Amino Acid Amides Research Articles

Fluorinated polybenzimidazopyrrolones with excellent alkaline‐hydrolysis resistance

ABSTRACTTwo novel aromatic tetraamines containing bulky lateral phenyl unit and multiple trifluoromethyl groups, 1,1‐bis[4‐(3′,4′‐diaminophenoxy)phenyl]‐1‐(3″‐trifluoromethylphenyl)−2,2,2‐trifluoroethane (6FTA) and 1,1‐bis[4‐(3′,4′‐diaminophenoxy)phenyl]‐1‐[3″,5″‐bis(trifluoromethyl)phenyl]‐2,2,2‐trifluoroethane (9FTA) were synthesized and characterized. A series of fluorinated aromatic polybenzimidazopyrrolones (polypyrrolones, PPys) were synthesized via a two‐step polycondensation procedure. The inherent viscosities of the precursors, poly(amide amino acid) (PAAA), ranged from 0.39 dL/g to 0.54 dL/g. All the FPPys were amorphous. The freestanding FPPy films could be prepared, which exhibited good thermal stability with the glass transition temperature of 315–389°C, the temperatures of 5% weight loss (T5%) of 497–535°C in nitrogen and residual weight retention at 700°C over 60%. All the FPPy films exhibited excellent alkaline‐hydrolysis resistance which retained their original shapes and toughness after boiling 7 days in 10% sodium hydroxide solution. Also after boiling 8 h in 10% sodium hydroxide solution, the tensile strength could retain as high as 56% of the original values. The alkaline‐hydrolysis resistance was much better than the polyimides which had similar chemical structures. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2014, 131, 40041.

Process design for enzymatic peptide synthesis in near-anhydrous organic media

This work is a case study on a process design for enzymatic peptide synthesis, which is based on and inspired by previously established data about the Alcalase-catalyzed coupling of an amino acid amide and a chemically synthesized activated N-protected amino acid carbamoylmethyl ester in near-anhydrous tetrahydrofuran. The choices with regard to Alcalase formulation, the type of reactor, method of controlling the water content, and whether or not to recycle the enzyme, are discussed. In addition, an estimate is given for the reactor size, volumes of solvent, amount of substrate, enzyme and molecular sieves, needed in order to meet a specific demand for peptides. We believe that this case study gives a good indication of the various choices that have to be made when designing a process for enzymatic peptide synthesis and the implications of these choices.

Ligand-free CuI-catalyzed selective C–N coupling of aliphatic amino group of α-amino acid amides with ortho-dihaloarenes

Many synthetic methods of racemic N-aryl (including N-(2-haloaryl)) α-amino acid amides have been reported, but there are only a few for eutomers and none for inactivated halo(hetero)arenes. Selective C–N coupling of aliphatic amino group of α-amino acid amides is a direct and valuable method, but still unresolved. Here we disclose a simple and cheap ligand-free CuI-catalyzed selective synthesis of chiral N-(2-halo(hetero)aryl) amino acid amides without obvious racemization. A rational mechanism is proposed.

A convenient synthesis of new NSAID esters containing amino acid, urea and amide moieties

Abstract A convenient synthetic method for the preparation of novel NSAID twin esters 6a-i containing amino acid residue, urea and amide moieties has been developed. The synthetic pathway applied for the preparation of target compounds and key intermediates 1-benzotriazolecarboxylic acid chloride (1), NSAID benzotriazolides 2a-c and N-(1-benzotriazolecarbonyl)-amino acids 3a-d involved benzotriazole as a synthetic auxiliary. The final preparation step of esters 6a-i included the solvent-free reaction of compounds 2a-c with amino acid derivatives 5a-g, bearing two hydroxyl groups, one at each terminal, beside urea and amide functionalities.

ChemInform Abstract: Synthesis of Chiral Amino Acid Anilides by Ligand‐Free Copper‐Catalyzed Selective N‐Arylation of Amino Acid Amides.

AbstractGenerally the reactivity of aryl‐/heteroaryl‐/styryl‐halides is I < Br < Cl.

A convenient method for the one-step synthesis of phosphonic peptides

A novel and efficient method for the synthesis of peptidyl derivatives of 1-aminoalkylphosphonate diaryl esters is presented. Phosphonic peptides were obtained in one step via an amidoalkylation reaction using amides of N-protected amino acids or peptides, triphenyl phosphite, and an appropriate aldehyde.

Purification and characterization of a novel thermo-active amidase from Geobacillus subterraneus RL-2a

A thermostable amidase produced by Geobacillus subterraneus RL-2a was purified to homogeneity, with a yield of 9.54% and a specific activity of 48.66Umg(-1). The molecular weight of the native enzyme was estimated to be 111kDa. The amidase of G. subterraneus RL-2a is constitutive in nature, active at a broad range of pH (4.5-11.5) and temperature (40-90°C) and has a half-life of 5h and 54min at 70°C. Inhibition of enzyme activity was observed in the presence of metal ions, such as Co(2+), Hg(2+), Cu(2+), Ni(2+), and thiol reagents. The presence of mid-chain aliphatic and amino acid amides enhances the enzymatic activity. The acyl transferase activity was detected with propionamide, butyramide and nicotinamide. The enzyme showed moderate stability toward toluene, carbon tetrachloride, benzene, ethylene glycol except acetone, ethanol, butanol, propanol and dimethyl sulfoxide. The K m and V max of the purified amidase with nicotinamide were 6.02±0.56mM and 132.6±4.4μmolmin(-1)mg(-1)protein by analyzing Michaelis-Menten kinetics. The results of MALDI-TOF analysis indicated that this amidase has homology with the amidase of Geobacillus sp. C56-T3 (gi|297530427). It is the first reported wide-spectrum thermostable amidase from a thermophilic G. subterraneus.

Creatine Amides: Perspectives for Neuroprotection

The neuroprotective activity of creatine amides – amino acid derivatives of creatine – was studied in a model of cerebral ischemia created by transient occlusion of the middle cerebral artery (OMCA) in rats. The neuroprotective effect of treatment with glycine (creatinylglycine ethyl ester acetate), phenylalanine (creatinyl-L-phenylalaninamide acetate), tyrosine (creatinyl-L-tyrosinamide acetate), and gamma-aminobutyric acid (creatinyl-γ-aminobutyric acid ethyl ester acetate) derivatives were studied after administration 1 h before 30-min cerebral ischemia. Brain damage was assessed by staining brain slices with triphenyltetrazolium chloride 48 h after ischemia. As compared with the control group, all the creatine amides studied significantly decreased the sizes of areas of brain damage (p < 0.05). However, the amides of creatine with tyrosine, phenylalanine, and GABA showed marked toxicity after intravenous administration and could only be used intraperitoneally. The amide of creatine and glycine was not toxic on administration of intravenous boluses at a dose of 1 mmol/kg. Conclusions: amides of creatine and amino acids decrease ischemic damage after transient occlusion of the middle cerebral artery in rats.

Direct Synthesis of Amides from Carboxylic Acids and Amines Using B(OCH2CF3)3

B(OCH2CF3)3, prepared from readily available B2O3 and 2,2,2-trifluoroethanol, is as an effective reagent for the direct amidation of a variety of carboxylic acids with a broad range of amines. In most cases, the amide products can be purified by a simple filtration procedure using commercially available resins, with no need for aqueous workup or chromatography. The amidation of N-protected amino acids with both primary and secondary amines proceeds effectively, with very low levels of racemization. B(OCH2CF3)3 can also be used for the formylation of a range of amines in good to excellent yield, via transamidation of dimethylformamide.

Production of hydroxamic acids by immobilized Pseudomonas aeruginosa cells: Kinetic analysis in reverse micelles

• Free and immobilized cells of Pseudomonas aeruginosa L10 contains biocatalyst amidase for hydroxamate derivatives synthesis. • Kinetic studies using a broad range of substrates in both media. • The immobilization in reverse micelles of cationic surfactant increases the biocatalyst affinity for the substrates. • Reverse micellar medium allowed obtaining higher biocatalyst stability and a greater percentage of substrate conversion. Intact cells from Pseudomonas aeruginosa strain L10 containing amidase were used as biocatalysts both free and immobilized in a reverse micellar system. The apparent kinetic constants for the transamidation reaction in hydroxamic acids synthesis, were determined using substrates such as aliphatic, amino acid and aromatic amides and esters, in both media. In reverse micelles, K m values decreased 2–7 fold relatively to the free biocatalyst using as substrates acetamide, acrylamide, propionamide and glycinamide ethyl ester. We have concluded that overall the affinity of the biocatalyst to each substrate increases when reactions are performed in the reversed micellar system as opposed to the buffer system. The immobilized biocatalyst in general, exhibits higher stability and faster rates of reactions at lower substrates concentration relatively to the free form, which is advantageous. Additionally, the immobilization revealed to be suitable for obtaining the highest yields of hydroxamic acids derivatives, in some cases higher than 80%.

Enantiocatalytic activity of substituted 5-benzyl-2-(pyridine-2-yl)imidazolidine-4-one ligands

Currently, asymmetric synthesis represents one of the main streams of organic synthesis. Although an extensive research has been carried out in this area, the synthesis of chiral compounds with the required enantiomeric purity is still a challenging issue. Herein, we focus on the preparation of new enantioselective catalysts based on pyridine-imidazolidinones. The substituted 5-benzyl-2-(pyridine-2-yl)imidazolidine-4-ones 5–8 were prepared by condensation of chiral amino acid amides (α-methylDOPA and α-methylphenylalanine) with 2-acetylpyridine and pyridine-2-carbaldehyde. The individual isomers of the described ligands 5–8 were separated chromatographically. The copper(II) complexes of these chiral ligands were studied as enantioselective catalysts for the asymmetric Henry reaction of substituted aldehydes with nitromethane or nitroethane. The ligands containing a methyl group at the 2-position of the imidazolidinone ring 6a and 8a exhibit a high degree of enantioselectivity (up to 91% ee). The nitroaldols derived from nitroethane (2-nitropropan-1-ols) were obtained with a comparable enantiomeric purity to derivatives of 2-nitroethanol. This group of ligands represents a new and promising class of enantioselective catalysts, which deserve further attention.

Synthesis of Chiral Amino Acid Anilides by Ligand‐Free Copper‐Catalyzed Selective N‐Arylation of Amino Acid Amides

AbstractAn atom‐economic, practical and cost‐effective protocol for synthesis of chiral amino acid anilides via ligand‐free copper‐catalyzed selective CN cross coupling of chiral amino acid amides and aryl halides, hetereoaryl halides and a vinyl bromide has been developed. No racemization occurred during the CN coupling. A plausible mechanism is proposed.

On the transferability of fractional contributions to the hydration free energy of amino acids

This study reports the application of the quantum mechanical self-consistent reaction field MST method to compute the solvation profile in water of the twenty natural amino acids. The aim is to derive intrinsic fractional contributions to the hydration free energy and to examine their transferability to peptides. To this end, IEF-MST calculations have been performed at the B3LYP/6-31G(d) level for the series of acetyl amino acid amides, which were chosen as model compounds. In order to account for the flexibility of both the backbone and the side chain in deriving the hydration fractional contributions, calculations have been performed for representative conformers taken from the Dunbrack’s backbone-dependent conformational library. The results allow us to dissect the hydration free energy into backbone and side chain contributions and examine the conformational dependence of the fragmental contributions to hydration. For the backbone, different hydration contributions are found for α-helical and β-sheet conformations, which mainly reflect differences in the electrostatic contribution to hydration of the carbonyl group. In contrast, the conformational flexibility of the side chain is found to have little impact on the fractional contribution to hydration. These findings should be valuable to refine semiempirical methods for predicting solvation properties of peptides and proteins in large-scale genomic studies.

Synthesis and biochemical activities of antiproliferative amino acid and phosphate derivatives of microtubule-disrupting β-lactam combretastatins

The synthesis and biochemical activities of novel water-soluble β-lactam analogues of combretastatin A-4 are described. The first series of compounds investigated, β-lactam phosphate esters 7a, 8a and 9a, exhibited potent antiproliferative activity and caused microtubule disruption in human breast carcinoma-derived MCF-7 cells. They did not inhibit tubulin polymerisation in vitro, indicating that biotransformation was necessary for their antiproliferative and tubulin binding effects in MCF-7 cells. The second series of compounds, β-lactam amino acid amides (including 10k and 11l) displayed potent antiproliferative activity in MCF-7 cells, disrupted microtubules in MCF-7 cells and also inhibited the polymerisation of tubulin in vitro. This indicates that the β-lactam amides did not require metabolic activation to have antiproliferative effects, in contrast to the phosphate series. Both series of compounds caused mitotic catastrophe and apoptosis in MCF-7 cells. Molecular modelling studies indicated potential binding conformations for the β-lactam amino acid amides 10k and 11l in the colchicine-binding site of tubulin. Due to their aqueous solubility and potent biochemical effects, these compounds are promising candidates for further development as microtubule-disrupting agents.

Variation of Body Temperature after Administration of Amino Acid Amides

Variation of Body Temperature after Administration of Amino Acid Amides

From Model Compounds to Proteins: A Volumetric Study of the Stabilizing Action of Glycine Betaine

Glycine betaine is a strong protecting osmolyte capable of stabilizing the folded conformations of proteins. A lingering problem has been to determine the molecular mechanisms underlying the enhancement of protein stability. One approach to tackle this problem is to examine the differential solvation properties of proteins and their components in water and glycine betaine. We present a new statistical thermodynamic formalism to quantify the individual binding affinities of glycine betaine for the polar and nonpolar moieties of globular proteins. This approach enables one to rationalize partial molar volume, V°, and adiabatic compressibility, Ks°, measurements in terms of interactions of glycine betaine with polar and nonpolar protein groups. We characterize in this way glycine betaine interactions with ribonuclease A, lysozyme, cytochrome C, and ovalbumin. To this end, we use our previous volumetric data on N-acetyl amino acid amides (models for amino acid side chains) and oligoglycines (models for peptide backbone) in solutions of glycine betaine at concentrations ranging from 0 to 4 M. We determine the average binding affinity, k, of glycine betaine for the proteins as well as changes in the volume, ΔVo, and adiabatic compressibility, ΔKso, associated with the binding of a glycine betaine molecule to the proteins. We find good agreement between these characteristics determined for proteins and their low molecular weight model compounds. These results suggest little or no cooperativity for glycine betaine interactions with proteins. Our experimental results in conjunction with the statistical thermodynamic formalism that we developed offer a new paradigm for investigating weak protein-ligand interactions.

Papain Catalyzed Synthesis of Protected Amino Acid Amides

Papain Catalyzed Synthesis of Protected Amino Acid Amides

Anti-tyrosinase, antioxidant and antimicrobial activities of hydroxycinnamoylamides

Synthetic hydroxycinnamoylamides of amino acids (precursors of aromatic amines) were studied for their antioxidant activity in vitro by two antioxidant assay systems, including 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and inhibition of lipid peroxidation (LPO). Furthermore, these compounds were tested and compared with their corresponding cinnamoylamides of aromatic amines for their inhibitory activity using mushroom tyrosinase. In addition, five hydroxycinnamoyl amino acid amides were investigated for their antimicrobial effect. Structure–activity relationships analysis disclosed that the presence of catechol rest at amino acid or at benzene moieties of substituted cinnamic acid amides significantly scavenged DPPH radical and inhibited LPO. The results obtained by LPO clearly expressed the positive influence of indole moiety on the activity. Moreover, the existence of p-hydroxy substituted cinnamic acid moiety leads to better tyrosinase inhibition. Amongst the tested compounds, amides of p-coumaroyldopamine or tyramine and their corresponding amino acid precursors are the most potent tyrosinase inhibitors.

Efficient kinetic resolution of amino acids catalyzed by lipase AS ‘Amano’ via cleavage of an amide bond

Herein the efficient kinetic resolution of non-natural alpha-amino acids catalyzed by lipase AS ‘Amano’ via cleaving the amide bond is reported. The starting materials were the corresponding amino acid amides and the amino acids were generated with ees of up to 99% with E values of >600. These results indicated that the lipase AS ‘Amano’ could be a powerful amide hydrolase for the kinetic resolution of amino acid starting from the corresponding amino acid amides.

Chiral Separation of Non-Natural Amide Amino Acid by Capillary Electrophoresis with CD Derivations as Chiral Selective Material

A capillary electrophoresis (CE) method for the separation of four kinds of enantiomers of non-natural carboxylic amino acid was built while hydroxypropyl-β- cyclodextrin (HP-β-CD) derivations as chiral selective material. Several different β-CD derivatives were tested for the chiral separation of non-natural carboxylic amino acid, and it was proved that HP-β-CD could show better chiral selectivity. The separation of enantiomers of amino acid was obtained by CE in a 50-μm i.d.×60 cm (effective length 45 cm) fused-silica capillary at 18 kV voltage, while 10 mM phosphate acted as running buffer and HP-β-CD served as selective material. The detective wavelength was set at 254 nm.