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PubMed1985

Na+-like effect of imidazole on the phosphorylation of (Na+ + K+)-ATPase.

A high basal level of phosphorylation (approx. 70% of the optimal Na+-dependent phosphorylation level) is observed in 50 mM imidazole-HCl (pH 7.0), in the absence of added Na+ and K+ and the presence of 10-100 microM Mg2+. In 50 mM Tris-HCl (pH 7.0) the basal level is only 5%, irrespective of the Mg2+ concentration. Nevertheless, imidazole is a less effective activator of phosphorylation than Na+ (Km imidazole-H+ 5.9 mM, Km Na+ 2 mM under comparable conditions). Imidazole-activated phosphorylation is strongly pH dependent, being optimal at pH less than or equal to 7 and minimal at pH greater than or equal to 8, while Na+-activated phosphorylation is optimal at pH 7.4. This suggests that imidazole-H+ is the activating species. Imidazole facilitates Na+-stimulated phosphorylation. The Km for Na+ decreases from 0.63 mM at 5 mM imidazole-HCl to 0.21 mM at 50 mM imidazole-HCl (pH 7; 0.1 mM Mg2+ in all cases). Imidazole-activated phosphorylation is more sensitive to inhibition by K+ (I50 = 12.5 microM) than Na+-activated phosphorylation (I50 = 180 microM). Mg2+ antagonizes activation by imidazole-H+ and also inhibition by K+. The Ki value for Mg2+ (approx. 0.3 mM) is the same for the two antagonistic effects. Tris buffer (pH 7.0) inhibits imidazole-activated phosphorylation with an I50 value of 30 mM in 50 mM imidazole-HCl (pH 7.0) plus 0.1 mM Mg2+. We conclude that imidazole-H+, but not Tris-H+, can replace Na+ as an activator of ATP-dependent phosphorylation, primarily by shifting the E2----E1 transition to the right, leading to a phosphorylating E1 conformation which is different from that in Tris buffer.

Animals↗

PubMed1998

Imidazole binding to horse metmyoglobin: dependence upon pH and ionic strength.

The reaction between metmyoglobin and imidazole has been studied as a function of pH between pH 4.2 and 11.5 and as a function of ionic strength at integral pH values (5 to 10) between 0.001 and 1.0 M ionic strength. The reaction between metmyoglobin and 1-methylimidazole has also been investigated as a function of pH. Comparison of the pH dependence of the association rate constants for the two ligands indicates that the negatively charged imidazolate ion does not contribute to the observed rate of imidazole binding at pH < or = 11.5. At all pH values between pH 4.2 and pH 11.5 the initial complex formed involves the neutral form of bound imidazole. At pH 11.5, the neutral imidazole complex is converted slowly (t1/2 approximately 10 s) into an imidazolate complex. The kinetic data were analyzed according to two mechanisms, one involving the binding of neutral imidazole only and one involving the direct binding of both imidazole and the imidazolium ion to metmyoglobin. Although secondary kinetic salt effects account for the ionic strength dependence of the association rate constant, evidence which indicates that metmyoglobin reacts with imidazole and with the imidazolium ion with similar rates is provided. A self-consistent analysis indicates that the rate constants for imidazole and imidazolium ion binding to metmyoglobin are 350 and 230 M-1 s-1, respectively, at neutral pH and 0.1 M ionic strength. Imidazole can react directly with hydroxymetmyoglobin with a rate of 56 M-1 s-1 at 0.1 M ionic strength, about sixfold slower than binding to aquometmyoglobin. Protonation of a second heme-linked group, thought to be His-97, has little influence on the binding of imidazole but does decrease the rate of imidazolium binding by about eightfold to 29 M-1 s-1 at 0.1 M ionic strength.

Animals↗

PubMed1994

1H-NMR measurement of fractional dissociation of imidazole in intact animals.

The alphastat hypothesis states that intracellular acid-base status is regulated to maintain constancy of the fractional dissociation of intracellular protein and enzyme imidazole-histidine (alpha-imidazole). A major drawback of this theory has been the lack of a means to directly measure alpha-imidazole in intact animals. We developed a method for directly measuring alpha-imidazole in intact unanesthetized animals using 1H-nuclear magnetic resonance spectroscopy (NMR). We measured carnosine alpha-imidazole of white skeletal muscle from intact unanesthetized newts at three body temperatures (10, 20, and 30 degrees C). alpha-Imidazole remained constant, approximately 0.56, with alterations in body temperature, whereas intracellular pH (pHi) changed significantly (-0.015 U/degrees C), affirming the validity of the imidazole alphastat hypothesis for this tissue. This method was also used to determine the pK values of the imidazole moiety of carnosine and the imidazole moiety alone over a temperature (T) range 4-40 degrees C. The pK values of carnosine differed from those of imidazole, but the delta pK/delta T was the same. pHi was also determined using 31P-NMR and found to be the same as that calculated from carnosine alpha-imidazole values. Therefore Pi and carnosine share a similar pHi environment. We describe a novel technique to directly measure alpha-imidazole in intact tissue.

Animals↗

PubMed2006

Naturally occurring and synthetic imidazoles: their chemistry and their biological activities.

Imidazoles are an important class of heterocycles and include many substances of both biological and chemical interest. They are part of a large number of highly significant biomolecules such as the essential amino acid histidine and related compounds, biotin, and the imidazole alkaloids. Insertion of the imidazole nucleus is an important synthetic strategy in drug discovery. Imidazole drugs have broad applications in many areas of clinical medicine. The imidazoles are a class of antifungal azole derivatives and have a broad spectrum of activities both in vitro and in vivo. The imidazole moiety is also contained in many histaminergic ligands for histamine H1, H2, and H3 receptors. These are currently used as tools in pharmacological studies. The important therapeutic properties of imidazole related drugs have encouraged the medicinal chemists to synthesize and test a large number of novel molecules. Some of these have chemotherapeutic properties, such as for example several FTase inhibitors with an imidazole moiety. Imidazole derivatives have also been shown to have antibacterial activity and recently several P38 MAP Kinase inhibitors and 5-Lipoxygenase inhibitors containing the imidazole moiety have been synthesized. This review reports current progress in the area of new biologically active imidazoles and recently discovered naturally occurring imidazole.

Alkyl and Aryl Transferases↗

PubMed1987

Prebiotic synthesis of imidazole-4-acetaldehyde and histidine.

The prebiotic synthesis of imidazole-4-acetaldehyde and imidazole-4-glycol from erythrose and formamidine has been demonstrated as well as the prebiotic synthesis of imidazole-4-ethanol and imidazole-4-glycol from erythrose, formaldehyde and ammonia. The products were identified by TLC, HPLC, and LC-MS by comparison with authentic samples. The maximum yields of imidazole-4-acetaldehyde, imidazole-4-ethanol, and imidazole-4-glycol obtained in these reactions are 1.6, 5.4, 6.8% respectively, based on the erythrose. Imidazole-4-acetaldehyde would have been converted to histidine on the primitive earth by a Strecker synthesis, and several prebiotic reactions would convert imidazole-4-glycol and imidazole-4-ethanol to imidazole-4-acetaldehyde.

Aldehydes↗

PubMed1975

Synthesis of 5-amino-1-(5-deoxy-beta-D-ribofuranosyl)imidazole-4-carboxamide and related 5'-deoxyimidazole ribonucleosides.

5-Amino-1-(beta-D-ribofuranosyl)imidazole-4-carboxamide (1, AICA ribonucleoside) was converted in two steps to 5-amino-1-(5-deoxy-5-iodo-2,3-O-isopropylidene-beta-D-ribofuranosyl)imidazole-4-carboxamide (3) which was hydrogenated in the presence of Pd/C to yield 5-amino-1-(5-deoxy-2,3-O-isopropylidene-beta-D-ribofuranosyl)imidazole-4-carboxamide (4). The dehydration of 4 yielded 5-amino-1-(5-deoxy-2,3-O-isopropylidene-beta-D-ribofuranosyl)imidazole-4-carbonitrile (7). The compounds 3, 4, and 7 were deblocked with formic acid to furnish 5-amino-1-(5-deoxy-5-iodo-beta-D-ribofuranosyl)imidazole-4-carboxamide (6). 5-amino-1-(5-deoxy-beta-D-ribofuranosyl)imidazole-4-carboxamide (5), and 5-amino-1-(5-deoxy-beta-D-ribofuranosyl)imidazole-4-carbonitrile (8), respectively. Compound 8 was acetylated and then deaminated to give 1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)imidazole-4-carbonitrile (11). The compounds 8 and 11 were converted into 5-amino-1-(5-deoxy-beta-D-ribofuranosyl)imidazole-4-thiocarboxamide (9) and 1-(5-deoxy-beta-D-ribofuranosyl)imidazole-4-thiocarboxamide (12), respectively. The synthesis of 1-(5-deoxy-beta-D-ribofuranosyl)imidazole-4-carboxamide (13) was achieved for the first time by the treatment of 11 with hydrogen peroxide in the presence of ammonium hydroxide. The compounds were tested for antibacterial, antifungal, and antiviral activity, with 5 and 6 significantly inhibitory to Staphylococcus aureus.

Cell Line↗

PubMed2005

Computational studies on imidazole heme conformations.

Density functional theory computations of heme with ionized propionic acid groups, axially coordinated with two imidazoles, were performed for different mutual orientations of the imidazole planes. Environmental influences from water or protein were considered with a continuum dielectric medium by solving the Poisson equation. In vacuum, optimized geometries yielded imidazole-heme conformations where the NH groups of imidazoles are oriented toward the heme propionic groups in agreement with data from crystal structures of heme proteins. Conformational free-energy dependencies of the mutual orientation of axially ligated imidazoles calculated in protein (epsilon=10) and water (epsilon=80) environments confirmed the vacuum results, albeit the energy difference between the preferred and the 180 degrees opposite orientations of the imidazole ligand decreased from 3.84 kcal/mol in vacuum to 2.35 and 2.40 kcal/mol in protein and water, respectively. Two main factors determine the imidazole orientation: (1) the direct intramolecular electrostatic interactions of propionic groups with the polar NH groups of imidazole and (2) the electrostatic interaction of the total dipole moment of the imidazole-heme complex with the reaction field. In vacuum, only the first type of interaction is present, while in a dielectric medium the latter effect becomes competitive at high dielectric constant, resulting in a decrease of the orientational preference. Interestingly, the orientational preference of the imidazole axially ligated to heme becomes even more pronounced, if the negatively charged propionates are neutralized by counter charges that mimic salt bridges or protonation of the propionates.

Heme↗

PubMed2004

Resonance Raman study on synergistic activation of soluble guanylate cyclase by imidazole, YC-1 and GTP.

Soluble guanylate cyclase (sGC), a physiological nitric oxide (NO) receptor, is a heme-containing protein and catalyzes the conversion of GTP to cyclic GMP. We found that 200 mM imidazole moderately activated sGC in the coexistence with 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), although imidazole or YC-1 alone had little effect for activation. GTP facilitated this process. Resonance Raman spectra of imidazole complex of native sGC and CO-bound sGC (CO-sGC) have demonstrated that a simple heme adduct with imidazole at the sixth coordination position is not present for both sGC and CO-sGC below 200 mM of the imidazole concentration and that the Fe-CO stretching band (nuFe-CO)) appears at 492 cm(-1) in the presence of imidazole compared with 473 cm(-1) in its absence. Both frequencies fall on the line of His-coordinated heme proteins in the nuFe-CO vs nuC-O plot. However, it is stressed that the CO-heme of sGC becomes apparently photo-inert in a spinning cell in the presence of imidazole, suggesting the formation of five-coordinate CO-heme or of six-coordinate heme with a very weak trans ligand. These observations suggest that imidazole alters not only the polarity of heme pocket but also the coordination structure at the fifth coordination side presumably by perturbing the heme-protein interactions at propionic side chains. Despite the fact that the isolated sGC stays in the reduced state and is not oxidized by O(2), sGC under the high concentration of imidazole (1.2 M) yielded nu4 at 1373 cm(-1) even after its removal by gel-filtration, but addition of dithionite gave the strong nu4 band at 1360 cm(-1). This indicated that imidazole caused autoxidation of sGC.

Animals↗

PubMed1994

Imidazol-1-ylalkanoic acids as extrinsic 1H NMR probes for the determination of intracellular pH, extracellular pH and cell volume.

The synthesis and biological evaluation of a novel series of extrinsic probes for intracellular pH (pHi), extracellular pH (pHo) and cell volume determination by 1H NMR is described. Imidazol-1-ylacetate, malonate, 3-glutarate and 2-succinate esters were synthesized by reaction of imidazole with alpha-bromo esters or with alpha, beta-unsaturated esters. The corresponding acids were prepared by hydrolysis. Rat erythrocytes were readily permeable to methyl imidazol-1-ylacetate, moderately permeable to diethyl 2-imidazol-1-ylsuccinate and impermeable to diethyl 3-imidazol-1-yl-glutarate esters. Imidazol-1-ylacetic acid was the only acid derivative which penetrated the erythrocyte interior when added directly to the incubation medium. Transport of the permeable compounds to the erythrocyte interior was non-saturable up to 200 mM added compound. Addition of methyl imidazol-1-ylacetate or diethyl 2-imidazol-1-ylsuccinate esters to erythrocyte suspensions, resulted in hydrolysis to imidazol-1-ylacetic acid and 2-imidazol-1-ylsuccinic acid mono-ethyl ester in the intracellular and extracellular spaces, respectively. pHi and pHo were determined from the different chemical shifts of the H-2 proton of the acid derivatives in the intracellular (H-2i) and extracellular (H-2o) compartments. In addition, the relative intracellular and extracellular volumes could be calculated from the areas of the intracellular and extracellular H-2 resonances.

Animals↗

PubMed2006

In vivo detection of gold-imidazole self-assembly complexes: NIR-SERS signal reporters.

Here we report in vitro and in vivo detection of self-assembled Au-imidazole by using near-infrared surface-enhanced Raman scattering (NIR-SERS). In vivo, the Au-imidazole structures were administered into tumor-bearing mice and detected noninvasively. The self-assembled Au-imidazole complexes were generated by the adsorption of imidazole molecules onto Au nanoparticles (NP) and were then characterized as aqueous suspensions by using NIR-SERS, angle-dependent light scattering with fractal dimension analysis, and visible extinction spectroscopy. The structure and optical activity was sensitive to imidazole concentration and Au NP size. Specifically, the Au-imidazole assemblies formed at lower imidazole concentrations had the lowest fractal dimension (D(f) = 1.2) and the largest Raman enhancement factors for the dominant NIR-SERS feature, a ring-breathing vibrational mode at 954 cm(-1). Changes in elastic scattering intensity, fractal dimension, and surface plasmon absorption were observed with increasing imidazole concentration. The Raman enhancement factor was also found to range between 10(6) and 10(9) with different primary Au nanoparticle sizes. For the higher enhancement factor systems, NIR-SERS detection of Au-imidazole was performed with data acquisitions time of only 5 s. The largest enhancement was observed for the 954-cm(-1) feature at an imidazole concentration of 1.9 microM when coupled to 54-nm-diameter Au NPs (the largest NP tested). Finally, we show the first demonstration of in vivo, noninvasive, and real-time SERS detection.

Animals↗

PubMed2001

Replacement of the axial histidine ligand with imidazole in cytochrome c peroxidase. 1. Effects on structure.

Replacement of the axial histidine ligand with exogenous imidazole has been accomplished in a number of heme protein mutants, where it often serves to complement the functional properties of the protein. In this paper, we describe the effects of pH and buffer ion on the crystal structure of the H175G mutant of cytochrome c peroxidase, in which the histidine tether between the heme and the protein backbone is replaced by bound imidazole. The structures show that imidazole can occupy the proximal H175G cavity under a number of experimental conditions, but that the details of the interaction with the protein and the coordination to the heme are markedly dependent on conditions. Replacement of the tethered histidine ligand with imidazole permits the heme to shift slightly in its pocket, allowing it to adopt either a planar or distally domed conformation. H175G crystallized from both high phosphate and imidazole concentrations exists as a novel, 5-coordinate phosphate bound state, in which the proximal imidazole is dissociated and the distal phosphate is coordinated to the iron. To accommodate this bound phosphate, the side chains of His-52 and Asn-82 alter their positions and a significant conformational change in the surrounding protein backbone occurs. In the absence of phosphate, imidazole binds to the proximal H175G cavity in a pH-dependent fashion. At pH 7, imidazole is directly coordinated to the heme (d(Fe--Im) = 2.0 A) with a nearby distal water (d(Fe--HOH) = 2.4 A). This is similar to the structure of WT CCP except that the iron lies closer in the heme plane, and the hydrogen bond between imidazole and Asp-235 (d(Im--Asp) = 3.1 A) is longer than for WT CCP (d(His--Asp) = 2.9 A). As the pH is dropped to 5, imidazole dissociates from the heme (d(Fe--Im) = 2.9 A), but remains in the proximal cavity where it is strongly hydrogen bonded to Asp-235 (d(Im--Asp) = 2.8 A). In addition, the heme is significantly domed toward the distal pocket where it may coordinate a water molecule. Finally, the structure of H175G/Im, pH 6, at low temperature (100 K) is very similar to that at room temperature, except that the water above the distal heme face is not present. This study concludes that steric restrictions imposed by the covalently tethered histidine restrain the heme and its ligand coordination from distortions that would arise in the absence of the restricted tether. Coupled with the functional and spectroscopic properties described in the following paper in this issue, these structures help to illustrate how the delicate and critical interactions between protein, ligand, and metal modulate the function of heme enzymes.

Amino Acid Substitution↗

PubMed2006

Masked imidazolyl-dipyrromethanes in the synthesis of imidazole-substituted porphyrins.

Imidazole-substituted metalloporphyrins are valuable for studies of self-assembly and for applications where water solubility is required. Rational syntheses of porphyrins bearing one or two imidazol-2-yl or imidazol-4-yl groups at the meso positions have been developed. The syntheses employ dipyrromethanes, 1-acyldipyrromethanes, and 1,9-diacyldipyrromethanes bearing an imidazole group at the 5-position. The polar, reactive imidazole unit was successfully masked by use of (1) the 2-(trimethylsilyl)ethoxymethyl (SEM) group at the imidazole pyrrolic nitrogen, and (2) a dialkylboron motif bound to the pyrrole of the dipyrromethane and coordinated to the imidazole imino nitrogen. The nonpolar nature of such doubly masked imidazolyl-dipyrromethanes facilitated handling. Selected masked dipyrromethanes were characterized by 11B and 15N NMR spectroscopy. Five distinct methods were examined to obtain trans-A2B2-, trans-AB2C-, and trans-AB-porphyrins. Each porphyrin contained one or two SEM-protected imidazole units. The SEM group could be removed with TBAF or HCl. Two zinc(II) porphyrins and a palladium(II) porphyrin bearing a single imidazole moiety were prepared and subjected to alkylation (with ethyl iodide, 1,3-propane sultone, or 1,4-butane sultone) to give water-soluble imidazolium- porphyrins. This work establishes the foundation for the rational synthesis of a variety of porphyrins containing imidazole units.

Imidazoles↗

PubMed1998

New imidazoles as probes of the active site topology and potent inhibitors of beta-glucosidase.

Series of 4-arylimidazoles, omega-N-acylhistamines and 4-(omega-phenylalkyl)imidazoles were synthesized in order to probe the active site topology of sweet almond beta-glucosidase. These imidazole derivatives were shown to be very powerful competitive inhibitors. Among the 20 tested compounds, omega-N-benzoylhistamine and 4-(3'-phenylpropyl)imidazole are the most potent inhibitors of the enzyme, with pH-independent Ki values of 0.06 and 0.07 microM, respectively. The inhibition of 4-(omega-phenylalkyl)imidazoles exhibited an interesting trend as to Ki values: 4-phenylimidazole (6.6 microM)>4-benzylimidazole (1.4 microM)>4-(2'-phenylethyl)imidazole (0.82 microM)>4-(3'-phenylpropyl)imidazole (0.07 microM)<4-(4'-phenylbutyl)imidazole (0.13 microM)<4-(5'-phenylpentyl)imidazole (0.3 microM). This revealed that the imidazole and aryl binding sites (which result from favorable interactions within the corresponding glycone and aglycone binding subsites) are separated by the optimal distance equivalent to the length of a -CH2-CH2-CH2- group. Substitutions of the phenyl moieties of 4-phenylimidazole and 4-benzoylhistamine result in weaker inhibition. These classes of imidazoles are particularly powerful inhibitors of sweet almond beta-glucosidase.

Binding Sites↗

PubMed1978

Antisecretory effect of imidazole and its derivatives in an isolated gastric mucosa preparation and an anesthetized young chicken preparation; comparison with a histamine H2-receptor antagonist.

We invesigated the influences of imidazole on the basal and the secretagogue-stimulated gastric acid secretion in isolated bullfrog gastric mucosa preparations and in anesthetized young chickens. Imidazoles (1 x 10(-4) g/ml) readily depressed the basal acid secretion in gastric mucosa in vitro. The inhibitory effect of imidazole was diminished considerably after washing out of the drug. The maximum acid secretion elicited by tetragastrin or bethanechol was completely antagonized by imidazole (1 x 10(-4) g/ml). The stimulatory action of histamine or dibutyryl cyclic AMP was also remarkably depressed in the presence of imidazole (3 x 10(-4) g/ml). after dibenamine pretreatment (5 x 10(-5) g/ml) for 60 min, the isolated gastric mucosa preparation became refractory to tetragastrin, bethanechol and histamine, but responded to dibutyryl cyclic AMP. Imidazole protected the histamine sensitivity against dibenamine blockade in the concentration of 5 x 10(-4) g/ml. In anesthetized young chickens, imidazole (200 mg/kg, s.c.) depressed tetragastrin- and histamine-stimulated gastric acid secretion. The effects of the imidazole derivatives and several antagonists (metiamide, atropine, diphenhydramine, acetazolamide and 2,4-dinitrophenol) on acid production were compared with that of imidazole. From these results, it is concluded that imidazole has a potent antisecretory effect on the basal and the secretagogue-stimulated acid secretion.

Animals↗

PubMed1987

Cytokinin Oxidase from Phaseolus vulgaris Callus Tissues : Enhanced in Vitro Activity of the Enzyme in the Presence of Copper-Imidazole Complexes.

The effects of metal ions on cytokinin oxidase activity extracted from callus tissues of Phaseolus vulgaris L. cv Great Northern have been examined using an assay based on the oxidation of N(6)-(Delta(2)-isopentenyl)-adenine-2,8-(3)H (i(6) Ade) to adenine (Ade). The addition of cupric ions to reaction mixtures containing imidazole buffer markedly enhanced cytokinin oxidase activity. In the presence of optimal concentrations of copper and imidazole, cytokinin oxidase activity was stimulated more than 20-fold. The effect was enzyme dependent, specific for copper, and observed only in the presence of imidazole. The substrate specificity of the copper-imidazole enhanced reaction, as judged by substrate competition tests, was the same as that observed in the absence of copper and imidazole. Similarly, in tests involving DEAE-cellulose chromatography, elution profiles of cytokinin oxidase activity determined using a copper-imidazole enhanced assay were identical to those obtained using an assay without copper and imidazole. On the basis of these results, the addition of copper and imidazole to reaction mixtures used to assay for cytokinin oxidase activity is judged to provide a reliable and specific assay of greatly enhanced sensitivity for the enzyme. The mechanism by which copper and imidazole enhance cytokinin oxidase activity is not certain, but the reaction catalyzed by the enzyme was not inhibited by anaerobic conditions when these reagents were present. This observation suggests that copper-imidazole complexes are substituting for oxygen in the reaction mechanism by which cytokinin oxidase effects cleavage of the N(6)-side chain of i(6)Ade.

Journal Article↗

PubMed1976

Proton NMR study of coordinated imidazoles in low-spin ferric heme complexes. Assignment of single proton histidine resonance in hemoproteins.

The proton signals for the coordinated axial imidazoles in a series of low-spin ferric bis-imidazole complexes with natural porphyrin derivatives have been located and assigned. The methyl signals of several methyl-substituted imidazoles have also been resolved for the mixed ligand complexes of imidazole and cyanide ion. The imidazole spectra for the bis complexes are essentially the same as those reported earlier for synthetic porphyrins, with the hyperfine shifts exhibiting comparable contributions from the dipolar and contact interactions. The contact contribution reflects spin transfer into a vacant imidazole pi orbital. The spectra of both the mono- and bis-imidazole complex concur in predicting that only the 2-H and 5-CH2 signals of an axial histidine are likely to resonate clearly outside the diamagnetic 0 to --10 ppm from TMS region in hemoproteins. However, both the 2-H and 4-H imidazole peaks are found to be too broad to detect in a hemoprotein. Hence, it is suggested that the pair of non-heme, single-proton resonances in low-spin met-myoglobin cyanides arise from the non-equivalent methylene protons at the 5-position of the histidyl imidazole. Both the resonance positions and relative linewidths in the model compounds are consistent with the data for this pair of protons in myoglobins. The possible interpretations of the average downfield bias of these signals as well as the magnitude of their spacing, are discussed in terms of the conformation of the proximal histidine relative to the heme group.

Chemical Phenomena↗

PubMed2004

Acid-base properties and copper(II) complexes of dipeptides containing histidine and additional chelating bis(imidazol-2-yl) residues.

Copper(II) complexes of dipeptides of histidine containing additional chelating bis(imidazol-2-yl) agent at the C-termini (PheHis-BIMA [N-phenylalanyl-histidyl-bis(imidazol-2-yl)methylamine] and HisPhe-BIMA [N-histidyl-phenylalanyl-bis(imidazol-2-yl)methylamine]) were studied by potentiometric, UV-Visible and Electron Paramagnetic Resonance (EPR) techniques. The imidazole nitrogen donor atoms of the bis(imidazol-2-yl)methyl group are described as the primary metal binding sites forming stable mono- and bis(ligand) complexes at acidic pH. The formation of a ligand-bridged dinuclear complex [Cu2L2]4+ is detected in equimolar solutions of copper(II) and HisPhe-BIMA. The coordination isomers of the dinuclear complex are described via the metal binding of the bis(imidazol-2-yl)methyl, amino-carbonyl and amino-imidazole(His) functions. In the case of the copper(II)-PheHis-BIMA system the [NH2, N-(amide), N(Im)] tridentate coordination of the ligand is favoured and results in the formation of di- and trinuclear complexes [Cu2H(-1)L]3+ and [Cu3H(-2)L2]4+ in equimolar solutions. The presence of these coordination modes shifts the formation of "tripeptide-like" ([NH2, N-, N-, N(Im)]-coordinated) [CuH(-2)L] complexes into alkaline pH range as compared to other dipeptide derivatives of bis(imidazol-2-yl) ligands. Although there are different types of imidazoles in these ligands, the deprotonation and coordination of the pyrrole-type N(1)H groups does not occur below pH 10.

Copper↗

PubMed2004

Comparative cytotoxicity of N-substituted N'-(4-imidazole-ethyl)thiourea in precision-cut rat liver slices.

In order to more rationally design thiourea-containing drugs and drug candidates, specifically thiourea-containing histamine H3 receptor antagonists, it is necessary to develop structure-toxicity relationships (STRs). For this purpose, the cytotoxicity of a series of thiourea-containing compounds was tested in precision-cut rat liver slices. A concentration of 1000 microM of N-p-bromophenyl, N'-(4-imidazole-ethyl)thiourea (8) or N-p-nitrophenyl, N'-(4-imidazole-ethyl)thiourea (9) was found to cause cytotoxicity, evidenced as LDH leakage, resulting in more than 95% LDH leakage after 6h. N-p-Methoxyphenyl, N'-(4-imidazole-ethyl)thiourea (6) caused 40.6 +/- 19.7% LDH leakage after 6h. Control levels of cell death (1% methanol as control vehicle) were below 20% in 6h. After 6h of exposure, N-p-chlorophenyl, N'-(4-imidazole-ethyl)thiourea (7), 8, and 9 were already found to cause significant cytotoxicity at a concentration of 100 microM. At 200 microM, 9 was found to cause significantly more cytotoxicity than 7 and 8. N-Naphthyl, N'-(4-imidazole-ethyl)thiourea (12) was found to cause significant cytotoxicity towards precision-cut rat liver slices after 6h of exposure to a concentration of 500 microM. All other N-substituted, N'-(4-imidazole-ethyl)thiourea tested in this study were not found to be cytotoxic towards precision-cut rat liver slices within the 6h of exposure up to a concentration of 1000 microM. Intracellular glutathione (GSH) content and mitochondrial MTT reduction activity were also examined after exposure of slices to N-substituted, N'-(4-imidazole-ethyl)thiourea. Both of these markers, however, were not found to provide additional information regarding the possible mechanisms of cytotoxicity, i.e. GSH depletion or reduced mitochondrial activity since these markers did not clearly precede LDH leakage. A correlation was found between cytotoxicity towards precision-cut rat liver slices and Vmax/Km values for the formation of sulfenic acids from N-substituted N'-(4-imidazole-ethyl)thiourea by hepatic rat flavin-containing monooxygenases (FMO). The compound with the highest Vmax/Km value for the formation of sulfenic acids, 9, was also the most cytotoxic. Compounds with a significantly lower Vmax/Km value, 7, 8, and 12, were less cytotoxic than 9. Compounds with a Vmax/Km value for the formation of sulfenic acids lower than 0.0788 ml/(minmg) were found not to be cytotoxic towards precision-cut rat liver slices for concentrations up to 1000 microM at an exposure time of 6h. It is concluded, from this study, that N-phenyl substituted N'-(4-imidazole-ethyl)thiourea-containing electron-withdrawing p-substituents are cytotoxic towards precision-cut rat liver slices. Cytotoxicity is increased with increasing electron-withdrawing capacity of the p-substituent. A correlation was found to exist between Vmax/Km value for the formation of sulfenic acids by rat liver FMO enzymes and cytotoxicity.

Animals↗