L-phenylalanine Methyl Ester Research Articles

Synthesis, crystal structure and local anti-inflammatory activity of the L-phenylalanine methyl ester derivative of dexamethasone-derived cortienic acid

L-phenylalanine methyl ester derivative of dexamethasone - derived cortienic acid (DF) was synthesized and its crystal structure was characterized by X-ray diffraction method. The crystal system is orthorhombic with space group P212121 and cell constants a = 8.2969 (3) ?, b = 18.9358 (8) ?, c = 20.0904 (6) ?, V = 3156.4 (2) ?3 and Z = 4. Ring A of the steroid nucleus and phenyl ring in the 17?-side chain are almost planar. Rings B and C have a slightly distorted chair conformation, whereas ring D has an envelope conformation. The packing of DF is characterized by a network of intermolecular hydrogen bonds involving the O4 atom from one side of the steroid nucleus and O1 and F1 atoms from the other side as hydrogen bond acceptors. Apart from the intermolecular hydrogen bonds in the crystal packing, there are also numerous intramolecular hydrogen bonds of the N-H...O, C-H...O and C-H...F type. Local anti-inflammatory activity of DF was evaluated by use of croton oil-induced ear edema test. This derivative achieved maximal inhibition of ear edema at significantly lower concentration in comparison with dexamethasone.

Improved Synthesis of Cyclic α-Hydrazino Acids of Five- to Nine-Membered Rings and Optical Resolution of 5,6,7-Membered Ring Hydrazino Acids

Synthesis of cyclic α-hydrazino acids of five- to nine-membered rings has been described. Di-tert-butyl or dibenzyl malonate was used as starting materials instead of diethyl malonate, which was used in our first report. Deprotection of tert-butyl or benzyl ester of the final compounds was much easier than that of ethyl or methyl esters. Overall yield of these acids were 39, 50, 47, 52, and 51%, respectively. These acids were then converted to the diastereomers either via the formation of peptides with L-phenylalanine methyl ester or via the formation of esters (for five- to seven-membered rings) with L-2-phenylalaninol. All diastereomers were separated except the nine-membered ring by flash chromatography. Hydrolysis of diastereomeric esters generated the optically pure five-, six- and seven-membered cyclic α-hydrazino acids. In this process, both the enantiomers have been isolated and the chiral auxiliary L-2-phenylalaninol was recovered. Absolute stereochemistry was determined from x-ray crystallographic analysis.

New Derivatives of Nonactic and Homononactic Acids from Bacillus pumilus Derived from Breynia fruticosa

Six new nonactic and homononactic acid derivatives, ethyl homononactate (1), ethyl nonactate (2), homononactyl homononactate (6), ethyl homononactyl nonactate (7), ethyl homononactyl homononactate (8), and ethyl nonactyl nonactate (9), as well as four known compounds, homononactic acid (3), nonactic acid (4), homononactyl nonactate (5), and bishomononactic acid (10), were isolated from culture broth of Bacillus pumilus derived from Breynia fruticosa. The structures of new compounds were elucidated by spectroscopic analysis and chemical methods. The optical purities of 1-6 were determined by HPLC/MS after treatment with L-phenylalanine methyl ester. The dimeric compounds 5-9 showed weak cytotoxic activities against five human cancer cell lines (IC50 19-100 μg/ml).

Synthesis and Reactions of New Chiral Linear Dipeptide Candidates Using Nalidixic Acid as Starting Material

A series of dipeptide heterocyclic derivatives 4-15 were synthesized using methyl 2-{[(1-ethyl- 7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridin-3-yl)carbonyl]amino}-3-ethylbutanoate (3) as starting material. Treatment of 3 with L-phenylalanine methyl ester hydrochloride afforded the corresponding dipeptide methyl ester derivative 4, which was treated with hydrazine hydrate to afford the dipeptide acid hydrazide 5. Compound 5 was coupled with aldehyde and acetophenone derivatives to afford the corresponding Schiff bases 6a-f. The hydrazide derivative 5 was reacted with ethyl acetoacetate or acetone to give compounds 7 and 8, respectively. Reaction of 5 with carbon disulfide at different conditions afforded compounds 9 and 10, which were treated with hydrazine hydrate to give the 1-amino-2-dipeptido-1,3,4-triazole derivative 11. In addition, 5 was reacted with phenyl isothiocyanate to give the thiosemicarbazide derivative 12, which was cyclized with sodium hydroxide to the dipeptido 1-phenyl-1,3,4-triazole derivative 13. Finally, treatment of 13 with methyl iodide afforded the S-methyl derivative 14, which was reacted with hydrazine hydrate to give the hydrazine derivative 15.

Interactions of some protonated α-amino acid methyl esters with hexaethyl p-tert-butylcalix[6]arene hexaacetate in nitrobenzene saturated with water

The exchange extraction constants corresponding to the general equilibrium C+(aq) + 1·Cs+(nb) ⇔ 1·C+ (nb) + Cs+(aq) occurring in the two-phase water–nitrobenzene system (C+ = protonated α-amino acid methyl ester, 1 = hexaethyl p-tert-butylcalix[6]arene hexaacetate; aq = aqueous phase, nb = nitrobenzene phase) were evaluated on the basis of extraction experiments and γ-activity measurements. Further, the stability constants of the 1·C+ cationic complex species in nitrobenzene saturated with water were calculated; they were found to increase in the following cation order: protonated l-tryptophan methyl ester < protonated l-phenylalanine methyl ester < protonated l-leucine methyl ester < protonated l-methionine methyl ester < protonated l-valine methyl ester.

English

Aspartame (L- aspartyl- L-phenylalanine methyl ester) is one of the most widely artificial sweeteners consumed in so many products worldwide in various countries which added to a large variety of food, most commonly found in low calorie beverages. On metabolism in humans and experimental animals, aspartame is rapidly and completely metabolized to aspartic acid (40%), phenylalanine (50%) and methanol (10%). Methanol, a toxic metabolite is primarily metabolized by oxidation to formaldehyde and then to formate; these processes are accompanied by the formation of superoxide anion and hydrogen peroxide. This study focus is to understand whether the oral administration of aspartame (40 mg/kg b.w) for 15, 30 and 90 days have any effect on the antioxidant status (enzymatic and non-enzymatic) in immune organs such as the spleen, thymus, lymph nodes and bone marrow of rats. To mimic human methanol metabolism, folate deficient rats were used. After 15 days of aspartame administration, animals showed a significant increase in free radical production as indicated by the increase in both enzymatic (superoxide dismutase, catalase, glutathione peroxidase) and non-enzymatic (reduced glutathione and vitamin C) antioxidant level along with the marked increase in lipid peroxidation and nitric oxide level. However, after repeated long term administration (30 and 90 days), the generation of reactive free radicals overwhelmed the antioxidant defense as indicated by an increase in lipid peroxidation with the decrease in antioxidants level. This study concludes that administration of aspartame even at the Food and Drug Administration permitted level its repeated exposure causes oxidative stress by altering the oxidant/antioxidant balance in immune organs of the rats and its effects also reflected in the histology of the spleen and lymph nodes Key words: Aspartame, folate- deficient, immune organs, oxidative stress.

Polypeptide nanogels with hydrophobic moieties in the cross-linked ionic cores: synthesis, characterization and implications for anticancer drug delivery

Polymer nanogels have gained considerable attention as a potential platform for drug delivery applications. Here we describe the design and synthesis of novel polypeptide-based nanogels with hydrophobic moieties in the cross-linked ionic cores. Diblock copolymer, poly(ethylene glycol)-b-poly(l-glutamic acid), hydrophobically modified with l-phenylalanine methyl ester moieties was used for controlled template synthesis of nanogels with small size (ca. 70 nm in diameter) and narrow particle size distribution. Steady-state and time-resolved fluorescence studies using coumarin C153 indicated the existence of hydrophobic domains in the ionic cores of the nanogels. Stable doxorubicin-loaded nanogels were prepared at high drug capacity (30 w/w%). We show that nanogels are enzymatically-degradable leading to accelerated drug release under simulated lysosomal acidic pH. Furthermore, we demonstrate that the nanogel-based formulation of doxorubicin is well tolerated and exhibit an improved antitumor activity compared to a free doxorubicin in an ovarian tumor xenograft mouse model. Our results signify the point to a potential of these biodegradable nanogels as attractive carriers for delivery of chemotherapeutics.

Complexation of some protonated α-amino acid methyl esters with benzo-18-crown-6 in nitrobenzene saturated with water

From extraction experiments and γ-activity measurements, the exchange extraction constants corresponding to the general equilibrium C+(aq)+1·Na+(nb)⇔⟺1·C+ (nb)+Na+ (aq) taking place in the two-phase water–nitrobenzene system (C+=protonated α-amino acid methyl ester, 1=benzo-18-crown-6; aq=aqueous phase, nb=nitrobenzene phase) were evaluated. Furthermore, the stability constants of the 1·C+ complex species in nitrobenzene saturated with water were calculated; they were found to increase in the following cation order: protonated l-tryptophan methyl ester<protonated l-phenylalanine methyl ester<protonated l-leucine methyl ester, protonated l-methionine methyl ester<protonated l-valine methyl ester.

Modification of Microbial Polymalic Acid With Hydrophobic Amino Acids for Drug‐Releasing Nanoparticles

Microbial poly(β, l-malic acid) was modified with either l-leucine ethyl ester (L) or l-phenylalanine methyl ester (F) to produce amphiphylic copolymers. The degradation of these copolymers in aqueous buffer took place under physiological conditions in a few weeks by hydrolysis of the side chain ester group followed by cleavage of the main chain. Spherical nanoparticles with diameters ranging between 70 and 230 nm were prepared from these copolymers by the dialysis-precipitation method. No alteration of the cell viability was observed after incubation of these nanoparticles in different cell lines. Anticancer drugs temozolomide and doxorubicin were encapsulated in the nanoparticles. Temozolomide was released within several hours whereas doxorubicin took several weeks to be completely liberated.

CATALYTIC RECEPTORS

CATALYTIC RECEPTORS

Enzyme activity evaluation of organic solvent-treated phenylalanine ammonia lyase

The direct one-step synthesis of L-phenylalanine methyl ester in an organic-aqueous biphasic system using phenylalanine ammonia lyase (E.C.4.3.1.5, PAL) containing Rhodotorula glutinis yeast whole cells was reported earlier. We report here further optimization of this biotransformation using isolated PAL, when the lyophilized enzyme is treated with different water miscible and water immiscible organic solvents. Use of isolated PAL enzyme is advantageous in overcoming diffusion barriers encountered when using PAL containing R.glutinis whole cells, and resulted in increased product yield due to better interaction of enzyme with the substrate. Among the water miscible solvents, ethanol treated and methanol-treated enzymes supported maximum PAL forward and reverse activities; respectively. In the water immiscible solvents category, heptane-treated enzyme exhibited maximal activity for both PAL forward and reverse reactions. PAL activity obtained with enzyme specimens treated with methanol, ethanol, and heptane varied in the range of 91–99% of that observed in aqueous buffer medium for the forward reaction; and 89–95% for the reverse reaction. n-butanol,acetone, and benzene were found to have a inhibitory effect on PAL enzyme, in that, it resulted in only 31–33% activity of that obtained with aqueous solution. Raman spectroscopy was used to monitor amide I and II bands which are sensitive to changes in the secondary structure of proteins. No changes in structure could be detected from the analyses of AI and AII bands of PAL spectra. This data obtained for PAL, a tetramer, could be significant in predicting how solvent interactions affect the structure and function of multimeric proteins and enzymes in nonaqueous media.

Synthesis and Crystal Structure of Bis(L-α-N-(2-Pyridylmethy)phenylalaninato-N, N', O)-Zinc(II) Trihydrate

N-(2-pyridylmethyl)-L-phenylalanine methyl ester was synthesized in our laboratory，and the title compound was synthesized by the reaction of N-(2-pyridylmethyl)-L-phenylalanine methyl ester and Zinc acetate dehydrate. Bis(L-α-N-(2-pyridylmethy)phenylalaninato-N, N', O)-Zinc(II) trihydrate was prepared and structurally characterized by X-ray diffraction. It crystallizes in orthorhombic, space group P21212 with a= 15.0928 (8), b = 16.4209 (6), c = 5.9930 (3) Å, V = 1485.29 (12) Å3, Z = 2, Mr= 630.00, Dx = 1.409 g/cm3, μ = 0.88 mm-1, F(000) = 660, Rint = 0.0205, R = 0.028 and wR = 0.059 for 2943 observed reflections with I &gt; 2σ(I). It is a mononuclear discrete structure. The zinc atom coordinates with two oxygen and four nitrogen atoms from two ligands in a distorted octahedral geometry, with the oxygen atom from the carboxylate, two of nitrogen atoms from NH parts and the other two nitrogen atoms from the pyridine ring. With three free water molecules, the present structure has a network of hydrogen bonds.

Syntheses and reactivities of non-symmetrical “active ester” bi-dentate cross-linking reagents having a phthalimidoyl and acid chloride, 2-benzothiazole, or 1-benzotriazole group

We have newly synthesized the non-symmetrical "phthalimidoyl active ester" bi-dentate cross-linking reagents having an acid chloride, 2-benzothiazole, or 1-benzotriazole group (i.e., 9, 15, and 16) on the basis of the reactivity study of the "active ester" model compounds, 11-14, toward the various nucleophiles and examined their reaction selectivity towards the same nucleophiles. Then, we applied for the modification of cholesterol at the more reactive site of the bi-dentate linkers to give 3β-cholesteryl 4-(phthalimidoyloxycarbonyl)butyrate (39), and the subsequent reaction of 39 with several amines, such as benzylamine, 4-chlorobenzylamine, 2-phenylethylamine, L-phenylalanine methyl ester, or diphenylalanine benzyl ester as a protein model of the cholesterol antigen.

Solvent Effects on the Protonation Constants of Some α-Amino Acid Esters in 1,4-Dioxane–Water Mixtures

The stoichiometric protonation constants of some α-amino acid esters (glycine methyl ester, glycine t-butyl ester, l-valine methyl ester, l-valine ethyl ester, l-valine t-butyl ester, l-serine methyl ester, l-serine ethyl ester, l-leucine methyl ester, l-leucine ethyl ester, l-leucine t-butyl ester, l-alanine methyl ester, l-alanine benzyl ester, l-phenylalanine methyl ester, l-phenylalanine ethyl ester, and l-phenylalanine t-butyl ester) in water and 20%, 40%, and 60% (v/v) 1,4-dioxane–water mixtures have been determined at an ionic strength of 0.10 mol⋅L−1 NaCl and at 25.0±0.1 °C under a nitrogen atmosphere. A potentiometric method was used and the calculation of the protonation constants has been carried out using the BEST computer program. The results were discussed in terms of macroscopic properties of the mixed solvent. The stoichiometric protonation constants were influenced by changes in solvent composition and their variations were discussed in terms of preferential solvation. Also, knowledge the protonation constant of α-amino acid esters will be helpful when determining the microscopic equilibrium constants of their corresponding amino acids.

Isolation and preliminary identification of a novel microorganism producing aspartame from soil samples

To develop a new method for producing aspartame (APM), a simple and efficient strategy for the isolation of certain microorganisms producing APM from soil samples was designed. A newly strain with secreting certain specific dipeptidase to directly synthesize APM from the substrates of l-aspartic acid (l-Asp) and l-phenylalanine methyl ester (l-PM) without protection for amino acid side chains was screened from soil samples. APM concentration in reaction mixture was quantified by high performance liquid chromatography (HPLC), yield reached 0.015 g/L. Examination of the general morphological characteristics and data from the sequence analysis of the rDNA-ITS gene led to identification of the isolate as a strain of fungal endophyte spp. The newly isolated strain had a high potential for application in industrial processes for APM production. In particular, this new method was low cost for synthesis of APM during the reaction due to avoiding protection for amino acid side chains and optical resolution of the mixtures. As we known it, this is first report that a newly strain with a high potential for selective synthesis of the APM was isolated from soil.

Synthesis and micellization behavior of chiral amphiphilic diblock copolymers bearing amino acid/dipeptide pendants

Novel chiral amphiphilic diblock copolymers bearing l-phenylalanine or α- l-aspartyl- l-phenylalanine methyl ester pendants were synthesized using a “click” reaction. The structure and composition of copolymers were characterized by gel permeation chromatography, 1H NMR, elemental analysis and optical rotation measurements, which showed that the synthetic route can produce copolymers with well-defined composition and optical activity. The results from surface tension measurements, dynamic light scattering, transmission electron microscopy and 1H NMR spectra indicated that these chiral copolymers formed spherical micelles with an optically active hydrophobic core in a NaH 2PO 4 buffer (pH 4.5) system.

Screening, purification, and identification of the enzyme producing N-(l-α-l-aspartyl)-l-phenylalanine methyl ester from l-isoasparagine and l-phenylalanine methyl ester

Screening was carried out for microorganisms able to produce N-(l-alpha-l-aspartyl)-l-phenylalanine methyl ester [APM] from l-isoasparagine and l-phenylalanine methyl ester hydrochloride. Of the 422 strains examined, 44 strains belonging to the family Enterobacteriaceae were found to produce APM. The enzyme catalyzing APM production was purified and identified as dipeptidase E.

Magnetic hydrophobic affinity nanobeads for lysozyme separation

N-Methacryloyl-l-phenylalanine (MAPA) containing poly(2-hydroxyethylmethacrylate) based magnetic [mag-poly(HEMA–MAPA)] nanobeads was prepared for lysozyme purification form chicken egg white. MAPA was synthesized by reacting methacryloyl chloride with l-phenylalanine methyl ester and provided hydrophobic functionality to the nanobeads. Size of mag-poly(HEMA–MAPA) nanobeads was 386 nm and obtained by surfactant free emulsion polymerization of HEMA and MAPA having a specific surface area of 580 m 2/g. Mag-poly(HEMA–MAPA) nanobeads were characterized by FTIR, AFM, TEM, ESR, and elemental analysis. Lysozyme adsorption experiments were investigated under different conditions in batch system (i.e., medium pH, protein concentration, temperature, salt type). Lysozyme adsorption capacity of mag-poly(HEMA) and mag-poly(HEMA–MAPA) nanobeads from aqueous solutions was estimated as 24 and 517 mg/g, respectively. Lysozyme molecules were desorbed with 50% ethylene glycol solution with 98% recovery. It was observed that mag-poly(HEMA–MAPA) nanobeads can be used without significant decrease in lysozyme adsorption capacity after ten adsorption–desorption cycles. Mag-poly(HEMA–MAPA) nanobeads was used for the purification of lysozyme from chicken egg white. Purity of lysozyme was estimated by SDS-PAGE.

Isolation and characterization of aromatase inhibitors from Brassaiopsis glomerulata (Araliaceae)

The hexane- and ethyl acetate-soluble extracts of the leaves of Brassaiopsis glomerulata (Blume) Regel (Araliaceae), collected in Indonesia, were found to inhibit aromatase, the rate-limiting enzyme in the production of estrogens from androgens, in both enzyme- and cell-based aromatase inhibition (AI) assays. Bioassay-guided fractionation led to the isolation of six known compounds of the steroid and triterpenoid classes ( 1– 6) from the hexane extract, of which 6β-hydroxystimasta-4-en-3-one ( 5), was moderately active in the cell-based AI assay. Fractionation of the ethyl acetate extract afforded seven pure isolates ( 7– 13) of the modified peptide, fatty acid, monoterpenoid, and benzenoid types, including six known compounds and the new natural product, N-benzoyl- l-phenylalanine methyl ester ( 9). The absolute stereochemistry of 9 and the other two peptides, 7 and 8, was determined by Marfey’s analysis. Linoleic acid ( 10) was found to be active in the enzyme-based AI assay, while 9 and (−)-dehydrololiolide ( 12) showed activity in the cell-based AI assay.

Spectroscopic and Electrochemical Studies of Ferrocenyl Triazole Amino Acid and Peptide Bioconjugates Synthesized by Click Chemistry

Ferrocenyl triazole amino acid (l-leucine methyl ester (2, 5), l-phenylalanine methyl ester (3, 7), l-alanine methyl ester (4), l-valine tert-butyl ester (6), l-proline methyl ester (8)) and peptide derivatives ([Leu5]-enkephalin (9, 10)) were prepared by Cu(I)-catalyzed [3+2] cycloaddition of azidoferrocene and 1,1′-diazidoferrocene with the corresponding alkyne-modified amino acids and peptide. A purity of >95% for the peptide conjugates was confirmed by HPLC. All new compounds were comprehensively characterized by elemental analysis, mass spectrometry (FAB and ESI-MS, including high-resolution MS), IR, and multinuclear 1D and 2D NMR spectroscopy. Solution structures were studied by circular dichroism (CD) and NMR spectroscopy, showing that compounds 5, 6, and 7 form intramolecular hydrogen bonds (IHBs) in noncoordinating solvents. Electrochemical studies show reversible processes of the redox couple Fc0/Fc+ (Fc = ferrocenyl) for compounds 2−9, whereas compound 10 exhibits an irreversible oxidation. A g...