Amino Acid Amides Research Articles

C2-Symmetric Amino Acid Amide-Derived Organocatalysts

N-alkylated C2-symmetric amino acid amide derivatives were shown to catalyse the Michael addition of 2-hydroxy-1,4-napthoquinone to β-nitrostyrene, achieving a maximum ee of 44%. The corresponding trifluoroacetic acid salts also catalysed the aldol reaction between 4-nitrobenzaldehyde and hydroxyacetone, leading to the formation of predominantly syn-aldol products in up to 55% ee. Aspects of the solvent dependence of the aldol reaction and the H-bonding of the catalyst were investigated.

Development of Iron‐Based Single Atom Materials for General and Efficient Synthesis of Amines

AbstractEarth abundant metal‐based heterogeneous catalysts with highly active and at the same time stable isolated metal sites constitute a key factor for the advancement of sustainable and cost‐effective chemical synthesis. In particular, the development of more practical, and durable iron‐based materials is of central interest for organic synthesis, especially for the preparation of chemical products related to life science applications. Here, we report the preparation of Fe‐single atom catalysts (Fe‐SACs) entrapped in N‐doped mesoporous carbon support with unprecedented potential in the preparation of different kinds of amines, which represent privileged class of organic compounds and find increasing application in daily life. The optimal Fe‐SACs allow for the reductive amination of a broad range of aldehydes and ketones with ammonia and amines to produce diverse primary, secondary, and tertiary amines including N‐methylated products as well as drugs, agrochemicals, and other biomolecules (amino acid esters and amides) utilizing green hydrogen.

Development of Iron-Based Single Atom Materials for General and Efficient Synthesis of Amines.

Earth abundant metal-based heterogeneous catalysts with highly active and at the same time stable isolated metal sites constitute a key factor for the advancement of sustainable and cost-effective chemical synthesis. In particular, the development of more practical, and durable iron-based materials is of central interest for organic synthesis, especially for the preparation of chemical products related to life science applications. Here, we report the preparation of Fe-single atom catalysts (Fe-SACs) entrapped in N-doped mesoporous carbon support with unprecedented potential in the preparation of different kinds of amines, which represent privileged class of organic compounds and find increasing application in daily life. The optimal Fe-SACs allow for the reductive amination of a broad range of aldehydes and ketones with ammonia and amines to produce diverse primary, secondary, and tertiary amines including N-methylated products as well as drugs, agrochemicals, and other biomolecules (amino acid esters and amides) utilizing green hydrogen.

Substrate-directed novel direct amidation of resin-bound amino acids

Abstract In peptide drug discovery, the C-terminal structure of peptide compounds is crucial for enhancing the affinity with target proteins and for optimizing the compound's dynamics and physical properties. In conventional solid-phase synthesis, two steps are necessary to modify the C-terminal structure: cleavage from the resin and subsequent amidation involving activation of the resulting carboxylic acid. This process can potentially lead to racemization of the C-terminal amino acid side chain. To address this issue, we developed a novel method that, in the presence of a Ta catalyst, directly allows amines to react with amino acid-loaded resins, thereby accomplishing both resin cleavage and amidation in a single step.

Interaction of melanoidins, proline, and valine with sorbents of various nature

The isolation of pure amino acids from industrial solutions is one of the important tasks of production. Solutions of amino acids obtained as a result of chemical or microbiological treatment contain a number of impurities, mostly organic ones. The microbiological synthesis of proline is accompanied by the presence of valine, leucine, alanine, and coloured high-molecular components in the culture liquid that belong to the melanoidin group. Melanoidins of proline acid production are high-molecular compounds containing amino acid fragments, heterocyclic structures, and amide bonds. Melanoidins in solutions can exist in cationic, bipolar, and anionic forms. They have different molecular weights, molecular sizes, and isoelectric states. Various ion exchange methods can be used to isolate the target amino acid. It should be noted that the interaction of amino acids with ion-exchange materials is a complex process depending on the electrolytic properties of the sorbate and sorbent and accompanied by multiple side effects. It is necessary to know the specific features of interaction in the “amino acid - sorbent” system and the factors that affect the transport of sorbate ions in the sorbent phase when choosing an isolation method for the target product. The goal of this work was to determine the impact of pH on the sorption process of proline and valine by high-basic ion exchangers, to identify the features of their interactions, and to use the obtained results to optimise the conditions for the separation of amino acids. We studied the process of interaction of bipolar ions and anions of proline (Pro±, Pro-) and valine (Val±, Val-) with anionites AV-17-8 and AV-17-2P. It was established that the mechanism of amino acid ion exchange in granular sorbents depended on the рН value in the “anionite - external solution” system. Based on the studied interactions, we suggested the methods of the anion-exchange separation of proline and valine. The selected conditions of separation of proline and valine were on anionite AV-17-2P in ОН-form (рН of the initial solution was 6.6-6.7; the solution flow rate was 2 cm3/min). The results of separation of proline and valine indicated that even in a one-step sorption process, five to seven fractions with proline contained no valine ions, while the concentration of proline was 2.0-2.7 times higher as compared to the original solution.

Synthesis of hydantoins from N‐Boc protected amino acid derived amides using polymer‐supported PPh3/CBr4 as a reagent

AbstractHydantoin derivatives are versatile structural motifs found in natural products and various compounds with different biological or other properties. Due to their importance in both organic and medicinal chemistry, a number of synthetic procedures have been developed. In this article, a novel methodology utilizing N‐Boc protected amino acid amides for their preparation has been described. The cyclisation process was accomplished using solid supported PPh3 and CBr4 as reagents affording substituted hydantoins in moderate to good yields (40%–77%).

Direct Amidation of Unprotected Amino Acids Mediated by Hexylsilane

Direct Amidation of Unprotected Amino Acids Mediated by Hexylsilane

N-acetyl amino acid amide solubility in aqueous 1,6-hexanediol solutions: Insights into the protein droplet deformation mechanism

Proteinaceous liquid droplets, generated by liquid–liquid phase separation, function as membraneless compartments that are essential for diverse biological functions. Studies addressing droplet generation have used 1,6-hexanediol (1,6-HD) as a droplet-discerning agent owing to its capacity to induce droplet deformation. Despite the empirical utility of 1,6-HD, the mechanism underlying 1,6-HD-induced droplet deformation remains unknown. In this study, the solubilities of N-acetyl amino acid amides, which correspond to proteinogenic amino acid residues, were examined in the presence of 1,6-HD at 25 °C. Other solvents included ethanol, 1-propanol, and amides. Remarkably, 1,6-HD effectively solubilized hydrophobic species (particularly aromatic species) and exhibited reduced efficacy in solubilizing hydrophilic species and peptide bond moieties. These solubilizing effects are reflected in changes in protein solubility and structure. Specifically, 1,6-HD primarily targets the hydrophobic regions of a protein, increasing protein solubility without causing substantial structural changes. This solubilization mechanism is essential for elucidating the role of 1,6-HD as a droplet-discerning agent and recognizing its potential limitations.

TiF4-catalyzed direct amidation of carboxylic acids and amino acids with amines.

Unlike other metal fluorides, catalytic titanium tetrafluoride enhances the direct amidation of aromatic and aliphatic carboxylic acids and N-protected amino acids in refluxing toluene. While aromatic acids were converted to amides with 10 mol% of the catalyst within 24 h, aliphatic acids underwent a faster reaction (12 h), with lower catalyst loading (5 mol%). This protocol is equally efficient with alkyl and aryl amines providing a variety of carboxamides and peptides in 60-99% yields.

Hexylsilane-mediated direct amidation of amino acids with a catalytic amount of 1,2,4-triazole.

In this study, we report amino acid amidation using hexylsilane and a catalytic amount of 1,2,4-triazole. The conventional protection/deprotection method for the α-amino group of amino acids is not required. The corresponding α-amino amides were obtained in moderate to good yields with low to no racemization.

Protective effect of N-(E)-p-coumaroyltyrosine on LPS-induced acute inflammatory injury and signaling pathway analysis

N-trans-p-coumaroyltyrosine (N-(E)-p-coumaroyltyrosine, NPCT), extracted and purified from Abri Mollis Herba, is an amino acid amide. The defense mechanism of NPCT against inflammatory response is still unknown. In this study, lipopolysaccharide (LPS)-induced zebrafish acute inflammatory injury model was established to observe the inhibitory effect of NPCT on the aggregation of inflammatory cells in the yolk sac of zebrafish, as well as the inhibitory effect of NPCT on inflammatory and gas signaling factors. Results show that NPCT could inhibit inflammatory cell infiltration in zebrafish yolk sac, the migration and aggregation of macrophages and neutrophils to the site of inflammation, and the release of Nitric Oxide (NO) and Reactive Oxygen Species (ROS) in zebrafish, indicating that NPCT could substantially significantly prevent the development of LPS-induced acute systemic inflammation. In addition, the analysis results of RNA-seq showed that in the model group versus the administered group, the differentially expressed genes were mainly enriched to inflammatory signaling pathways, such as the NOD-like receptor signaling pathway and Toll-like receptor signaling pathway, which were down-regulated in the administered group. The TLR4, MyD88, IRAK4, NF-κB, IκB, NLRP3, Caspase-1, ASC, IL-1β, and IL-6 genes were significantly different in the transcripts, and the overall trend of the qPCR results was consistent with the transcriptome sequencing results. Therefore, NPCT had a significant inhibitory effect on LPS-induced acute inflammatory injury in zebrafish, and its anti-inflammatory mechanism may be through the regulation of key genes on the NOD-like receptor signaling pathway and Toll-like receptor signaling pathway, thereby affecting the release of relevant inflammatory cytokines.

(N-Alkyloxalamido)-Amino Acid Amides as the Superior Thixotropic Phase Selective Gelators of Petrol and Diesel Fuels.

(N-Alkyloxalamido)-amino acid amides 9-12 exhibit excellent gelation capacities toward some lipophilic solvents as well as toward the commercial fuels, petrol and diesel. Gelator 10 exhibits an excellent phase-selective gelation (PSG) ability and also possesses the highest gelation capacity toward petrol and diesel known to date, with minimum gelation concentration (MGC) values (%, w/v) as low as 0.012 and 0.015, respectively. The self-assembly motif of 10 in petrol and toluene gel fibres is determined from xerogel X-ray powder diffraction (XRPD) data via the simulated annealing procedure (SA) implemented in the EXPO2014 program and refined using the Rietveld method. The elucidated motif is strongly supported by the NMR (NOE and variable temperature) study of 10 toluene-d8 gel. It is shown that the triple unidirectional hydrogen bonding between gelator molecules involving oxalamide and carboxamide groups, together with their very low solubility, results in the formation of gel fibres of a very high aspect ratio (d = 10-30 nm, l = 0.6-1.3 μm), resulting in the as-yet unprecedented capacity of gelling commercial fuels. Rheological measurements performed at low concentrations of 10 confirmed the strength of the self-assembled network with the desired thixotropic properties that are advantageous for multiple applications. Instantaneous phase-selective gelation was obtained at room temperature through the addition of the 10 solution to the biphasic mixture of diesel and water in which the carrier solvent was congealed along with the diesel phase. The superior gelling properties and PSG ability of 10 may be used for the development of more efficient marine and surface oil spill recovery and waste water treatment technologies as well as the development of safer fuel storage and transport technologies.

Derivatives of glycyrrhetinic acid with amino acid: Modifications, structural characterization, hypoglycemic activity and mechanism

Glycyrrhetinic acid (GA) is found in the roots and rhizomes of the legume licorice genus. The sweetness of GA is 250 times of sucrose. GA has a variety of biological activities. To develop new functional additive with hypoglycemic properties, the GA was modified with amino acids. The carboxyl group in C-30 of GA was modified with glycine, aspartic acid and arginine, respectively, to successfully prepare three amino acid amide derivatives of GA. The total yields of N-glycyrrhetinylglycine, N-glycyrrhetinyl aspartic acid and N-glycyrrhetinylarginine were 43.60%, 39.33% and 35.10%, respectively. The modification of C-30 of GA was modified with amino acid can significantly reduce the logP value and promote the hydrophilicity of GA. The N-glycyrrhetinylarginine had effective inhibition on α-glucosidase and is superior to GA. The inhibition on α-glucosidase by GA and N-Glycyrrhetinyl amino acid were reversible and mixed type. The GA and N-glycyrrhetinylarginine can effectively increase glucose consumption and glycogen synthesis to regulate insulin resistance. The GA and N-glycyrrhetinylarginine can regulate the insulin resistance in HepG2-IR cells via PI3K/Akt signaling pathway.

Heat Capacities of N-Acetyl Amides of Glycine, L-Alanine, L-Valine, L-Isoleucine, and L-Leucine.

As a follow-up to our effort to establish reliable thermodynamic data for amino acids, the heat capacity and phase behavior are reported for N-acetyl glycine amide (CAS RN: 2620-63-5), N-acetyl-L-alanine amide (CAS RN: 15962-47-7), N-acetyl-L-valine amide (CAS RN: 37933-88-3), N-acetyl-L-isoleucine amide (CAS RN: 56711-06-9), and N-acetyl-L-leucine amide (CAS RN: 28529-34-2). Prior to heat capacity measurement, thermogravimetric analysis and X-ray powder diffraction were performed to determine decomposition temperatures and initial crystal structures, respectively. The crystal heat capacities of the five N-acetyl amino acid amides were measured by Tian-Calvet calorimetry in the temperature interval (266-350 K), by power compensation DSC in the temperature interval (216-471 K), and by relaxation (heat-pulse) calorimetry in the temperature interval (2-268 K). As a result, reference heat capacities and thermodynamic functions for the crystalline phase from 0 K up to 470 K were developed.

Differential Effects of Histidine and Histidinamide versus Cysteine and Cysteinamide on Copper Ion-Induced Oxidative Stress and Cytotoxicity in HaCaT Keratinocytes.

Metal chelators are used for various industrial and medical purposes based on their physicochemical properties and biological activities. In biological systems, copper ions bind to certain enzymes as cofactors to confer catalytic activity or bind to specific proteins for safe storage and transport. However, unbound free copper ions can catalyze the production of reactive oxygen species (ROS), causing oxidative stress and cell death. The present study aims to identify amino acids with copper chelation activities that might mitigate oxidative stress and toxicity in skin cells exposed to copper ions. A total of 20 free amino acids and 20 amidated amino acids were compared for their copper chelation activities in vitro and the cytoprotective effects in cultured HaCaT keratinocytes exposed to CuSO4. Among the free amino acids, cysteine showed the highest copper chelation activity, followed by histidine and glutamic acid. Among the amidated amino acids, cysteinamide showed the highest copper chelation activity, followed by histidinamide and aspartic acid. CuSO4 (0.4-1.0 mM) caused cell death in a concentration-dependent manner. Among the free and amidated amino acids (1.0 mM), only histidine and histidinamide prevented the HaCaT cell death induced by CuSO4 (1.0 mM). Cysteine and cysteinamide had no cytoprotective effects despite their potent copper-chelating activities. EDTA and GHK-Cu, which were used as reference compounds, had no cytoprotective effects either. Histidine and histidinamide suppressed the CuSO4-induced ROS production, glutathione oxidation, lipid peroxidation, and protein carbonylation in HaCaT cells, whereas cysteine and cysteinamide had no such effects. Bovine serum albumin (BSA) showed copper-chelating activity at 0.5-1.0 mM (34-68 mg mL-1). Histidine, histidinamide, and BSA at 0.5-1.0 mM enhanced the viability of cells exposed to CuCl2 or CuSO4 (0.5 mM or 1.0 mM) whereas cysteine and cysteinamide had no such effects. The results of this study suggest that histidine and histidinamide have more advantageous properties than cysteine and cysteinamide in terms of alleviating copper ion-induced toxic effects in the skin.

Enzymatic Synthesis of 2-Chloropurine Arabinonucleosides with Chiral Amino Acid Amides at the C6 Position and an Evaluation of Antiproliferative Activity In Vitro

A number of purine arabinosides containing chiral amino acid amides at the C6 position of the purine were synthesized using a transglycosylation reaction with recombinant E. coli nucleoside phosphorylases. Arsenolysis of 2-chloropurine ribosides with chiral amino acid amides at C6 was used for the enzymatic synthesis, and the reaction equilibrium shifted towards the synthesis of arabinonucleosides. The synthesized nucleosides were shown to be resistant to the action of E. coli adenosine deaminase. The antiproliferative activity of the synthesized nucleosides was studied on human acute myeloid leukemia cell line U937. Among all the compounds, the serine derivative exhibited an activity level (IC50 = 16 μM) close to that of Nelarabine (IC50 = 3 μM) and was evaluated as active.

Liquid products of meat and bone meal pyrolysis: comprehensive assessment by chromatographic methods

Dorogov’s antiseptic stimulators (fractions 2 and 3) are products of meat and bone meal pyrolysis that are used to treat farm animals. However, there is a lack of detailed information about their chemical composition. We aimed to study individual compositions of organic substances in the water- and oil-soluble condensates of these preparations.
 Dorogov’s antiseptic stimulators ASD-2F and ASD-3F (Agrovetzashchita, Russia) were used as samples of the water- and oil-soluble condensates of meat and bone meal pyrolysis. Volatile substances were identified by gas chromatography and gas chromatography-mass spectrometry, while amino acids were determined by high-performance liquid chromatography.
 The initial water-soluble condensate contained ammonium salts, amides of carboxylic acids, N-heterocyclic compounds, hydantoins, amino acids, and dipeptides, with a total content of 8% of the condensate’s weight. Its dehydrated concentrate had almost no ammonium salts and amides of carboxylic acids, but its contents of hydantoins, amino acids, dipeptides, and lowvolatile nitrogen-containing heterocycles were 10–15 times as high as those in the initial condensate. The condensate contained 13 dipeptides and 19 amino acids with a total content of 2.5%. According to gas chromatography-mass spectrometry, the oilsoluble condensate contained over 30% of nitriles; 7–10% of higher and aromatic hydrocarbons, phenols, and amides (with esters); and 1–3% of N-heterocyclic compounds, naphthalenes, pyridines, and dipeptides. The nitrogen-containing heterocycles, as well as dipeptides, were similar to those in the water-soluble condensate.
 We identified 80% of individual organic substances in the water-soluble pyrolytic condensate. Together with its concentrate, they contained more than 220 organic substances divided into 10 main groups. The oil-soluble condensate consisted of over 350 individual organic compounds. The full composition of the preparations can be further identified by three-quadrupole liquid mass spectrometry.

Release of Volatile Cyclopentanone Derivatives from Imidazolidin-4-One Profragrances in a Fabric Softener Application

Imidazolidin-4-ones were investigated as hydrolytically cleavable profragrances to increase the long-lastingness of perfume perception in a fabric softener application. The reaction of different amino acid amides with 2-alkyl- or 2-alkenylcyclopentanones as the model fragrances to be released afforded the corresponding bi- or tricyclic imidazolidin-4-ones as mixtures of diastereoisomers, which were separated by column chromatography. In polar solution, the different stereoisomers equilibrated under thermodynamic conditions to form mixtures with constant isomeric distributions, as shown by NMR spectroscopy. Dynamic headspace analysis on dry cotton demonstrated the controlled fragrance release from the precursors in practical application. Under non-equilibrium conditions (continuous evaporation of the fragrance) and depending on the structure and stereochemistry of the profragrances, the recorded headspace concentrations of the fragrance released from the precursors increased by a factor of 2 up to 100 with respect to the unmodified reference. Prolinamide-based precursors released the highest amount of fragrance and were thus found to be particularly suitable for prolonging the evaporation of cyclopentanone-derived fragrances on a dry cotton surface.

Aminopeptidase B can bioconvert L-type amino acid transporter 1 (LAT1)-utilizing amide prodrugs in the brain.

A prodrug approach is a powerful method to temporarily change the physicochemical and thus, pharmacokinetic properties of drugs. However, in site-selective targeted prodrug delivery, tissue or cell-specific bioconverting enzyme is needed to be utilized to release the active parent drug at a particular location. Unfortunately, ubiquitously expressed enzymes, such as phosphatases and carboxylesterases are well used in phosphate and ester prodrug applications, but less is known about enzymes selectively expressed, e.g., in the brain and enzymes that can hydrolyze more stable prodrug bonds, such as amides and carbamates. In the present study, L-type amino acid transporter 1 (LAT1)-utilizing amide prodrugs bioconverting enzyme was identified by gradually exploring the environment and possible determinants, such as pH and metal ions, that affect amide prodrug hydrolysis. Based on inducement by cobalt ions and slightly elevated pH (8.5) as well as localization in plasma, liver, and particularly in the brain, aminopeptidase B was proposed to be responsible for the bioconversion of the majority of the studied amino acid amide prodrugs. However, this enzyme hydrolyzed only those prodrugs that contained an aromatic promoiety (L-Phe), while leaving the aliphatic promoeities (L-Lys) and the smallest prodrug (with L-Phe promoiety) intact. Moreover, the parent drugs' structure (flexibility and the number of aromatic rings) largely affected the bioconversion rate. It was also noticed in this study, that there were species differences in the bioconversion rate by aminopeptidase B (rodents > human), although the in vitro-in vivo correlation of the studied prodrugs was relatively accurate.

Ascorbic Acid (Vitamin C) as a Cosmeceutical to Increase Dermal Collagen for Skin Antiaging Purposes: Emerging Combination Therapies.

Ascorbic acid (AA) is an essential nutrient and has great potential as a cosmeceutical that protects the health and beauty of the skin. AA is expected to attenuate photoaging and the natural aging of the skin by reducing oxidative stress caused by external and internal factors and by promoting collagen gene expression and maturation. In this review, the biochemical basis of AA associated with collagen metabolism and clinical evidence of AA in increasing dermal collagen and inhibiting skin aging were discussed. In addition, we reviewed emerging strategies that have been developed to overcome the shortcomings of AA as a cosmeceutical and achieve maximum efficacy. Because extracellular matrix proteins, such as collagen, have unique amino acid compositions, their production in cells is influenced by the availability of specific amino acids. For example, glycine residues occupy 1/3 of amino acid residues in collagen protein, and the supply of glycine can be a limiting factor for collagen synthesis. Experiments showed that glycinamide was the most effective among the various amino acids and amidated amino acids in stimulating collagen production in human dermal fibroblasts. Thus, it is possible to synergistically improve collagen synthesis by combining AA analogs and amino acid analogs that act at different stages of the collagen production process. This combination therapy would be useful for skin antiaging that requires enhanced collagen production.