L-histidine Methyl Ester Research Articles

Synthesis of new hetero- and carbocyclic aromatic amides of glycyrrhizic acid as potential anti-HIV agents

Members of a new group of di- and trisubstituted amides of glycyrrhizic acid (GA), the major component of licorice root extract, were synthesized; derivatives contained fragments of heterocyclic and aromatic amines (2-aminopyridine, 4-aminopyridine, 5-aminouracil, sulfadimezine, sulfapyridazine, and L-histidine methyl ester) using the dicyclohexylcarbodiimide method. Amides of GA containing 2-aminopyridine and 5-aminopurine residues had anti-HIV-1 activity in MT-4 cell cultures. The index of selectivity (IS) of the amide of GA with 5-aminouracil was, using various parameters, from 27.73 to 277.32, exceeding values for GA (from 4.45 to 24.0).

A New Metal Chelate Affinity Adsorbent for Cytochrome c

We have prepared a novel metal-chelate adsorbent utilizing N-methacryloyl-L-histidine methyl ester (MAH) as a metal-chelating ligand. MAH was synthesized by using methacryloyl chloride and l-histidine methyl ester dihydrochloride. Spherical beads with an average diameter of 75-125 microm were produced by suspension polymerization of 2-hydroxyethyl methacrylate (HEMA) and MAH carried out in an aqueous dispersion medium. Then, Cu(2+) ions were chelated directly on the chelating beads. Cu(2+)-chelated beads were used in the adsorption of cytochrome c (cyt c) from aqueous solutions. The maximum cyt c adsorption capacity of the Cu(2+)-chelated beads (658.2 micromol/g Cu(2+) loading) was found to be 31.7 mg/g at pH 10 in phosphate buffer. The nonspecific cyt c adsorption on the naked PHEMA beads was 0.2 mg/g. Cyt c adsorption increased with increasing Cu(2+) loading. Cyt c adsorption capacity was demonstrated for the buffer types with the effects in the order phosphate > HEPES > MOPS > MES > Tris-HCl. Cyt c molecules could be adsorbed and desorbed five times with these adsorbents without noticeable loss in their cyt c adsorption capacity.

Synthesis of Cyclic Oligomers from Histidine-Derived Building Blocks Using Dynamic Combinatorial Chemistry

Histidine-derived hydrazide acetal monomers (3-dimethoxymethylbenzoyl)-L-histidine methyl ester 1 and (3-dimethoxymethylbenzoyl)-tau-benzyl-L-histidine methyl ester 2 were prepared from a histidine methyl ester and a tau-benzyl-histidine methyl ester by N-acylation with 3-(dimethoxymethyl)benzoic acid (3) followed by hydrazinolysis. Acid-promoted hydrolysis of each acetal hydrazide initially produced a library of cyclic oligomers that eventually converted to a cyclic dimer. The cyclic dimers 12 and 22 were spectroscopically characterized and found to direct their imidazole-bearing sidechains outward (exo). No evidence for templating the cyclic oligomers was observed using various metal ions and anionic substrates. The average of pKa1 and pKa2 of dimer 12 was determined by potentiometric titration to be 6.6. Dimer 12 was found to catalyze the hydrolysis of p-nitrophenylacetate 10 times faster than 4-methyl imidazole.

An Expedient, Scalable Synthesis of the Natural Product l-Anserine

To date, the synthesis of l-anserine has relied on the use of naturally occurring 1-methyl-l-histidine as a precursor, however its high cost prevents its use in the large-scale synthesis of l-anse­rine. With this in mind, we report herein a concise and efficient synthetic strategy, employing the 160-fold less expensive, l-histidine methyl ester dihydrochloride as a starting material, to afford the title compound in an overall yield of 88%, over four reaction steps.

N-methacryloyl-( l)-histidine methyl ester carrying porous magnetic beads for metal chelate adsorption of cytochrome c

A magnetic metal-chelate adsorbent utilizing N-methacryloyl-( l)-histidine methyl ester (MAH) as a metal-chelating ligand was prepared. MAH was synthesized using methacryloyl chloride and l-histidine methyl ester. Magnetic beads with an average diameter of 50–100 μm were produced by suspension polymerization of ethylene glycol dimethacrylate (EGDMA) and MAH carried out in a dispersion medium. Specific surface area of the magnetic beads was found to be 80 m 2/g. Elemental analysis of the magnetic beads for nitrogen was estimated as 70 μmol MAH/g polymer. Magnetic beads were complexed with the Cu 2+ ions directly via MAH for the adsorption of cytochrome c from aqueous solutions. The cytochrome c adsorption on the mag-poly(EGDMA–MAH) beads was 51 mg/g. Cu 2+ complexing increased the cytochrome c adsorption significantly. The maximum cytochrome c adsorption capacity of the Cu 2+-chelated beads (carrying 68 μmol Cu 2+ per gram of polymer) was found to be 222 mg/g at pH 8.0 in phosphate buffer. Cytochrome c adsorption decreased with increasing temperature. Cytochrome c molecules could be reversibly adsorbed and desorbed ten times with the magnetic adsorbents without noticeable loss in their cytochrome c adsorption capacity. The resulting magnetic chelator beads posses excellent long term storage stability.

PH-dependent redox and CO binding properties of chelated protoheme-l-histidine and protoheme-glycyl-l-histidine complexes

The pH dependence of redox properties, spectroscopic features and CO binding kinetics for the chelated protohemin-6(7)-L-histidine methyl ester (heme-H) and the chelated protohemin-6(7)-glycyl-L-histidine methyl ester (heme-GH) systems has been investigated between pH 2.0 and 12.0. The two heme systems appear to be modulated by four protonating groups, tentatively identified as coordinated H(2)O, one of heme's propionates, N(epsilon) of the coordinating imidazole, and the carboxylate of the histidine residue upon hydrolysis of the methyl ester group (in acid medium). The pK (a) values are different for the two hemes, thus reflecting structural differences. In particular, the different strain at the Fe-N(epsilon) bond, related to the different length of the coordinating arm, results in a dramatic alteration of the bond strength, which is much smaller in heme-H than in heme-GH. It leads to a variation in the variation of the pKa for the protonation of the N(epsilon) of the axial imidazole as well as in the proton-linked behavior of the other protonating groups, envisaging a cross-talk communication mechanism among different groups of the heme, which can be operative and relevant also in the presence of the protein matrix.

Synthesis and pH-dependent micellization of sulfonamide-modified diblock copolymer

The main objective of this study was to develop and characterize pH-sensitive biodegradable polymeric materials. For pH-sensitivity, we employed three kinds of moieties: 2-amino-3-(1H-imidazol-4-yl)-propionic acid (H),N-[4-(4,6-dimethyl-pyrimidin-2ylsulfamoyl)-phenyl]succinamic acid (SM), and 2-{3-[4-(4,6-dimethyl-pyrimidin-2-ylsulfamoyl)-phenylcarbamoyl]-propionylamino}-3-(3H-imidazol-4-yl)-propionic acid (SH). The pH-sensitive diblock copolymers were synthesized by ring opening polymerization and coupling reaction from poly(ethylene glycol) (MPEG), e-caprolactone (CL), D,L-lactide (LA) and pH-sensitive moieties. The pH-sensitive SH molecule was synthesized in a two-step reaction. The first step involved the synthesis of SHM, a methyl ester derivative of SH, by coupling reaction of SM and L-histidine methyl ester dihydrochloride, whereas the second step involved the hydrolysis of the same. The synthesized SM, SHM and SH molecules were characterized by FTIR,1H-NMR and13C-NMR spectroscopy, whereas diblock copolymers and pH-sensitive diblock copolymer were characterized by 1H-NMR and GPC analysis. The critical micelle concentrations were determined at various pH conditions by fluorescence technique using pyrene as a probe. The micellization and demicellization studies of pH-sensitive diblock copolymers were also done at different pH conditions. The pH-sensitivity was further established by acid-based titration and DLS analysis.

Electrochemical Synthesis of L-Histidinol Using Solvated Electrons

The feasibility of the preparation of L-histidinol (I) by reduction of L-histidine methyl ester (II) using an electrogenerated solvated electrons solution has been studied in a laboratory scale reactor. The solvated electrons solution was obtained by electrolysis of a solution of LiCl in that permits an easier handling than or . All components of the electrochemical setup have been optimized for the reaction conditions used. The influence of some reaction variables on the yield of (I) has been studied. Thus, increasing current intensity and temperature enhances the yield of L-histidinol. Nevertheless, the volatility of ethylamine limits the increase of the intensity current and the temperature. A fractionated feeding procedure of (II) was shown to be desirable. The work-up and isolation procedure of (I) has also been described. It includes an electrodialysis process that makes easier the isolation of (I), as well as the recovered LiCl could be recycled as supporting electrolyte.

A comparative reactivity study of microperoxidases based on hemin, mesohemin and deuterohemin

Three microperoxidases – hemin-6(7)-gly-gly-his methyl ester (HGGH), mesohemin-6(7)-gly-gly-his methyl ester (MGGH) and deuterohemin-6(7)-gly-gly-his methyl ester (DGGH) – have been prepared as models for heme-containing peroxidases by condensation of glycyl-glycyl- l-histidine methyl ester with the propionic side chains of hemin, mesohemin and deuterohemin, respectively. The three microperoxidases differ in two substituents, R, of the protoporphyrin IX framework (HGGH: R = vinyl, MGGH: R = ethyl, DGGH: R = H). X-band and high field EPR spectra show that the microperoxidases exhibit spectroscopic properties similar to those of metmyoglobin, i.e. a high spin ferric S = 5/2 signal at g ⊥ = 6 and g ∥ = 2 and an estimated D value of 7.5 ± 1 cm −1. The catalytic activities of the microperoxidases towards K 4[Fe(CN) 6], l-tyrosine methyl ester and 2,2′-azino(bis(3-ethylbenzothiazoline-6-sulfonic acid)) (ABTS) have been investigated. It was found that all three microperoxidases exhibit peroxidase activity and that the reactions follow the generally accepted peroxidase reaction scheme [Biochem. J. 145 (1975) 93–103] with the exception that the initial formation of a Compound I analogue is the rate-limiting step for the whole process. The general activity trend was found to be MGGH ≈ DGGH > HGGH. For each microperoxidase, DFT calculations (B3LYP) were made on the reactions of compounds 0, I and II with H +, e − and H + + e −, respectively, in order to probe the possible relationship between the nature of the 2- and 4-substituents of the hemin and the observed reactivity. The computational modeling indicates that the relative energy differences are very small; solvation and electrostatic effects may be factors that decide the relative activities of the microperoxidases.

Novel metal-chelate affinity sorbents for reversible use in catalase adsorption

A novel metal-chelate adsorbent utilizing N-methacryloyl-( l)-histidine methyl ester (MAH) as a metal-chelating ligand was prepared. MAH was synthesized by using methacryloyl chloride and l-histidine methyl ester dihydrochloride. Magnetic beads with an average size of 150–250 μm were obtained by suspension polymerization of ethylene glycol dimethacrylate (EGDMA), and MAH conducted in aqueous dispersion medium. The specific surface area of the porous beads was found to be 80.1 m 2/g. Mag-poly(EGDMA–MAH) beads were characterized by swelling tests, electron spin resonance (ESR), nuclear magnetic resonance (NMR) and scanning electron microscopy (SEM). Elemental analysis of MAH for nitrogen was estimated as 43.9 μmol/g. Then, Fe 3+ ions were chelated on the magnetic beads. Fe 3+-chelated magnetic beads with a swelling ratio of 40% were used in the adsorption of catalase in batch system. The maximum catalase adsorption capacity of the mag-poly(EGDMA–MAH)–Fe 3+ beads was observed as 83.2 mg/g at pH 7.0. The K m values for immobilized catalase (mag-poly(EGDMA–MAH)–Fe 3+) (20.5 mM) were higher than that of free enzyme (16.5 mM). Storage stability was found to increase with immobilization. It was observed that enzyme could be repeatedly adsorbed and desorbed without significant loss in adsorption capacity or enzyme activity.

Novel metal-chelate affinity adsorbent for purification of immunoglobulin-G from human plasma

Metal-chelating ligand and/or comonomer 2-methacrylolyamidohistidine (MAH) was synthesized by using methacryloyl chloride and l-histidine methyl ester. MAH was characterized by NMR and FTIR. Spherical beads with an average diameter of 75–125 μm were produced by suspension polymerization of methylmethacrylate (MMA) and MAH carried out in an aqueous dispersion medium. Poly(MMA-MAH) beads had a specific surface area of 37.5 m 2/g. Poly(MMA-MAH) beads were characterized by water uptake studies, FTIR, SEM and elemental analysis. Elemental analysis of MAH for nitrogen was estimated as 34.7 μmol/g of polymer. Then, Cu 2+ ions were chelated on the beads. Cu 2+-chelated beads with a swelling ratio of 38% were used in the adsorption of human-immunoglobulin G (HIgG) from both aqueous solutions and human plasma. The maximum adsorption capacities of the Cu 2+-chelated beads were found to be 12.2 mg/g at pH 6.5 in phosphate buffer and 15.7 mg/g at pH 7.0 in MOPS. Higher adsorption value was obtained from human plasma (up to 54.3 mg/g) with a purity of 90.7%. The metal-chelate affinity beads allowed one-step separation of HIgG from human plasma. The adsorption–desorption cycle was repeated 10 times using the same beads without noticeable loss in their HIgG adsorption capacity.

Ultraviolet spectrophotometric characterization of copper(II) complexes with imidazole N-methyl derivatives of l-histidine in aqueous solution

In this study we considered π-methyl- l-histidine (π-methis) and τ-methyl- l-histidine (τ-methis) as ligands for copper(II) ion, in order to clarify, by means of ultraviolet (UV) spectroscopy in aqueous solution ( T=25 °C, I=0.1 M), some aspects of the co-ordination mode with respect to other ligands of a previous study in which copper(II) complexes of l-histidine, N-acetyl- l-histidine, histamine, l-histidine methyl ester or carnosine were investigated. Particularly, UV spectra (300–400 nm) were recorded on solutions at various pH values, containing each binary system Cu–L; afterwards, an UV absorption spectrum for single complexes was calculated, taking into account the chemical model previously assessed, in order to fulfil a correct spectrum–structure correlation. The problem related to the eventual superimposition of the CT shoulder (≈330 nm) to copper(II) of OH − and imidazole pyridine nitrogen groups were now solved by means of a comparison of the UV spectra of dimer species formed by both π-methis or τ-methis. Finally, copper(II) complex formation with 2,2′-bipyridine was taken into account to compare the behaviour of pyridine (from 2,2′-bipyridine) and pyridine imidazole nitrogens (from π-methis or τ-methis) with respect to the UV charge transfer process to copper(II) ion.

Interaction of copper(II) with imidazole pyridine nitrogen-containing ligands in aqueous medium: a spectroscopic study

UV (300–400 nm) and FT/IR (4000–850 cm −1) spectra were considered for a structural discussion of the copper(II) complexes formed with a series of imidazole-containing ligands (namely l-histidine, N-acetyl- l-histidine, histamine, l-histidine methyl ester and carnosine) in aqueous solution ( T=25°C, I=0.1 M). A shoulder at 330 nm was recorded for the main copper(II) complexes with all the ligands considered with the exception of carnosine: this singularity is discussed and a spectrum–structure correlation is proposed. ε 330 values were evaluated for CuL (59 M −1 cm −1) and Cu 2L 2H −2 (577 M −1 cm −1) complexes with histamine and for CuL 2 (49 M −1 cm −1) and CuL 3 (163 M −1 cm −1) with N-acetyl- l-histidine, thus indicating the usefulness of UV spectra in the explored region for the purpose of structural definition. FT/IR spectra (recorded both in aqueous solution and on the residue of evaporated solutions of carnosine and N-acetyl- l-histidine only) help to reveal a significant conformational rearrangement of the ligand, corresponding to complex formation in solution: in fact, modifications in the fingerprint region of the FT/IR spectrum for the dimer of carnosine are observed. Indications of a copper(II)–imidazole nitrogen interaction are also obtained from FT/IR data in the 1000–1100 cm −1 range.

Regiospecific Synthesis of 2,3-Disubstituted- l-Histidines and Histamines

Regiospecific synthesis of 2,3-disubstituted- l-histidines and 2,3-disubstituted histamines starting from l-histidine methyl ester and histamine is reported. The key step involves homolytic free radical alkylation via silver catalyzed oxidative decarboxylation of alkylcarboxylic acids with ammonium persulfate.

Europium(III)-N,N′-Ethylenebis(l-amino acid) Complexes as New Chiral NMR Lanthanide Shift Reagents for Unprotected α-Amino Acids in Neutral Aqueous Solution

Abstract Three N,N′-ethylenebis(l-amino acid) ligands have been obtained simultaneously with three α,α′-(1,4-piperazinediyl)bis[(S)-alkanoic acid] and four N,N′-ethylenedipeptide products, by reacting a mixture of l-histidine methyl ester and l-aspartic acid dimethyl ester with glyoxal in the presence of sodium cyanotrihydroborate in methanol. Europium(III) complexes with N,N′-ethylenebis(l-amino acid) ligands were useful as chiral NMR shift reagents for some unprotected natural α-amino acids as substrates in neutral aqueous solution, as characterized by large enantiomeric shift differences and unbroadened signal shapes on high-resolution NMR spectroscopy. In addition, the acid-dissociation constants of six bis(amino acid) ligands and the stability constant of the europium(III) complex with N,N′-ethylenedi(l-histidine) were obtained by potentiometric titration.

Properties and reactivity of myoglobin reconstituted with chemically modified protohemin complexes.

The synthetic complexes protohemin-6(7)-L-arginyl-L-alanine (HM-RA) and protohemin-6(7)-L-histidine methyl ester (HM-H) were prepared by condensation of suitably protected Arg-Ala or His residues with protohemin IX. HM-RA and HM-H were used for reconstitution of apomyoglobin from horse heart, yielding the Mb-RA and Mb-H derivatives, respectively, of the protein. The spectral, binding and catalytic properties of Mb-RA and Mb-H are significantly different from those of Mb. As shown by MM and MD calculations, these differences are determined by some local structural changes around the heme which are generated by increased mobility of a key peptide segment (Phe43-Lys47), containing the residue (Lys45) that in native Mb interacts with one of the porphyrin carboxylate groups. In the reconstituted Mbs this carboxylate group is bound to the Arg-Ala or His residue and is no longer available for electrostatic interaction with Lys45. The mobility of the peptide segment near the active site allows the distal histidine to come to a closer contact with the heme, and in fact Mb-RA and Mb-H exist as an equilibrium between a high-spin form and a major low-spin, six-coordinated form containing a bis-imidazole ligated heme. The two forms are clearly distinguishable in the NMR spectra, that also show that each of them consists of a mixture of the two most stable isomers resulting from cofactor reconstitution, as also anticipated by MM and MD calculations. Exogenous ligands such as cyanide, azide, or hydrogen peroxide can displace the bound distal histidine, but their affinity is reduced. On the other hand, mobilization of the peptide chain around the heme in the reconstituted Mbs increases the accessibility of large donor molecules at the heme periphery, with respect to native Mb, where a rigid backbone limits access to the distal pocket. The increased active site accessibility of Mb-RA and Mb-H facilitates the binding and electron transfer of phenolic substrates in peroxidase-type oxidations catalyzed by the reconstituted proteins in the presence of hydrogen peroxide.

Modification of Histidine Residues by 4,5-Epoxy-2-alkenals

The reactions of 4,5(E)-epoxy-2(E)-heptenal with 4-methylimidazole and N(alpha)-acetyl-L-histidine methyl ester were studied to characterize the adducts produced in the modification of histidine residues by epoxyalkenals and to develop a methodology for the determination of these adducts in protein hydrolysates. The reaction products, which were isolated and characterized, resulted in the Michael adducts produced in the addition of one of the imidazolic nitrogens to the carbon-carbon double bond of the epoxyalkenal. Only some of the theoretical isomers were produced. Thus, in the reaction with 4-methylimidazole, the main product was 4, 5-epoxy-3-(4-methylimidazol-1-yl)heptanol (88%), although the formation of 4,5-epoxy-3-(5-methylimidazol-1-yl)heptanol (12%) was also observed. On the other hand, the reaction with N(alpha)-acetyl-L-histidine methyl ester produced exclusively N(alpha)-acetyl-1-[1'-(1' ',2' '-epoxybutyl)-3'-hydroxypropyl]-L-histidine methyl ester. This last compound was used to develop a procedure for the determination of 4, 5(E)-epoxy-2(E)-heptenal-histidine adducts in protein hydrolysates. When this procedure was applied to the analysis of bovine serum albumin treated with 0.01-10 mM 4,5(E)-epoxy-2(E)-heptenal, the formation of the adduct was observed and its concentration increased with the concentration of the aldehyde and the incubation time, and was parallel to the histidine losses observed in the protein after acid hydrolysis as well as to the formation of protein carbonyls. In addition, the number of histidine residues lost in the protein was very similar to the number of adduct residues produced, suggesting that the addition reaction is the major mechanism for histidine losses suffered by proteins following their reaction with epoxyalkenals.

Cytochrome c oxidase models. Dinuclear iron/copper complexes derived from covalently modified deuteroporphyrins

The deuterohemin complex obtained by covalent modification of the propionic acid side chains of the porphyrin with a glycyl- l-histidine methyl ester residue and a bis(benzimidazole) residue, respectively, is reported. The bis(benzimidazole) arm can be used as a ligand for a copper(II) ion, giving an heterodinuclear complex that mimics the dioxygen reduction center found in cytochrome c oxidase. The relevance of the present model system is shown by the smooth reactivity that the reduced form of the heme/copper complex exhibits to dioxygen. The reaction, in fact, proceeds nondestructively even at room temperature to give the fully oxidized Fe(III) Cu(II) species.

L-histidine methyl ester dihydrochloride.

The title compound, C7H13N3O2(2+).2Cl-, has distances and angles quite similar to those of histidine hydrochloride monohydrate [Donohue & Caron (1964). Acta Cryst. 17, 1178-1180], except for the distances within the ester functionality.

Oxovanadium(IV) and amino acids—VIII. l-histidine derivatives and related ligands: A spectroscopic study

The coordination structures of various species in aqueous solutions of oxo-vanadium(IV) + derivatives of l-histidine ( 1) and related ligands (3-methyl- l-histidine, 1-methyl- l-histidine, l-histidine methyl ester, l-histidinol, Nα- acetyl- l-histidine and histamine) have been studied by investigating the pH dependence of the circular dichroism, isotropic absorption and electron spin resonance spectra, and are compared with the structures of the corresponding complexes of l-histidine. Comparison of the spectroscopic results for all systems studied indicates coordination geometries.