic sulfenamides with methylpropiolate or tosylacetylene catalyzed by pyridine, via a postulated allenolate intermediate; or by an α-sulfenylation reaction promoted by diethylamine and a subsequent acid catalyzed condensation reaction. [Copyright &y& Elsevier]

CLC CI-/H+ exchangers are homodimers with Cl--binding and H+-coupling residues contained within each subunit. It is not known whether the transport mechanism requires conformational rearrangement between subunits or whether each subunit operates as a separate exchanger. We designed various cysteine substitution mutants on a cysteine-less background of CLC-ec1, a bacterial CLC exchanger of known structure, with the aim of covalently linking the subunits. The constructs were cross-linked in air or with exogenous oxidant, and the cross-linked proteins were reconstituted to assess their function. In addition to conventional disulfides, a cysteine-lysine cross-bridge was formed with I2 as an oxidant. The constructs, all of which contained one, two, or four cross-bridges, were functionally active and kinetically competent with respect to Cl- turnover rate, Cl-/H+ exchange stoichiometry, and H+ pumping driven by a Cl- gradient. These results imply that large quaternary rearrangements, such as those known to occur for "common gating" in CLC channels, are not necessary for the ion transport cycle and that it is therefore likely that the transport mechanism is carried out by the subunits working individually, as with "fast gating" of the CLC channels. [ABSTRACT FROM AUTHOR]

Abstract: The objective of this report is to introduce the novel concept of utilizing sulfenamides as prodrugs for compounds containing an NH-acidic functionality, particularly weakly acidic amide-type functionalities (amides, ureas, carbamates, etc.). Included are the syntheses and physicochemical characterizations of some model sulfenamides to illustrate the promise of this new prodrug technology. [Copyright &y& Elsevier]

The gas--phase reaction mechanism of O-acylhydroxamate with cysteine proteases has been investigated using ab initio and density functional theory. On the irreversible process, after breakdown of tetrahedral intermediate (INT1), small 1-2 anionotropic has been formed and rearranged to give stable by-products sulfenamide (P1) and thiocarbamate (P2) with considerable energy loss. While, on the reversible part of this reaction mechanism, intermediate (INT2) breaks down on oxidation, to form a stable product (P3). Topological and AIM analyses have been performed for hydrogen bonded complex in this reaction profile. Intrinsic reaction coordinates [IRC, minimum-energy path (MEP)] calculation connects the transition state between R-INT1, INT1-P1 and INT1-P2. The products P1, P2 and P3 are energetically more stable than the reactant and hence the reaction enthalpy is found to be exothermic. [ABSTRACT FROM AUTHOR]

The copper-catalyzed coupling of diaryl disulfides with alkyl amines can afford various sulfenamides in good yields. Furthermore, the present reaction is efficient and can be used for both of the aryl sulfide groups on disulfide. [ABSTRACT FROM AUTHOR]