Cysteine Derivatives Research Articles

Single-molecule force spectroscopic study on chiral recognition of cysteine derivatives immobilized on a gold substrate by using AFM tips chemically modified with optically active crown ethers

The chiral recognition of cysteine derivatives on a gold substrate was investigated using AFM tips modified with optically active crown ethers.

An open‐label pilot study of N‐acetylcysteine for skin‐picking in Prader–Willi syndrome

Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder caused by an abnormality on the long arm of chromosome 15 (q11-q13) that results in a host of behavioral characteristics including excessive interest in food, skin picking, difficulty with a change in routine, and obsessive and compulsive behaviors. Skin-picking can result in serious and potentially life-threatening infections. Recent evidence suggests that the excitatory neurotransmitter glutamate is dysregulated in obsessive-compulsive behaviors, and modulation of the glutaminergic pathway may decrease compulsive behaviors, such as recurrent hair pulling or skin-picking behaviors. N-acetylcysteine (NAC), a derivative of the amino acid cysteine, is thought to act either via modulation of NMDA glutamate receptors or by increasing glutathione in pilot studies. Thirty-five individuals with confirmed PWS (ages 5-39 years, 23 females/12 males) and skin-picking behavior for more than 1 year were treated with N-acetylcysteine (Pharma-NAC®) at a dose of 450-1,200 mg/day. Skin-picking symptoms and open lesions were assessed after 12 weeks of treatment by counting and measuring lesions before and after the medication. All 35 individuals had improvement in skin-picking behaviors. Ten (29%) individuals (six males and four females) did not have complete resolution of skin-picking behavior, but had significant reduction in the number of active lesions. Longer-term, placebo-controlled trials are needed to further assess the potential benefit of this treatment.

The roles of counterion and water in a stereoselective cysteine-catalyzed Rauhut-Currier reaction: a challenge for computational chemistry.

The stereoselective Rauhut-Currier (RC) reaction catalyzed by a cysteine derivative has been explored computationally with density functional theory (M06-2X). Both methanethiol and a chiral cysteine derivative were studied as nucleophiles. The complete reaction pathway involves rate-determining elimination of the thiol catalyst from the Michael addition product. The stereoselective Rauhut-Currier reaction, catalyzed by a cysteine derivative as a nucleophile, has also been studied in detail. This reaction was experimentally found to be extremely sensitive to the reaction conditions, such as the number of water equivalents and the effect of potassium counterion. The E1cB process for catalyst elimination has been explored computationally for the eight possible stereoisomers. The effect of explicit water solvation and the presence of counterion (either K(+) or Na(+) ) has been studied for the lowest energy enantiomer pair (1S, 2R, 3S)/(1R, 2S, 3R).

EP03 Therapeutic outlook for hydrogen sulfide donors

Considerable evidence has accumulated in recent years suggesting that H 2 S, synthesised from l -cysteine via cystathionine γ lyase (CSE) or cystathionine β synthase (CBS) or from 3-mercaptopyruvate via 3-mercaptopyruvate transferase (3-MST), plays a significant part in a range of physiological and/or pathophysiological processes. The possibility that either manipulating endogenous H 2 S biosynthesis or using H 2 S donor drugs may lead to new therapeutic entities was raised several years ago (e.g. [1] ). Increasingly, H 2 S is being thought of as a cytoprotective agent which restores physiological function in diseased cells or organ systems and hence interest has centred on identifying novel H 2 S donors. To date, a number of H 2 S donors have been characterized. These include thiones such as 5-( p -hydroxyphenyl)-1,2-dithione-3-thione (ADT-OH), cysteine derivatives such as S-allylcysteine (SAC) and S-propargyl-cysteine (S-SPRC), GYY4137 (morpholin-4-ium 4 methoxyphenyl (morpholino) phosphinodithioate), H 2 S-releasing derivatives of non-steroidal anti-inflammatory drugs (NSAID) such as S-diclofenac and, recently, a nitric oxide (NO) and H 2 S-releasing derivative of aspirin. In addition, sulfide salts such as sodium hydrosulfide (NaHS) also release H 2 S. Other H 2 S-releasing drugs are no doubt in the pipeline. Potential applications of some or all of these compounds include such diverse conditions as hypertension, cardiac failure, ischemic reperfusion injury, acute and chronic inflammation, cancer and even to promote healthy aging. For example, GYY4137 reduces knee joint swelling in mice injected with Freund’s adjuvant [2] and is anti-tumor in the mouse [3] . Thus, H 2 S donors have shown early promise in a range of therapeutic areas. The further development of H 2 S donors presents a number of difficulties. For example, equating plasma concentration of released H 2 S from such donors with biological activity in an animal model (or in man) is problematic since, not only is H 2 S rapidly metabolized to an array of products, but current techniques to measure the concentration of this endogenous gas are likely insufficiently sensitive or selective. In addition, efficacy would be better correlated with H 2 S concentration at the site where the gas produces its biological effect (not plasma) which may be extracellular or even intracellular perhaps close to or in mitochondria. Further work is also needed to assess the cell permeability of H 2 S donors in order to determine whether they ‘carry’ H 2 S into cells thereby ‘loading’ the cell with the gas. This presentation will provide an overview of the potential for H 2 S donors in the clinic.

Solid-phase synthesis of reduced selenocysteine tetrapeptides and their oxidized analogs containing selenenylsulfide eight-membered rings

A series of protected and reduced forms of model tetrapeptides that mimic the C-terminus of human thioredoxin reductases were obtained in good yields, using solid-phase peptide synthesis (SPPS). SPPS was performed on the Knorr Amide MBHA resin for Fmoc chemistry using especially protected cystein and selenocystein derivatives. All amino acids have been coupled according to the HBTU/HOBt/DIPEA method. Furthermore, the corresponding oxidized peptides containing eight-membered rings with intramolecular S-S and S-Se bridges were prepared via I[Formula: see text]/MeOH or DMSO/TFA oxidation, respectively.

A Chemical Proteomics Approach to Profiling the ATP-binding Proteome of Mycobacterium tuberculosis

Tuberculosis, caused by Mycobacterium tuberculosis, remains one of the leading causes of death worldwide despite extensive research, directly observed therapy using multidrug regimens, and the widespread use of a vaccine. The majority of patients harbor the bacterium in a state of metabolic dormancy. New drugs with novel modes of action are needed to target essential metabolic pathways in M. tuberculosis; ATP-competitive enzyme inhibitors are one such class. Previous screening efforts for ATP-competitive enzyme inhibitors identified several classes of lead compounds that demonstrated potent anti-mycobacterial efficacy as well as tolerable levels of toxicity in cell culture. In this report, a probe-based chemoproteomic approach was used to selectively profile the M. tuberculosis ATP-binding proteome in normally growing and hypoxic M. tuberculosis. From these studies, 122 ATP-binding proteins were identified in either metabolic state, and roughly 60% of these are reported to be essential for survival in vitro. These data are available through ProteomeXchange with identifier PXD000141. Protein families vital to the survival of the tubercle bacillus during hypoxia emerged from our studies. Specifically, along with members of the DosR regulon, several proteins involved in energy metabolism (Icl/Rv0468 and Mdh/Rv1240) and lipid biosynthesis (UmaA/Rv0469, DesA1/Rv0824c, and DesA2/Rv1094) were found to be differentially abundant in hypoxic versus normal growing cultures. These pathways represent a subset of proteins that may be relevant therapeutic targets for development of novel ATP-competitive antibiotics.

Thermoresponsive Oligo(ethylene glycol) Functionalized Poly-l-cysteine

A series of new functional amino acids were prepared in high yield via thiol–ene Michael addition between l-cysteine and monomethoxy oligo(ethylene glycol) (OEG) functionalized methacrylates (OEGxMA) and acrylate (OEGxA). These OEGylated cysteine derivatives were converted into polymerizable N-carboxyanhydride (NCA) monomers using triphosgene. Subsequent ring-opening polymerization (ROP) of these NCA monomers gave a series of OEGylated poly-l-cysteine (poly-EGxMA-C or poly-EGxA-C) homopolypeptides. Depending on the length of OEG side chains, poly-EGxMA-C and poly-EGxA-C polypeptides displayed different solubility and secondary structure in water. More importantly, the obtained polypeptides can display reversible thermoresponsive properties in water when the x value is between 3 and 5. The synthetic strategy represents a highly efficient method to prepare nonionic functional polypeptides with tunable thermoresponsive properties.

Effect of fudosteine, a cysteine derivative, on airway hyperresponsiveness, inflammation, and remodeling in a murine model of asthma

AimsFudosteine is a cysteine derivative that is used as an expectorant in chronic bronchial inflammatory disorders. It has been shown to decrease the number of goblet cells in an animal model. This study examined the effects of fudosteine on airway inflammation and remodeling in a murine model of chronic asthma. Main methodsBALB/c mice were sensitized by an intraperitoneal injection of ovalbumin (OVA), and subsequently challenged with nebulized ovalbumin three days a week for four weeks. Seventy-two hours after the fourth challenge, airway hyperresponsiveness (AHR) and the cell composition of bronchoalveolar lavage (BAL) fluid were assessed. Fudosteine was administered orally at 10mg/kg or 100mg/kg body weight from the first to the fourth challenge. Key findingsWe investigated the effects of fudosteine on the development of allergic airway inflammation and airway hyperresponsiveness after chronic allergen challenges. The administration of fudosteine during the challenge with ovalbumin prevented the development of airway hyperresponsiveness and accumulation of lymphocytes in the airways. Eotaxin, IL-4, and TGF-β levels and the relative intensity of matrix metalloproteinase-2 and matrix metalloproteinase-9 (MMP-2 and MMP-9) in BAL fluid were reduced by the fudosteine treatment; however, the number of eosinophils in BAL fluid and serum IgE levels did not change. The expression of TGF-β, the development of goblet cell hyperplasia, subepithelial collagenization, and basement membrane thickening were also reduced by the fudosteine treatment. SignificanceThese results indicate that fudosteine is effective in reducing airway hyperresponsiveness, airway inflammation, and airway remodeling in a murine model of chronic asthma.

Identification of unitary tight junction pore opening/closing events in MDCK monolayers

Analyses of epithelial barrier function have led to the hypothesis that tight junctions are populated by claudin‐dependent pores that define paracellular ion conductance and charge selectivity. Consistent with this claudin‐2 expression increases paracellular Na+ permeability of MDCK I monolayers. However, available measures cannot resolve function of individual pores. To overcome this limitation, we have used patch clamp techniques to define local tight junction function. Local tight junction recordings reveal transient 63±8 pS openings (0.004±0.001 Hz). Claudin‐2 expression reduces global TER by a 71±1% and increases the frequency of individual openings to 0.023±0.007 Hz without changing their size (57±3 pS). Ion substitution analyses demonstrate that the openings are selective for cations (PNa/PCl = 4.9 ± 0.9) with radii <2.8Å. Global analyses suggest that flux across claudin‐2I66C pores is blocked by cysteine derivatization. Consistent with this, while claudin‐2I66C expression had effects similar to claudin‐2 expression, openings in MDCK I expressing claudin‐2I66C were acutely terminated upon cysteine derivatization. These data show that claudin‐2 creates local, transient tight junction flux events that define global epithelial barrier function. We suggest that opening and closing of paracellular claudin pores forms the molecular basis of tight junction size and charge selectivity.

Flavor Precursors and Sensory-Active Sulfur Compounds in Alliaceae Species Native to South Africa and South America

Profiles of S-substituted cysteine flavor precursors were determined in 42 Alliaceae species native to South Africa and South America. It was found that the pool of cysteine derivatives present in these plants is remarkably very simple, with S-((methylthio)methyl)cysteine 4-oxide (marasmin) being the principal flavor precursor, typically accounting for 93-100% of the pool. Out of the other cysteine derivatives, only minor quantities of methiin were present in some species. The marasmin-derived thiosulfinate marasmicin (2,4,5,7-tetrathiaoctane 4-oxide), a major sensory-active compound of the freshly disrupted plants, was isolated, and its organoleptic properties were evaluated. Furthermore, sulfur-containing volatiles formed upon boiling of these alliaceous species were studied by GC-MS. The profile of the volatiles formed was relatively simple, with 2,3,5-trithiahexane and 2,4,5,7-tetrathiaoctane being the major components. Despite the traditional belief, ingestion of the marasmin-rich plants was always accompanied by development of a strong "garlic breath". We believe that especially several Tulbaghia species deserve to attract much greater attention from the food industry thanks to their pungent garlicky taste and unusual yet pleasant alliaceous smell.

Study of a cysteine derivative as a corrosion inhibitor for carbon steel in phosphoric acid solution

Inhibition of corrosion of carbon steel in phosphoric acid solution by use of l-cysteine methyl ester hydrochloride has been investigated by measurement of weight loss and use of electrochemical methods. The efficiency of inhibition was increased by increasing the concentration of the inhibitor and reduced by increasing the temperature. Polarization studies revealed that this compound behaves as mixed-type inhibitor. Electrochemical impedance spectroscopy showed that dissolution of the steel occurs as a result of charge-transfer. Adsorption of the inhibitor obeyed the Langmuir adsorption isotherm. Kinetic and thermodynamic data were calculated and are discussed.

Rational design, characterization and catalytic application of metal clusters functionalized with hydrophilic, chiral ligands: a proof of principle study

A proof of principle is presented for the rational design of metal clusters functionalized with hydrophilic, chiral ligands. A colloidal method is used to prepare "unprotected" metal clusters of well-defined size that are subsequently functionalized in a separate step with hydrophilic, chiral ligands. As clusters from the same batch are functionalized with different organic molecules while the cluster size is maintained, the approach allows for systematic investigations and the differences in the observed properties to be related to the influence of the functionalizing ligand. Within this work cysteine and two cysteine derivatives (glutathione and N-acetyl-cysteine) are used as functionalizing ligands for Pt clusters. The materials are characterized using various methods allowing for the determination of ligand coverage, binding mode and chiro-optical properties. Finally, 2-butanone hydrogenation is used as a simple model reaction to demonstrate that these systems exhibit the potential to be used as asymmetric, heterogeneous catalysts. The observed differences in selectivity and reactivity are discussed based on the knowledge gained from the characterization.

Maleimide-containing polymer inverse opals: a new kind of reactive photonic structure with significant extendibility

In this work, maleimide-containing polymer inverse opals have been successfully prepared by utilization of an acrylate monomer bearing a masked (protected) maleimide unit. As an ideal clickable functional group, maleimide can promote the Michael addition of thiol-containing molecules and the thermoreversible Diels–Alder reaction of furan derivatives, providing tremendous opportunities to produce various functional materials from one maleimide-containing polymer. As a demonstration, four chemical systems were facilely evolved from the prepared maleimide-containing inverse opal. By exploiting the nucleophilic thiol–ene reaction of maleimide, the zwitterionic pH-responsive inverse opal and electroactive inverse opal were first fabricated by reacting with cysteine and thiol-containing ferrocene derivatives, respectively. Based on the same reaction, it was also found that the maleimide-containing inverse opal could serve as a self-reporting sensing platform to sensitively detect the reduction of oxidized glutathione by specific enzymes. On the other hand, the thermoreversible nature of the Diels–Alder reaction of the maleimide groups made it possible to construct a dynamic molecule gating system by reacting with alkyl-chain-substituted furan derivatives from the prepared interconnected macroporous film. In fact, due to the unlimited variety provided by the two kinds of reactions mentioned above, the described photonic material exhibits a significant extendibility and could be easily post-modified for special purposes with maintenance of the opaline structure. Thus, this novel clickable maleimide-containing polymer inverse opal could serve as a reactive platform for producing a variety of functional photonic materials.

The phenacyl group as an efficient thiol protecting group in a peptide condensation reaction by the thioester method

One of the condensation methods for the preparation of long-chain peptides, the so-called thioester method requires protecting groups for amino and thiol groups for regioselective ligation. In this study, we demonstrated that the phenacyl (Pac) group acts as an efficient protecting group of cysteine side chains. We synthesized a cysteine derivative carrying the Pac group at the side chain sulfur atom, and Pac-containing peptides and peptide thioesters were synthesized using it by the ordinary 9-fluorenylmethoxycarbonyl (Fmoc)-based solid-phase peptide synthesis strategy. Pac-containing peptide segments could be condensed by the thioester method. After the condensation reaction, Pac groups could be removed by Zn/AcOH treatment. In addition, the azido group, which was used for the protection of lysine side chains, was simultaneously converted into an amino group, demonstrating that this protecting group scheme simplified the deprotecting reaction after the peptide condensation reaction to a single step.

Intramolecular hydrogen-bonding activation in cysteines: a new effective radical scavenger

The challenge of developing organic molecules with improved antioxidant activities for a competitive marketplace requires, given the great amount of possibilities, much laboratory work. Nowadays, the ability of methodologies based on quantum chemistry to determine the influence of different modifications on a molecule core provides a powerful tool for selecting the most useful derivatives to be synthesized. Here, we report the results of the assessment of antioxidant activity for quaternary amino acids, specifically for cysteine derivatives. The effect of introducing different substituents on the cysteine core is evaluated by using DFT to obtain an adequate structure-antioxidant activity relationship. This theoretical study shows a small panel of targets among which (R)-N-acetyl-2-methylcysteine methyl ester 15 exhibits special features and relevant antioxidant activity. The conformational (1)H NMR study of this synthesized compound indicates the existence of an intramolecular C7 member ring involving S-HO[double bond, length as m-dash]C substructure, which is reported for the first time in the literature for this amino acid unit. This unusual conformation seems to be the reason for the high antioxidant capacity experimentally found for this compound.

튀긴 마늘 flake 제조조건의 최적화 및 이화학적 특성

This study was carried out in order to optimize the manufacturing condition of fried garlic flakes as well as to investigate the physicochemical properties of the flakes. Fried garlic flake samples were prepared as follows: garlic was sliced by a thickness of 1.5 mm, 2.0 mm, 2.5 mm, which were measured by a thickness gage. The samples were fried in vegetable oil under different temperatures of <TEX>$140{\sim}150^{\circ}C$</TEX>, <TEX>$160{\sim}170^{\circ}C$</TEX> and <TEX>$180{\sim}185^{\circ}C$</TEX>. The compression strength depending on the height (h) was measured in order to find the thickness effect by the rheometer (force control: 50 N, h: 3.25 mm). Moreover, the sample with 1.5 mm thickness showed crisp phenomena of the split compared with the crush shape of the 2.0 mm and 2.5 mm thick samples. The result of strength for time dependence showed a sample with a thickness of 1.5 mm, which was measured 5~9 times more than the 2.0 mm and 2.5 mm thick samples. We thought the reason that the 1.5 mm sample had less response power equivalent to compression force than the other samples. Alliin has been found to affect the immune responses in the blood, it is a derivative of the amino acid cysteine and is also quite heat stable. The LC system with a UV detection at 210 nm consists of a separation on a Zorbax TMS column and isocratic elution with water and ACN as a mobile phase. The alliin contents of raw and fried garlic flake under <TEX>$140{\sim}150^{\circ}C$</TEX>, <TEX>$160{\sim}170^{\circ}C$</TEX> and <TEX>$180{\sim}185^{\circ}C$</TEX> were 18.10 mg/mL, 14.0 mg/mL, 11.6 mg/mL and 11.1 mg/mL, respectively. The decrement of alliin content under different temperature was a small quantity hence, we confirmed that the increasing manufacturing temperature was not affected by the alliin content. Examining for the particle structure of fried garlic flakes by a polarization microscope, the color of the sample treated at <TEX>$160{\sim}170^{\circ}C$</TEX> was pure yellow. Furder, the fiber shaped particle, which has an effect on the tough texture, almost did not appear compared to the different temperature conditions. Finally, the sensory test for the preference of fried garlic flake under different conditions was carried out and the scores for various sensory characteristics were surveyed. According to the physicochemical measurements and sensory evaluation, we confirmed that the optimum manufacturing condition of fried garlic flake was 1.5 mm thick at a temperature of <TEX>$160{\sim}170^{\circ}C$</TEX>.

Selective detection of cysteine/cystine using silver nanoparticles

The selective detection of cysteine and cystine amino acids over other standard amino acids was possible with the naked eye using silver nanoparticles (AgNPs) in a simple procedure at room temperature. The change in color and the aggregation of NPs were studied using UV–vis spectroscopy and transmission electron microscopy, respectively. It was observed that when the derivative and substructures of cysteine were employed as analytes the detection was possible only when there is free SH or S–S group present in the analytes. The method was extended to a dipeptide ‘cys-gly’ as a model peptide where the detection was successful due to the presence of SH moiety.

N-acetylcysteine augmentation in treatment resistant obsessive compulsive disorder: A case series

BackgroundEvidence-based, first-line treatments for obsessive compulsive disorder, (OCD) include the serotonin reuptake inhibitors (SRI), however, 40–60% of OCD patients do not respond. A wide variety of agents have been examined as adjuncts to standard SRI treatment in cases of treatment resistance, however, no gold-standard approach has been identified. Glutamate dysfunction is now thought to have a role in OCD, and use of glutamatergic treatment agents may hold promise. N-acetylcysteine (NAC) is an amino acid derivative of cysteine, available as a health supplement. It has shown efficacy in OCD-spectrum disorders and in 1 case report of treatment resistant OCD. MethodA retrospective chart review of 6 treatment resistant OCD patients, who had been treated with NAC for 6–12 weeks. Symptom severity was evaluated at regular clinic visits. ResultsFive of 6 patients took NAC for 12 weeks. The mean endpoint dose was 2833.3±408.2mg/day. Only 1/6 patients responded to treatment with NAC; two patients reported a worsening of symptoms; no patients reported adverse events. ConclusionsNAC was not effective in this sample of treatment-refractory OCD patients. Whether this result was a function of the mechanism of action of NAC or of the pathophysiology of treatment refractory OCD, remains unclear.

N-Acetylcysteine ethyl ester (NACET): A novel lipophilic cell-permeable cysteine derivative with an unusual pharmacokinetic feature and remarkable antioxidant potential

Recent large clinical trials failed to confirm the supposed beneficial effects of N-acetylcysteine (NAC) in preventing oxidative stress-related diseases. This may be due to its low bioavailability. We thought that esterification of the carboxyl group of NAC to produce N-acetylcysteine ethyl ester (NACET) would drastically increase the lipophilicity of NAC, thus greatly improving its pharmacokinetics.In the present work, we report on representative chemical, pharmacological and anti-oxidant properties of NACET, especially in direct comparison with its congener NAC. We found that NACET is rapidly absorbed in rats after oral administration but reaches very low concentrations in plasma. This is due to a unique feature of NACET: it rapidly enters the cells where it is trapped being transformed into NAC and cysteine. After oral treatment, NACET (but not NAC) was able to increase significantly the glutathione content of most tissues examined, brain included, and to protect from paracetamol intoxication in the rat. NACET has also the unique feature to accumulate in human erythrocytes where it behaves as a potent protector against hydroperoxide-induced oxidative damage. Our study shows that being able to enter cells and to produce NAC and cysteine, NACET increases circulating hydrogen sulfide (H2S), thus representing a good candidate for the oral use as an H2S producer, with clear advantages over NAC.NACET has the potential to substitute NAC as a mucolytic agent, as a paracetamol antidote and as a GSH-related antioxidant.

Characterization of Products from the Reaction of Glucosinolate-Derived Isothiocyanates with Cysteine and Lysine Derivatives Formed in Either Model Systems or Broccoli Sprouts

Glucosinolates, present in Brassica vegetables, are thought to contribute to human health prevention because of their enzymatically induced breakdown products, primarily isothiocyanates (ITCs). ITCs are reactive substances that readily react with nucleophilic (food) compounds. The reactivity of allyl-ITC and 4-(methylsulfinyl)butyl-ITC (sulforaphane) toward thiol and amino groups of cysteine and lysine derivatives was studied in buffered model systems as well as broccoli sprouts. The thiol group is the preferred reaction site, and it was demonstrated that even endogenously released sulforaphane is able to react very fast with cysteine in broccoli sprouts. Amino groups reacted slower and only under basic conditions. However, great differences in the reactivity between the different amino compounds were revealed. The aliphatic allylamine reacted very fast with allyl-ITC, forming N,N'-diallylthiourea, a compound identified as a main thermal degradation product of allyl-ITC.