Sulfinic Acid Research Articles

Determining the Molecular Basis for Differential Hyperoxidation Sensitivity in Peroxiredoxin 1 & 2

Oxidative stress, a cellular condition in which the levels of reactive oxygen species (ROS; e.g., hydrogen peroxide, H2O2) are too high, causes damage to macromolecules and has been linked to several pathologies including cancer, diabetes, Alzheimer's disease, and cardiovascular disease. One way cells maintain homeostatic levels of ROS is to produce a variety of peroxiredoxins (Prxs). Prxs are redox‐sensitive, antioxidant enzymes that remove H2O2. However, Prxs can be inactivated by hyperoxidation of the active site cysteine (Cys‐SPH) residue to Cys sulfinic acid (Cys‐SPO2H). Interestingly, Prx1 is more resistant to hyperoxidation than Prx2, despite the fact that they share 77% sequence identity and are both located in the cytoplasm. The molecular basis for this variability between isoforms in their susceptibilities to inactivation is unknown, but it is important to study since Prx inactivation is implicated in oxidative stress‐associated diseases. We hypothesize that residues unique to hPrx1 cause it to be more resistant to hyperoxidation. We have successfully cloned, expressed, and purified a library of chimeras that target groups of the most dissimilar residues between the two isoforms. We have determined the hyperoxidation sensitivity of the wild type hPrx1 and hPrx2 as well as each chimera using a variety of kinetic assays. By analyzing the changes these chimeras cause in hyperoxidation sensitivity, we have identified two novel, resistance‐conferring motifs.Sources of research support: AHA MAA: 14PRE19970007, NIGMS/NIH: R01 GM072866

ChemInform Abstract: Metal‐Free, High Yielding Synthesis of Unsymmetrical Biaryl, Bi(heteroaryl), Aryl Vinyl, Aryl Alkyl Sulfones via Coupling of Aryne with Sulfinic Acid Salts.

Here, we report a metal-free, high yielding method for the synthesis of unsymmetrical biaryl sulfones via coupling of aryne with sulfinic acid salts. The optimized condition also works efficiently for bi(heteroaryl), aryl vinyl and aryl alkyl sulfones. The present method took comparatively shorter reaction times and has good functional group compatibility.

Structural and optical properties of CdTe-nanocrystals thin films grown by chemical synthesis

By mans of a chemical synthesis technique stoichiometric CdTe-nanocrystals thin films were prepared on glass substrates at 70°C. First, Cd(OH)2 films were deposited on glass substrates, then these films were immersed in a growing solution prepared by dissolution of Te in hydroxymethane sulfinic acid to obtain CdTe. The structural analysis indicates that CdTe thin films have a zinc-blende structure. The average nanocrystal size was 19.4nm and the thickness of the films 170nm. The Raman characterization shows the presence of the longitudinal optical mode and their second order mode, which indicates a good crystalline quality. The optical transmittance was less than 5% in the visible region (400–700nm). The compositional characterization indicates that CdTe films grew with Te excess.

A one-pot O-sulfinative Passerini/oxidation reaction: synthesis of α-(sulfonyloxy)amide derivatives.

We have developed a one-pot O-sulfinative Passerini/oxidation reaction, in which a combination of an aldehyde, an isocyanide, and a sulfinic acid react, followed by the addition of mCPBA as an oxidant to give the corresponding α-(sulfonyloxy)amides in high yields. This reaction is the first reported demonstration of an isocyanide-based multicomponent reaction using a sulfinic acid in place of a carboxylic acid. A wide range of aldehydes and isocyanides are applicable to this reaction.

Catalytic Asymmetric Addition of Meldrum’s Acid, Malononitrile, and 1,3‐Dicarbonyls to ortho‐Quinone Methides Generated In Situ Under Basic Conditions

A new approach to the utilization of highly reactive and unstable ortho-quinone methides (o-QMs) in catalytic asymmetric settings is presented. The enantioselective reactions are catalysed by bifunctional organocatalysts, and the o-QM intermediates are formed in situ from 2-sulfonylalkyl phenols through base-promoted elimination of sulfinic acid. The use of mild Brønsted basic conditions for transiently generating o-QMs in catalytic asymmetric processes is unprecedented, and allows engaging productively in the reactions nucleophiles such as Meldrum's acid, malononitrile and 1,3-dicarbonyls. The catalytic transformations give new and general entries to 3,4-dihydrocoumarins, 4H-chromenes and xanthenones. These frameworks are recurring structures in natural product and medicinal chemistry, as testified by the formal syntheses of (R)-tolterodine and (S)-4-methoxydalbergione from the catalytic adducts.

ChemInform Abstract: Iron‐Catalyzed Direct Difunctionalization of Alkenes with Dioxygen and Sulfinic Acids: A Highly Efficient and Green Approach to β‐Ketosulfones.

A novel iron-catalyzed direct difunctionalization of alkenes with sulfinic acids and dioxygen for the synthesis of β-ketosulfones has been developed under mild conditions. The present protocol, which utilizes an inexpensive iron salt as the catalyst, readily available benzenesulfinic acids as the sulfonylating reagents, and dioxygen as the oxidant and oxygen source, provides a cost-effective and environmentally benign approach to access various β-ketosulfones.

Direct difunctionalization of alkenes with sulfinic acids and NBS leading to β-bromo sulfones

A new and metal-free method has been developed for the synthesis of β-bromo sulfones through the direct difunctionalization of alkenes with sulfinic acids and NBS. This protocol provides a simple, convenient, and efficient approach to various β-bromo sulfones in moderate to good yields with excellent selectivity, and especially does not require any catalyst or additive.

One-pot synthesis of aryl sulfones from organometallic reagents and iodonium salts.

A transition-metal-free arylation of lithium, magnesium, and zinc sulfinates with diaryliodonium salts is described. The sulfinic acid salts were prepared from the reaction of the corresponding organometallic reagents and sulfur dioxide. Combination of the three single steps (preparation of the organometallic compound, sulfinate formation, and arylation) leads to a one-pot sequence for the synthesis of aryl sulfones from simple starting materials. The chemoselectivity of unsymmetrical diaryliodonium salts has been investigated. Potential and limitations of this method will be discussed.

Pharmacological characterization of mGlu1 receptors in cerebellar granule cells reveals biased agonism

The majority of existing research on the function of metabotropic glutamate (mGlu) receptor 1 focuses on G protein-mediated outcomes. However, similar to other G protein-coupled receptors (GPCR), it is becoming apparent that mGlu1 receptor signaling is multi-dimensional and does not always involve G protein activation. Previously, in transfected CHO cells, we showed that mGlu1 receptors activate a G protein-independent, β-arrestin-dependent signal transduction mechanism and that some mGlu1 receptor ligands were incapable of stimulating this response. Here we set out to investigate the physiological relevance of these findings in a native system using primary cultures of cerebellar granule cells. We tested the ability of a panel of compounds to stimulate two mGlu1 receptor-mediated outcomes: (1) protection from decreased cell viability after withdrawal of trophic support and (2) G protein-mediated phosphoinositide (PI) hydrolysis. We report that the commonly used mGlu1 receptor ligands quisqualate, DHPG, and ACPD are completely biased towards PI hydrolysis and do not induce mGlu1 receptor-stimulated neuroprotection. On the other hand, endogenous compounds including glutamate, aspartate, cysteic acid, cysteine sulfinic acid, and homocysteic acid stimulate both responses. These results show that some commonly used mGlu1 receptor ligands are biased agonists, stimulating only a fraction of mGlu1 receptor-mediated responses in neurons. This emphasizes the importance of utilizing multiple agonists and assays when studying GPCR function.

Acid catalyzed alcoholysis of sulfinamides: unusual stereochemistry, kinetics and a question of mechanism involving sulfurane intermediates and their pseudorotation.

The synthesis of optically active sulfinic acid esters has been accomplished by the acid catalyzed alcoholysis of optically active sulfinamides. Sulfinates are formed in this reaction with a full or predominant inversion of configuration at chiral sulfur or with predominant retention of configuration. The steric course of the reaction depends mainly on the size of the dialkylamido group in the sulfinamides and of the alcohols used as nucleophilic reagents. It has been found that bulky reaction components preferentially form sulfinates with retention of configuration. It has been demonstrated that the stereochemical outcome of the reaction can be changed from inversion to retention and vice versa by adding inorganic salts to the acidic reaction medium. The unusual stereochemistry of this typical bimolecular nucleophilic substitution reaction, as confirmed by kinetic measurements, has been rationalized in terms of the addition-elimination mechanism, A-E, involving sulfuranes as intermediates which undergo pseudorotations.

Mitochondrial peroxiredoxin functions as crucial chaperone reservoir in Leishmania infantum

Cytosolic eukaryotic 2-Cys-peroxiredoxins have been widely reported to act as dual-function proteins, either detoxifying reactive oxygen species or acting as chaperones to prevent protein aggregation. Several stimuli, including peroxide-mediated sulfinic acid formation at the active site cysteine, have been proposed to trigger the chaperone activity. However, the mechanism underlying this activation and the extent to which the chaperone function is crucial under physiological conditions in vivo remained unknown. Here we demonstrate that in the vector-borne protozoan parasite Leishmania infantum, mitochondrial peroxiredoxin (Prx) exerts intrinsic ATP-independent chaperone activity, protecting a wide variety of different proteins against heat stress-mediated unfolding in vitro and in vivo. Activation of the chaperone function appears to be induced by temperature-mediated restructuring of the reduced decamers, promoting binding of unfolding client proteins in the center of Prx's ringlike structure. Client proteins are maintained in a folding-competent conformation until restoration of nonstress conditions, upon which they are released and transferred to ATP-dependent chaperones for refolding. Interference with client binding impairs parasite infectivity, providing compelling evidence for the in vivo importance of Prx's chaperone function. Our results suggest that reduced Prx provides a mitochondrial chaperone reservoir, which allows L. infantum to deal successfully with protein unfolding conditions during the transition from insect to the mammalian hosts and to generate viable parasites capable of perpetuating infection.

ChemInform Abstract: Tandem Diels—Alder and Retro‐Ene Reactions of 1‐Sulfenyl‐ and 1‐Sulfonyl‐1,3‐dienes as a Traceless Route to Cyclohexenes.

A pericyclic approach for the synthesis of six-membered ring structures is described. The method employs 1,3-dienes with a 1-sulfur substituent in a tandem sequence of Diels–Alder and retro-ene reactions. In this pairing of [4 + 2] cycloaddition and 1,5-sigmatropic rearrangement, 1-sulfenyl-1,3-dienes engage in Diels–Alder reactions with electron-deficient dienophiles. Subsequently, the sulfenyl group of the cycloadducts is oxidized and unmasked to form allylic sulfinic acids, which undergo sterospecific reductive transposition via sulfur dioxide extrusion. The sequence can also include an inverse electron demand Diels–Alder reaction by using a 1-sulfonyl-1,3-diene. This combination of two pericyclic events offers novel stereocontrolled access to cyclohexenes that are inaccessible via a direct [4 + 2] cycloaddition route.

ChemInform Abstract: Synthesis of Oxindoles Through Silver‐Catalyzed Trifluoromethylation—, Difluoromethylation— and Arylsulfonylation—Cyclization Reaction of N‐Arylacrylamides.

Efficient synthesis of trifluoromethyl and difluoromethyl-substituted oxindoles was achieved by reacting Langlois reagent or Baran reagent with N-arylacrylamides. However, the reaction of aryl sulfinic acid sodium salts with N-arylacrylamides did not give the desulfinative products, instead, aryl sulfonated products were produced.

Alkyl Sulfinates: Formal Nucleophiles for Synthesizing TosMIC Analogs.

Alkyl sulfinates function as formal nucleophiles in Mannich-type reactions to give sulfonyl formamides, which are readily dehydrated to the corresponding sulfonylmethyl isonitriles. The efficient, two-step synthesis provides a general route to sulfonylmethyl isonitriles from readily available methyl sulfinates or thiols. Mechanistic analysis reveals that the unusual nucleophlicity of the alkyl sulfinates arises from the in situ release of sulfinic acids.

ChemInform Abstract: Sulfinate Derivatives: Dual and Versatile Partners in Organic Synthesis

AbstractReview: [58 refs.

Peroxide-mediated oxidation and inhibition of the peptidyl-prolyl isomerase Pin1

Pin1 is a phosphorylation-dependent peptidyl-prolyl isomerase that plays a critical role in mediating protein conformational changes involved in signaling processes related to cell cycle control. Pin1 has also been implicated as being neuroprotective in aging-related neurodegenerative disorders including Alzheimer's disease where Pin1 activity is diminished. Notably, recent proteomic analysis of brain samples from patients with mild cognitive impairment revealed that Pin1 is oxidized and also displays reduced activity. Since the Pin1 active site contains a functionally critical cysteine residue (Cys113) with a low predicted pKa, we hypothesized that Cys113 is sensitive to oxidation. Consistent with this hypothesis, we observed that treatment of Pin1 with hydrogen peroxide results in a 32Da mass increase, likely resulting from the oxidation of Cys113 to sulfinic acid (Cys-SO2H). This modification results in loss of peptidyl-prolyl isomerase activity. Notably, Pin1 with Cys113 substituted by aspartic acid retains activity and is no longer sensitive to oxidation. Structural studies by X-ray crystallography revealed increased electron density surrounding Cys113 following hydrogen peroxide treatment. At lower concentrations of hydrogen peroxide, oxidative inhibition of Pin1 can be partially reversed by treatment with dithiothreitol, suggesting that oxidation could be a reversible modification with a regulatory role. We conclude that the loss of Pin1 activity upon oxidation results from oxidative modification of the Cys113 sulfhydryl to sulfenic (Cys-SOH) or sulfinic acid (Cys-SO2H). Given the involvement of Pin1 in pathological processes related to neurodegenerative diseases and to cancer, these findings could have implications for the prevention or treatment of disease.

Direct difunctionalization of alkynes with sulfinic acids and molecular iodine: a simple and convenient approach to (E)-β-iodovinyl sulfones

A simple and convenient approach for the construction of β-iodovinyl sulfones has been developed via direct difunctionalization of alkynes with sulfinic acids and molecular iodine.

Operando X-ray absorption and EPR evidence for a single electron redox process in copper catalysis.

An unprecedented single electron redox process in copper catalysis is confirmed using operando X-ray absorption and EPR spectroscopies. The oxidation state of the copper species in the interaction between Cu(ii) and a sulfinic acid at room temperature, and the accurate characterization of the formed Cu(i) are clearly shown using operando X-ray absorption and EPR evidence. Further investigation of anion effects on Cu(ii) discloses that bromine ions can dramatically increase the rate of the redox process. Moreover, it is proven that the sulfinic acids are converted into sulfonyl radicals, which can be trapped by 2-arylacrylic acids and various valuable β-keto sulfones are synthesized with good to excellent yields under mild conditions.

Byproduct promoted regioselective sulfenylation of indoles with sulfinic acids.

An unprecedented method to synthesise 3-sulfenylindoles is demonstrated via byproduct promoted sulfenylation of indoles with sulfinic acids in the absence of an external catalyst. The reaction selectively afforded structurally diverse indole thioethers in good to excellent yields in 1,2-dichloroethane at 80 °C.

Spectroscopic and Computational Studies of Nitrile Hydratase: Insights into Geometric and Electronic Structure and the Mechanism of Amide Synthesis.

Nitrile hydratases (NHases) are mononuclear nonheme enzymes that catalyze the hydration of nitriles to amides. NHase is unusual in that it utilizes a low-spin (LS) FeIII center and a unique ligand set comprised of two deprotonated backbone amides, cysteine-based sulfenic acid (RSO(H)) and sulfinic acid (RSO2-), and an unmodified cysteine trans to an exogenous ligand site. Electron paramagnetic resonance (EPR), magnetic circular dichroism (MCD) and low-temperature absorption (LT-Abs) spectroscopies are used to determine the geometric and electronic structures of butyrate-bound (NHaseBA) and active (NHaseAq) NHase. These data calibrate DFT models, which are then extended to explore the mechanism of nitrile hydration by NHase. In particular, the nitrile is activated by coordination to the LS FeIII and the sulfenate group is found to be deprotonated and a significantly better nucleophile than water that can attack the coordinated nitrile to form a cyclic species. Attack at the sulfenate S atom of the cyclic species is favorable and leads to a lower kinetic barrier than attack by water on coordinated, uncyclized nitrile, while attack at the C of the cyclic species is unfavorable. The roles of the unique ligand set and low-spin nature of the NHase active site in function are also explored. It is found that the oxidized thiolate ligands are crucial to maintaining the LS state, which is important in the binding and activation of nitrile susbtrates. The dominant role of the backbone amidate ligands appears to be as a chelate in keeping the sulfenate properly oriented for nucleophilic attack on the coordinated substrate.