Amino Acid Derivatives Research Articles

A Method for Rigorously Selective Capture and Simultaneous Fluorescent Labeling of N-Terminal Glycine Peptides.

Although chemical methods for the selective derivatization of amino acid (AA) side chains in peptides and proteins are available, selective N-terminal labeling is challenging, especially for glycine, which has no side chain at the α-carbon position. We report here a double activation at glycine's α-methylene group that allows this AA to be differentiated from the other 19 AAs. A condensation reaction of dibenzoylmethane with glycine results in the formation of an imine, and subsequent tautomerization is followed by intramolecular cyclization, leading to the formation of a fluorescent pyrrole ring. Additionally, the approach exhibits compatibility with AAs possessing reactive side chains. Further, the method allows for selective pull-down assays of N-terminal glycine peptides from mixtures without prior knowledge of the N-terminal peptide distribution.

Stereoselective Synthesis of 2‐Deoxy‐α‐N‐Glycosides from Glycals with 1,4,2‐Dioxazol‐5‐ones

Comprehensive SummaryThe synthesis of N‐glycosides has received significant attention due to their crucial role in carbohydrate chemistry. Despite considerable advancements developed in the construction of N‐glycosides, methods for the stereoselective construction of 2‐deoxy‐α‐N‐glycosides are still limited. Herein, we disclosed a nickel‐catalyzed hydroamination of glycals under mild conditions. This transformation could allow for the stereoselective synthesis of an array of 2‐deoxy‐α‐N‐glycosides with excellent α‐stereoselectivity. Nickel‐catalyzed glycosylation reactions, particularly those involving anomeric C(sp3)‐metal bond formation, have proven to be an effective and stereoselective strategy for producing various N‐glycosides. Additionally, with highlight of the application of this reaction, γ‐sugar amino acid derivatives were synthesized.

Construction of C5‐Indole Unnatural Amino Acid Motifs via Diastereoselective Pd(II)‐Catalyzed β‐C(sp3)‐H Functionalization

We report the construction of C5‐indole unnatural amino acid derivatives via the diastereoselective Pd(II)‐catalyzed prochiral β‐C(sp3)‐H arylation of racemic (DL), and enantiopure L‐ and D‐carboxamides of amino acids with 5‐iodoindoles. Independently, indole‐based compounds and amino acid motifs are important small molecules in organic synthesis and drug discovery research. This report aimed to contribute to enriching the library of indole‐based unnatural amino acid derivatives. The synthesis of examples of C5‐indole motif‐installed amino acid derivatives comprising norvaline, phenylalanine, leucine, norleucine, 2‐aminooctanoic acid having anti‐stereochemistry was accomplished. The synthesis of the C5‐indole motif‐containing non‐α‐amino acid (aminoalkanoic acid) derivatives was also reported. The C‐H arylation reactions of racemic and enantiopure carboxamides with 5‐iodoindoles afforded the corresponding indole unnatural amino acid derivatives with good diastereoselectivity (anti, dr >95:5 and enantiopurity (er up to 99:1). Removal of the directing group (8‐aminoquinoline), phthalimide group and preparation of indole amino acid esters and free amino group‐containing indole unnatural amino acid motifs were also shown. The utility of the methodology was shown by synthesizing indole motif‐containing pyrrolidone and peptide molecules. The stereochemistry of the major (anti) diastereomers was ascertained from the X‐ray structure of a representative compound.

A chiral metal–organic polyhedron used as stationary phase for gas chromatographic separations

Metal-organic polyhedra (MOPs), as a novel class of porous materials, exhibit distinctive application potential in molecular recognition, separation, catalysis, luminescent materials, drug delivery, and biomedicine owing to their tunable geometric shape and size, well-defined cavities, and discrete characteristics. In this study, we report that a chiral MOP [Cu12(LV)12(H2O)12] (V = L-valine) coated capillary column was used for gas chromatographic separations. The MOP coated capillary column offered the efficient separation of n-alkanes, alkylbenzenes, n-alcohols, multiple types of isomers, and enantiomers with high selectivity. Various enantiomers including esters, halogenated hydrocarbons, alcohols, ethers, aldehydes, and amino acid derivatives were well resolved on this chiral column, especially for some amino acid derivatives (e.g., Rs = 5.24 for tyrosine derivative). Compared with the commercial β-DEX 120 column for separation of the tested racemates, the chiral resolution performance of the MOP coated column can be complementary to that of β-DEX 120 column. Using 1,2-dichloropropane and o, m, p-dichlorobenzene as analytes, the MOP coated column exhibited good stability and reproducibility for gas chromatographic separations. The relative standard deviations (RSDs) of the retention time and peak area for repeated separation of 1, 2-dichloropropane and o, m, p-dichlorobenzene were less than 1.15 and 0.79 %, respectively. The results show that the chiral MOP holds great potential as a novel type of CSP for application in gas chromatography.

Multifunctional Amino Acid Derivative Coordination Compounds: Novel Contrast Agent and Luminescence Materials.

In this work a family of multidimensional (2-(1H-tetrazol-5-yl)ethyl) amino acid coordination compounds have been synthesized and thoroughly characterized. For this purpose, glycine, valine, phenylalanine and tyrosine have been selected as starting amino acids and Mn2+, Zn2+ and Cd2+ as metallic nodes. From one side, for Mn2+ based dimer magnetic resonance imaging studies have been conducted, prompted by the number and disposition of the coordinated water molecules and taking into consideration the promising future of manganese-based coordination compounds as bio-compatible substitutes to conventional Gd based contrast agents. From another side, d10 block metal-based complexes allowed exploring photoluminescence properties derived by in situ synthesized ligands. Finally, amino acid preserved structural chirality allowed us to examine chiroptical properties, particularly focusing on circularly polarized luminescence.

Regulation of Root Exudation in Wheat Plants in Response to Alkali Stress.

Soil alkalization is an important environmental factor limiting crop production. Despite the importance of root secretion in the response of plants to alkali stress, the regulatory mechanism is unclear. In this study, we applied a widely targeted metabolomics approach using a local MS/MS data library constructed with authentic standards to identify and quantify root exudates of wheat under salt and alkali stresses. The regulatory mechanism of root secretion in alkali-stressed wheat plants was analyzed by determining transcriptional and metabolic responses. Our primary focus was alkali stress-induced secreted metabolites (AISMs) that showed a higher secretion rate in alkali-stressed plants than in control and salt-stressed plants. This secretion was mainly induced by high-pH stress. We discovered 55 AISMs containing -COOH groups, including 23 fatty acids, 4 amino acids, 1 amino acid derivative, 7 dipeptides, 5 organic acids, 9 phenolic acids, and 6 others. In the roots, we also discovered 29 metabolites with higher levels under alkali stress than under control and salt stress conditions, including 2 fatty acids, 3 amino acid derivatives, 1 dipeptide, 2 organic acids, and 11 phenolic acids. These alkali stress-induced accumulated carboxylic acids may support continuous root secretion during the response of wheat plants to alkali stress. In the roots, RNAseq analysis indicated that 5 6-phosphofructokinase (glycolysis rate-limiting enzyme) genes, 16 key fatty acid synthesis genes, and 122 phenolic acid synthesis genes have higher expression levels under alkali stress than under control and salt stress conditions. We propose that the secretion of multiple types of metabolites with a -COOH group is an important pH regulation strategy for alkali-stressed wheat plants. Enhanced glycolysis, fatty acid synthesis, and phenolic acid synthesis will provide more energy and substrates for root secretion during the response of wheat to alkali stress.

Synthesis of Mixed Phosphonate Esters and Amino Acid-Based Phosphonamidates, and Their Screening as Herbicides.

While organophosphorus chemistry is gaining attention in a variety of fields, the synthesis of the phosphorus derivatives of amino acids remains a challenging task. Previously reported methods require the deprotonation of the nucleophile, complex reagents or hydrolysis of the phosphonate ester. In this paper, we demonstrate how to avoid these issues by employing phosphonylaminium salts for the synthesis of novel mixed n-alkylphosphonate diesters or amino acid-derived n-alkylphosphonamidates. We successfully applied this methodology for the synthesis of novel N-acyl homoserine lactone analogues with varying alkyl chains and ester groups in the phosphorus moiety. Finally, we developed a rapid, quantitative and high-throughput bioassay to screen a selection of these compounds for their herbicidal activity. Together, these results will aid future research in phosphorus chemistry, agrochemistry and the synthesis of bioactive targets.

Evaluating the efficacy of newly synthesized amino acid derivatives as corrosion inhibitors in acidic solutions

Three benzimidazole derivatives, with tryptophan (BIT), tyrosine (BIY), and histidine (BIH) amino acid units, have remarkable protective properties as eco-friendly corrosion inhibitors for steel under severe acidic conditions. At a temperature of 303 K, the corrosion inhibition efficiency of BIT, BIY, and BIH at a concentration of 10 mM is 90.09 %, 92.53 %, and 93.43 %, respectively. Electrochemical tests indicate that the adsorption of these substances on the substrate leads to an increase in charge transfer resistance and interfacial electric double layer thickness. This effectively hinders the dissolution of metal and the evolution of hydrogen. The analysis of the surface structure and appearance using SEM-EDS indicates that the inhibitors have the ability to create a protective coating through both chemical and physical bonding, effectively protecting the metal from corrosive substances. Theoretical calculations, such as Density Functional Theory (DFT) and Natural Bond Orbital (NBO) analysis, along with FUKUI analysis, help identify active sites and adsorption configuration. This enhances our understanding of the corrosion mitigation mechanism. These findings align with the experimental conclusion that the formation of a stable protective film contributes to superior inhibition performance against acidic corrosion conditions.

Design, synthesis, and evaluation of novel arecoline-linked amino acid derivatives for insecticidal and antifungal activities

A series of arecoline derivatives with amino acid moieties were designed and synthesised using an acylamide condensation strategy, taking arecoline as the foundational structure. The insecticidal efficacy of these compounds against Aphis craccivora and Tetranychus cinnabarinus was evaluated. Notably, derivatives 3h and 3i demonstrated superior insecticidal activity compared with arecoline. Additionally, 3h and 3i showed good fungicidal effectiveness against two types of plant fungi. Moreover, molecular docking analyses suggested that 3h and 3i could affect the nervous systems of A. craccivora and T. cinnabarinus by binding to neuronal nicotinic acetylcholine receptors. These findings suggest that compounds 3h and 3i represent promising leads for further development in insecticide and fungicide research.

A Study of the Micellar Formation of N-Alkyl Betaine Ethyl Ester Chlorides Based on the Physicochemical Properties of Their Aqueous Solutions.

In this study, a series of four surface-active compounds-N-alkyl betaine ethyl ester chlorides, CnBetC2Cl-were synthesized and characterized in aqueous solutions. As with other alkyl betaines, these amphiphiles can be practically used, for example, as co-surfactants and/or solubility enhancers acting according to hydrotropic or micellar mechanisms, depending on the alkyl chain length in the amine. We focused on the representatives of the medium alkyl chain length (C6-C12) to find the dependence between the alkyl chain length in N-alkyl betaine ethyl ester chlorides and the surface, volumetric, acoustic, and viscometric properties of their solutions. Ethyl esters, the derivatives of amino acids, were chosen to increase functionality and take advantage of possible hydrolysis in solutions at higher pH, which is also a key parameter in biodegradability. The micellization parameters were calculated based on the physicochemical characteristics. We focused our interest on the ester with a dodecyl substituent since we can compare and discuss its properties with some other C12 representatives that are available in literature. Surprisingly, its micellization characteristic is almost temperature-independent in the investigated temperature range, t = (15-45) °C. Particularly interesting are the results of dynamic light scattering (DLS), which show that the changes in physicochemical parameters of the C12 homolog around the CMC are caused by the two types of micelles of different sizes present in solutions.

Approach to Spirocyclohexadienes via Visible Light‐Mediated ipso‐Cyclization of Amino Acid Derivatives with N‐(2‐Phenyl)benzoyl Groups

Spirocycles are important structural motifs, found in natural and pharmaceutical compounds, which have attracted considerable interest in modern drug discovery research. Herein, we describe the development of a visible light‐mediated ipso‐cyclization of amino acid derivatives with N‐(2‐phenyl)benzoyl groups, allowing easy access to a variety of spirocyclohexadienes. The addition of water was found to be beneficial in promoting the reaction progress. Investigation of the substrate scope revealed that incorporating an electron‐donating moiety at the 3'‐position of the biphenyl group resulted in a more favorable outcome for spirocycle formation.

Inhibition of kynurenine production by N,O-substituted hydroxylamine derivatives

The inhibition of kynurenine production is considered a promising target for cancer immunotherapy. In this study, an amino acid derivative, compound 1 was discovered using a cell-based assay with our screening library. Compound 1 suppressed kynurenine production without inhibiting indoleamine 2,3-dioxygenase 1 (IDO1) activity. The activity of 1 was derived from the inhibition of IDO1 by a metabolite of 1, O-benzylhydroxylamine (OBHA, 2a). A series of N-substituted 2a derivatives that exhibit potent activity in cell-based assays may represent effective prodrugs. Therefore, we synthesized and evaluated novel N,O-substituted hydroxylamine derivatives. The structure–activity relationships revealed that N,O-substituted hydroxylamine 2c inhibits kynurenine production in a cell-based assay. We conducted an in vivo experiment with 2c, although the effectiveness of O-substituted hydroxylamine derivatives in vivo has not been previously reported. The results indicate that N,O-substituted hydroxylamine derivatives are promising IDO1 inhibitors.

Compounds based on Adamantyl-Substituted Amino Acids and Peptides as Potential Antiviral Drugs Acting as Viroporin Inhibitors.

The discussion has revolved around the derivatives of amino acids and peptides containing carbocycles and their potential antiviral activity in vitro against influenza A, hepatitis C viruses, and coronavirus. Studies conducted on cell cultures reveal that aminoadamantane amino acid derivatives exhibit the capacity to hinder the replication of viruses containing viroporins. Furthermore, certain compounds demonstrate potent virucidal activity with respect to influenza A/H5N1 and hepatitis C virus particles. A conceptual framework for viroporin inhibitors has been introduced, incorporating carbocyclic motifs as membranotropic carriers in the structure, alongside a functional segment comprised of amino acids and peptides. These components correspond to the interaction with the inner surface of the channel's pore or another target protein.

Carbonyl group-assisted 1,3-amine addition to α,β-unsaturated aldehydes

An unusual 1,3-addition products were obtained when amines were reacted with α,β-unsaturated aldehydes compounds in the presence of iodine and an oxidant. The versatile unsaturated α-amino acetals are highly useful amino acid derivatives and can be converted to a wide variety of synthetically useful building blocks. Various control experiments have shown that the reaction proceeded via a mechanism involving the formation of imine/enamine intermediates followed by a 1,2-amine group migration reaction.

Widely targeted metabolomics reveals the species‐specific, matureness‐specific and post‐harvest‐specific discriminations in the chemical profiles of Vietnamese endemic golden camellias

SummaryVietnam is one of the countries with the highest diversity of golden camellias in the world, with more than forty endemic species. However, studies on Vietnamese golden camellias need to be expanded to fill a knowledge gap on these species' chemical profiles and pharmacological properties. This qualitative study focuses on six golden camellias: four endemic species from Tam Dao district, Vinh Phuc province, including Camellia hakodae, Camellia phanii, Camellia tamdaoensis, Camellia tienii and two species commonly cultivated in Quang Ninh province including Camellia petelotii and Camellia euphlebia. A mutual profile of 131 metabolites was obtained by using widely targeted metabolomics analysis using ultra‐performance liquid chromatography coupled with tandem mass spectrometry. Comparative metabolomics was performed among leaf extracts of six golden teas, between young and mature leaves and between freeze‐drying and oven‐drying leaves to discriminate these species, and determine the effect of developmental stage and post‐harvesting method on the plant metabolism. The PLS‐DA model successfully illustrated a clear separation of the six species and suggested apigenin C‐glycoside derivatives as chemical markers for the diversity. Young and mature leaves of all six species also produced distinguished metabolomes, differentiated by mostly amino acid derivatives. The multivariate analysis also indicated the conversion of some flavonoids and amino acids induced by heat in the drying process. These results offer metabolite markers for quality control of Vietnamese golden camellias and recommendations for their usage and preparation.

Chemical range recognized by the ligand-binding domain in a representative amino acid-sensing taste receptor, T1r2a/T1r3, from medaka fish.

Taste receptor type 1 (T1r) proteins are responsible for recognizing nutrient chemicals in foods. In humans, T1r2/T1r3 and T1r1/T1r3 heterodimers serve as the sweet and umami receptors that recognize sugars or amino acids and nucleotides, respectively. T1rs are conserved among vertebrates, and T1r2a/T1r3 from medaka fish is currently the only member for which the structure of the ligand-binding domain (LBD) has been solved. T1r2a/T1r3 is an amino acid receptor that recognizes various l-amino acids in its LBD as observed with other T1rs exhibiting broad substrate specificities. Nevertheless, the range of chemicals that are recognized by T1r2a/T1r3LBD has not been extensively explored. In the present study, the binding of various chemicals to medaka T1r2a/T1r3LBD was analyzed. A binding assay for amino acid derivatives verified the specificity of this protein to l-α-amino acids and the importance of α-amino and carboxy groups for receptor recognition. The results further indicated the significance of the α-hydrogen for recognition as replacing it with a methyl group resulted in a substantially decreased affinity. The binding ability to the protein was not limited to proteinogenic amino acids, but also to non-proteinogenic amino acids, such as metabolic intermediates. Besides l-α-amino acids, no other chemicals showed significant binding to the protein. These results indicate that all of the common structural groups of α-amino acids and their geometry in the l-configuration are recognized by the protein, whereas a wide variety of α-substituents can be accommodated in the ligand binding sites of the LBDs.

Effect of fermentation containers on the taste characteristics and microbiota succession of soy sauce

Modernization of the traditional fermentation industry has been a major trend recently, such as the upgrading of fermentation containers. This study investigated the taste differences and their material basis of soy sauce fermented in tank and pond (SSFT and SSFP), and further explore the key influencing factors of taste. The intensities of umami, kokumi and sour taste in SSFT were weaker than SSFP, which were associated with 9 basic taste-active compounds, including acetic acid, lactic acid, propanedioic acid, citric acid, glutamic acid, alanine, tyrosine, d-galactose and erythritol. Moreover, 270 peptides and amino acid derivatives were potential compounds for taste difference, of which 78 % were more abundant in SSFP. Five bacterial genera (Kocuria, Tetragenococcus, Pediococcus, Staphylococcus, Weissella) and 4 fungal genera (Wickerhamiella, Millerozyma, Candida, Zygosaccharomyces) may be the functional core microbe for flavor differences in SSFT and SSFP. This study will provide theoretical value for quality improvement in the modern large-scale production of soy sauce.

A Thiourea Derivative of 2-[(1R)-1-Aminoethyl]phenol as a Chiral Sensor for the Determination of the Absolute Configuration of N-3,5-Dinitrobenzoyl Derivatives of Amino Acids.

In the exploration of chiral solvating agents (CSAs) for nuclear magnetic resonance (NMR) spectroscopy designed for the chiral analysis of amino acid derivatives, notable advancements have been made with thiourea-CSAs. 1-TU, derived from 2-[(1R)-1-aminoethyl]phenol and benzoyl isothiocyanate, is effective in the enantiodifferentiation of N-3,5-dinitrobenzoyl (N-DNB) amino acids. In order to broaden the application of 1-TU for configurational assignment, enantiomerically enriched N-DNB amino acids were analyzed via NMR. A robust correlation was established between the relative position of specific 1H and 13C NMR resonances of the enantiomers in the presence of 1-TU. 1,4-Diazabicyclo[2.2.2]octane (DABCO) was selected for the complete solubilization of amino acid substrates. Notably, the para and ortho protons of the N-DNB moiety displayed higher frequency shifts for the (R)-enantiomers as opposed to the (S)-enantiomers. This trend was consistently observed in the 13C NMR spectra for quaternary carbons bonded to NO2 groups. Conversely, an inverse correlation was noted for quaternary carbon resonances of the carboxyl moiety, amide carbonyl, and methine carbon at the chiral center. This observed trend aligns with the interaction mechanism previously reported for the same chiral auxiliary. The configurational correlation can be effectively exploited under conditions of high dilution or, significantly, under sub-stoichiometric conditions.

Chemical Synthesis of a Key Precursor Relevant to the Tetrasaccharide Repeating Unit from Treponema mediumATCC 700293

Comprehensive SummaryTreponema is a Gram‐negative anaerobic bacterium, among which the pathogenic Treponema can cause various diseases, such as venereal syphilis (Treponema pallidum), yaws (Treponema carateum), and oral diseases (Treponema denticola and Treponema medium). Although different from conventional lipopolysaccharides, the extracellular glycoconjugate of Treponema may still be a potential antigen and provide a candidate for vaccine development. Hence, we completed the first chemical synthesis of Treponema medium ATCC 700293 tetrasaccharide precursor containing L‐ornithine (L‐Orn) and D‐aspartic acid (D‐Asp) derivatives. The efficiency of non‐reducing end disaccharide formation has been improved by optimizing the assembly of the protecting groups in the donors and acceptors. Our [3+1] glycosylation strategy attempted to reduce the length of the acceptor to increase the nucleophilicity of the hydroxyl group, thereby improving the efficiency of synthesizing the target tetrasaccharide. The L‐Orn derivative was introduced at the final stage due to its influence on the glycosylation stereospecificity and efficiency. Therefore, the successful introduction of two amino acid derivatives and the synthesis of a tetrasaccharide precursor with complex functional‐group modifications have provided valuable insights for synthesizing other complex bacterial glycans.

Isohexide-Based Tunable Chiral Platforms as Amide- and Thiourea-Chiral Solvating Agents for the NMR Enantiodiscrimination of Derivatized Amino Acids.

New arylamide- and arylthiourea-based chiral solvating agents (CSAs) were synthesized starting from commercially available isomannide and isosorbide. The two natural isohexides were transformed into the three amino derivatives, having isomannide, isosorbide, and isoidide stereochemistry, then the amino groups were derivatized with 3,5-dimethoxybenzoyl chloride or 3,5-bis(trifluoromethyl)phenyl isothiocyanate to obtain the CSAs. Bis-thiourea derivative containing the 3,5-bis(trifluoromethyl)phenyl moiety with exo-exo stereochemistry was remarkably efficient in the differentiation of NMR signals (NH and acetyl) of enantiomers of N-acetyl (N-Ac) amino acids in the presence of 1,4-diazabicyclo[2,2,2]octane (DABCO). Nonequivalences in the ranges of 0.104-0.343 ppm and 0.042-0.107 ppm for NH and acetyl groups, respectively, allowed for very accurate enantiomeric excess determination, and a reliable correlation was found between the relative positions of signals of enantiomers and their absolute configuration. Therefore, a complete stereochemical characterization could be performed. Dipolar interactions detected in the ternary mixture CSA/N-Ac-valine/DABCO led to the identification of a different interaction model for the two enantiomers, involving the formation of a one-to-one substrate/CSA complex for (S)-N-Ac-valine and a one-to-two complex for (R)-N-Ac-valine, as suggested by the complexation stoichiometry.