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PubMed2004

Kinetic and mechanistic study on the reaction of alkylcobaloximes with azoles.

The kinetics of axial water substitution by azoles (pyrazole and 1,2,4-triazole) in three different cobaloximes, viz.trans-[Co(Hdmg)(2)(R)H(2)O] where Hdmg = dimethylglyoximate, R = PhCH(2), Et and CF(3)CH(2), were studied as a function of azole concentration, temperature and pressure in aqueous solution. The second order rate constants for the substitution of water in trans-[Co(Hdmg)(2)(R)H(2)O] for R = Et at pH 6.0, 25 degrees C and I= 0.1 M (NaClO(4)), were found to be 1309 and 1200 M(-1) s(-1) for pyrazole (Pz) and 1,2,4-triazole (Tz), respectively, and those obtained for R = PhCH(2) were found to be 755 and 691 M(-1) s(-1), respectively. The second order rate constants in the case of R = CF(3)CH(2) were found to be 0.358 and 0.348 M(-1) s(-1) for Pz and Tz, respectively. The relative order of reactivity for the different alkyls being Et > PhCH(2) > CF(3)CH(2). The activation parameters (DeltaH([not equal]), DeltaS([not equal]) and DeltaV([not equal])) obtained for these reactions were found to be in the range of 65-87 kJ mol(-1), 24-47 J mol(-1) K(-1) and 2.5-7.7 cm(3) mol(-1), respectively. These data suggest that an I(d) substitution mechanism operates where the azoles participate in the transition state.

Journal Article↗
PubMed2005

Can weak interactions modify the binding properties of a strong nitrogen donor? Unusual N-coordination of a phosphoranylidene-substituted pyrazolone unit towards palladium(II) centres: an experimental and theoretical study.

Selective N(2)-binding of 3-methyl-1-phenyl-4-(triphenylphosphoranylidene)-2-pyrazolin-5-one (L) has been found in two palladium(II) complexes, [PdCl(2)L(2)](2) and [Pd(o-C(6)H(4)CH(2)NMe(2))Cl](3). X-Ray diffraction studies show that the pyrazole rings lie almost perpendicular to the coordination plane. In both complexes the metal atom is located out of the plane defined by the pyrazole ring(s)(dihedral angle between the plane and the Pd-N vector approximately 30 degrees). To investigate the origin of this distortion, a theoretical study was carried out on a simplified model of complex , where a single pyrazolone ligand was replaced by NH(3). From this study it could be inferred that the out-of-plane distortion mainly involves weak, electrostatic interactions between a chlorine atom and an ortho-aromatic H atom of the N(1)-linked phenyl group, as well as between the other chlorine atom and an ortho-aromatic H atom of the PPh(3) group.

Journal Article↗
PubMed2006

Targeted construction of azido-bridged Ni4 complexes with decisive effect of mu-1,3-azide torsion on the spin ground state.

Highly preorganized pyrazolate-based dinickel(II) systems are shown to constitute suitable building blocks for the targeted assembly of azido-bridged Ni4 complexes with rectangular arrangement of the metal ions. A set of such complexes has been prepared and structurally characterized. mu-1,1-Azide binding within the bimetallic sub-units is controlled by the chosen topology of the pyrazolate ligand scaffold and gives rise to the anticipated ferromagnetic intradimer coupling. Overall magnetic properties of the Ni4 array, however, are mainly determined by the Ni-NNN-Ni torsion of the interdimer mu-1,3-azido linkages. According to the crystallographic results, these torsion angles vary over a wide range, and partial disorder of the mu-1,3-azide bridge in one of the compounds indicates high structural flexibility even in the solid state. Two of the compounds represent rare examples of molecular complexes with a Ni-NNN-Ni torsion angle of almost exactly 90 degrees . The resulting magnetic ground state (neglecting zero-field splitting) is either S = 0 or S = 4 depending on the Ni-NNN-Ni torsion, and in one case a drastic change is observed upon extrusion of lattice solvent.

Journal Article↗
PubMed1972

Utilization and metabolic effects of acetaldehyde and ethanol in the perfused rat liver.

1. Removal of acetaldehyde and ethanol has been studied in perfused rat livers. 2. The maximum rate of ethanol oxidation was 2mumol/min per g of liver, which was less than the calculated capacity of the ethanol-oxidizing system. The lactate/pyruvate ratio of the medium increased with the rate of ethanol removal. At low ethanol concentrations most of the acetaldehyde formed was oxidized further, but at ethanol concentrations above 16mm about 60% of the acetaldehyde left the liver unmetabolized. 3. At lower concentrations the greater part of added acetaldehyde was oxidized, but above 5mm, 50-60% of that removed was recovered as ethanol. 4. When the reduction of acetaldehyde was blocked by pyrazole, removal was strongly diminished. There was no effect on the lactate/pyruvate ratio during oxidation of low concentrations of acetaldehyde, even in the presence of pyrazole, but at higher concentrations a gradual increase occurred. 5. The results indicate that during ethanol oxidation the ethanol/acetaldehyde pair is not in redox equilibrium with the lactate/pyruvate pair. Ethanol oxidation was abolished by addition of acetaldehyde. Under these conditions the lactate/pyruvate ratio was 1.5-1.8 times the ethanol/acetaldehyde ratio, indicating equilibration of the alcohol dehydrogenase and lactate dehydrogenase systems. 6. The results support the view that ultimately the rate of mitochondrial oxidation of NADH limits the removal of ethanol in the liver.

Acetaldehyde↗
PubMed1976

Effect of maternal ethanol consumption on foetal and neonatal rat hepatic protein synthesis.

Effects of maternal ethanol consumption were investigated on the rates of protein synthehsis by livers of foetal and neonatal rats both in vivo and in vitro, and on the activities of enzymes involved in protein synthesis and degradation. The rates of general protein synthesis by ribosomes in vitro studied by measuring the incorporation of [14C]leucine into ribosomal protein showed that maternal ethanol consumption resulted in an inhibition of the rates of protein synthesis by both foetal and neonatal livers from the ethanol-fed group. The rates of incorporation of intravenously injected [14C]leucine into hepatic proteins were also significantly lower in the foetal, neonatal and adult livers from the ethanol-fed group. Incubation of adult-rat liver slices with ethanol resulted in an inhibition of the incorporation of [14C]leucine into hepatic proteins; however, this effect was not observed in the foetal liver slices. This effect of externally added ethanol was at least partially prevented by the addition of pyrazole to the adult liver slices. Pyrazole addition to foetal liver slices was without significant effect on the rates of protein synthesis. Cross-mixing experiments showed that the capacity of both hepatic ribosomes and pH5 enzyme fractions to synthesize proteins was decreased in the foetal liver from the ethanol-fed group. Maternal ethanol consumption resulted in a decrease in hepatic total RNA content, RNA/DNA ratio and ribosomal protein content in the foetal liver. Foetal hepatic DNA content was not significantly affected. Ethanol consumption resulted in a significant decrease in proteolytic activity and the activity of tryptophan oxygenase in the foetal, neonatal and adult livers. It is possible that the mechanisms of inhibition of protein synthesis observed here in the foetal liver after maternal ethanol consumption may be responsible for at least some of the changes observed in 'foetal alcohol syndrome'.

Animals↗
PubMed1981

Coordination environment of the active-site metal ion of liver alcohol dehydrogenase.

The coordination environment of the catalytically active metal ion of horse liver alcohol dehydrogenase (alcohol:NAD+ oxidoreductase, EC 1.1.1.1) has been investigated by electron paramagnetic resonance (EPR) methods with use of the active-site-specific Co2+-reconstituted enzyme. The EPR absorption spectrum of the metal-substituted enzyme is characteristic of a rhombically distorted environment. The spectrum of the enzyme--NAD+ complex shows approximate axial symmetry of the metal ion site, indicating that binding of the coenzyme induces a structural alteration in the active-site region. This environment is not significantly altered further by binding of the competitive inhibitor pyrazole. To assign the coordination number of the active-site metal ion, the zero-field splitting was determined on the basis of the temperature dependence of the spin--lattice relaxation of the Co2+ ion. The zero-field splitting energies are approximately 9 cm-1 for the free Co2+-reconstituted enzyme and approximately 46 and approximately 47 cm-1 for the enzyme--NAD+ and enzyme--NAD+--pyrazole complex, respectively. On the basis of studies of structurally defined small molecule complexes, these values are compatible with a tetracoordinate metal ion in the active site of the free enzyme but a pentacoordinate metal ion in the binary enzyme--NAD+ complex and in the ternary enzyme--NAD+--inhibitor complex and, therefore, presumably also in the catalytically active ternary enzyme--NAD+--alcohol complex formed in the course of alcohol oxidation.

Alcohol Dehydrogenase↗
PubMed2002

Development of a physiologically based pharmacokinetic model for methyl ethyl ketone in F344 rats.

A physiologically based pharmacokinetic (PBPK) model to describe the absorption, distribution, metabolism, and elimination of methyl ethyl ketone (MEK) in rats was developed. Partition coefficients were experimentally determined in rat tissues and blood samples using an in vitro vial equilibration technique. These solubility ratios were in agreement with previous human-based estimates that MEK is uniformly soluble within all tissues. The in vivo metabolism of MEK was evaluated using groups of three F344 male rats exposed to 100-2000 ppm MEK in a closed, recirculating gas uptake system. An optimal fit of a family of uptake curves was obtained by adjusting Michaelis-Menten metabolic constants, Km (affinity), and Vmax (capacity) using the PBPK model. At the highest chamber concentration, the uptake curve could not be modeled without the addition of a first-order (Kfo) metabolic pathway. Pretreatment with pyrazole, an inhibitor of oxidative microsomal metabolism, decreased the slope of the gas uptake curve but did not abolish metabolism. Optimal model fit to the gas uptake curve from pyrazole-pretreated animals required the apparent Km to be increased roughly 50 times the value determined in naive rats. The completed PBPK model was evaluated against real-time exhaled breath data collected from rats receiving an intravenous (iv) injection of MEK via a jugular vein cannula. Model simulation of the iv-treated animals required alveolar ventilation to be reduced 30% in order to match the data. Exhaled breath profiles from animals treated with MEK by oral gavage or intraperitoneal (ip) injection were evaluated and absorption rates was determined. Development of a comprehensive PBPK model for MEK in rats is the first step toward future extrapolations to apply to humans.

Administration, Oral↗
PubMed2004

2,4,5-Tribromo-1H-imidazole in the egg masses of three muricid molluscs.

From analysis by gas chromatography/mass spectrometry (GC/MS), the presence of either 2,4,5-tribromo-1H-imidazole (1) or 3,4,5-tribromo-1H-pyrazole (2) was tentatively identified in lipophilic extracts from the egg masses of three muricid molluscs. Synthesis of these compounds, followed by comparison of the GC retention times and fragmentation patterns from electron impact MS, with those of the natural products, indicated that it was 2,4,5-tribromo-1H-imidazole rather than the pyrazole. This imidazole is likely to be responsible for some of the antimicrobial activity observed in the egg extracts. This is the first report of this compound from a natural source.

Animals↗
PubMed2005

Expression of alpha-expansin and xyloglucan endotransglucosylase/hydrolase genes associated with shoot elongation enhanced by anoxia, ethylene and carbon dioxide in arrowhead (Sagittaria pygmaea Miq.) tubers.

BACKGROUND AND AIMS: Shoot elongation of arrowhead tubers (Sagittaria pygmaea Miq.) is stimulated by anoxia, ethylene and CO2. The aim of this study was to characterize anoxic elongation by comparison with elongation stimulated by ethylene and CO2. METHODS: The effects of the inhibitors aminoethoxyvinylglycine (AVG) as an ethylene biosynthesis inhibitor, 1-methylcyclopropene (1-MCP) as a potent inhibitor of ethylene action, and pyrazol, an inhibitor of alcohol dehydrogenase, on shoot elongation were examined. Moreover, the effects of these gaseous factors on expression of genes possibly involved in modification of cell wall architecture were examined by polymerase chain reaction (PCR) methods. KEY RESULTS AND CONCLUSIONS: In air, promotion by 5% CO2 and 5 microL L-1 ethylene of shoot elongation occurred. At 1% O2, ethylene also stimulated shoot elongation but CO2 did not. Pyrazol inhibited shoot elongation in hypoxia but not in normoxia, suggesting that alcohol fermentation contributes to elongation enhanced by hypoxia. AVG and 1-MCP partially prevented shoot elongation both in normoxia and in hypoxia, but they did not have significant effects in anoxia, suggesting that endogenous ethylene acts as a stimulator of shoot elongation in normoxia and in hypoxia but not in anoxia. Ethylene is not involved in anoxia-enhanced elongation. We cloned four cDNAs (SpEXPA1, 2, 3 and 4) encoding alpha-expansin (EXPA) and five cDNAs (SpXTH1, 2, 3, 4 and 5) encoding xyloglucan endotransglucosylase/hydrolase (XTH) from shoots of arrowhead tubers. The transcript levels of SpEXPA1 and 2 were increased by anoxia and those of SpEXPA2 were increased by 5% CO2. Ethylene slightly elevated the level of SpEXPA4 transcripts. Anoxia enhanced the transcript levels of SpXTH1 and 4; neither ethylene nor CO2 had any effect. CO2 enhanced transcript levels of SpXTH3 and depressed those of SpXTH5. Ethylene decreased transcript levels of SpXTH5. These results suggest that four SpEXPA genes and five SpXTH genes are differently responsive to anoxia, CO2 and ethylene. Enhancement of SpEXPA1 and 2, and SpXTH1 and 4 transcript levels suggests that these gene products are involved in anoxic shoot elongation through modification of cell wall architecture.

Amino Acid Sequence↗
PubMed1998

Suppression of mutagenic activity of a series of 5HT2c receptor agonists by the incorporation of a gem-dimethyl group: SAR using the Ames test and a DNA unwinding assay.

A positive result in the Ames test is generally taken as a strong indication for a genotoxic (i.e. DNA damaging) property of the test compound, often sufficient to cause termination of its development as a new therapeutic agent. A number of serotonin receptor ligands have been tested for their mutagenic potential in the Ames assay at an early stage of development. For several compounds increases in the number of revertant colonies were observed in strain TA1537. Consequently, structure-activity relationship investigations were undertaken to search for compounds without mutagenic liability. All compounds are three ringed heterocyclic structures consisting of a benzene ring, a central (generally non-aromatic) 5- or 6-membered ring and a pyrrole or pyrazole ring. Using a gel shift assay we provide evidence that the observed genotoxic effects are strongly influenced by the intercalating properties of the compounds. The highest mutagenic response was seen with a compound possessing a central aromatic ring. The mutagenic activity of the naphthaleno derivatives appears to be stronger when compared with the indeno compounds, probably because of the less curved structure. Dimethyl substitution of the indeno substructure reduces the intercalating ability of the compounds and leads to loss of mutagenic activity. Pyrazole analogues of both indeno and naphthaleno structures appear to produce stronger mutagenic responses than the pyrrole derivatives.

Animals↗
PubMed2000

4-Aminopyrazolo[3,4-d]pyrimidine (4-APP) as a novel inhibitor of the RNA and DNA depurination induced by Shiga toxin 1.

Shiga toxin 1 (Stx1) catalyses the removal of a unique and specific adenine from 28S RNA in ribosomes (RNA-N-glycosidase activity) and the release of multiple adenines from DNA (DNA glycosylase activity). Added adenine behaves as an uncompetitive inhibitor of the RNA-N-glycosidase reaction binding more tightly to the Stx1-ribosome complex than to the free enzyme. Several purine derivatives and analogues have now been assayed as inhibitors of Stx1. Most of the compounds showed only minor differences in the rank order of activity on the two enzymatic reactions catalysed by Stx1. The survey highlights the importance of the amino group in the 6-position of the pyrimidine ring of adenine. Shifting (2-aminopurine) or substituting (hypoxanthine, 6-mercapto-purine, 6-methylpurine) the group greatly decreases the inhibitory power. The presence of a second ring, besides the pyrimidine one, is strictly required. Substitution, by introducing an additional nitrogen, of the imidazole ring of adenine with triazole leads to loss of inhibitory power, while rearrangement of the nitrogen atoms of the ring from the imidazole to the pyrazole configuration greatly enhances the inhibitory power. Thus 4-aminopyrazolo[3,4-d]pyrimidine (4-APP), the isomer of adenine with the five-membered ring in the pyrazole configuration, is by far the most potent inhibitor of both enzymatic reactions catalysed by Stx1. This finding opens perspectives on therapeutic strategies to protect endothelial renal cells once endocytosis of Stx1 has occurred (haemolytic uraemic syndrome). In the RNA-N-glycosidase reaction 4-APP binds, as adenine, predominantly to the Stx1-ribosome complex (uncompetitive inhibition), while inhibition of the DNA glycosylase activity by both inhibitors is of the mixed type.

Adenine↗
PubMed2002

Role of endotoxin in NF-kappaB activation by ethanol in rat hepatocytes.

BACKGROUND: Endotoxin plays an important role in the progression of alcoholic liver injury. However, the role of endotoxin in acute activation of NF-kappaB by ethanol remains unclear. METHODS: In primary rat hepatocyte cultures treated with ethanol and/or endotoxin, the DNA-binding activity of NF-kappaB in the nuclear extract was estimated by electrophoretic mobility shift assay. After pretreatment of a CYP2E1 inhibitor, 4-methyl pyrazole or diallyl sulfide, NF-kappaB activity was also measured in the same manner. RESULTS: Ethanol or endotoxin caused activation of NF-kappaB in primary rat hepatocytes. Taking 50 mM of ethanol and endotoxin together raised the rapid increase in NF-kappaB activation, but both 100 mM of ethanol and endotoxin treatment reduced the increase. Addition of diallyl sulfide decreased the activity at rapid phase but increased it after 60 min, whereas addition of 4-methyl pyrazole caused no change of the activity at rapid phase but raised it after 60 min. Pretreatment with both endotoxin and a CYP2E1 inhibitor raised the activation of NF-kappaB constantly after ethanol addition. These findings suggest that endotoxin plays a critical role in the metabolism-independent activation of NF-kappaB by ethanol. CONCLUSIONS: Endotoxin raised metabolism-independent activation of NF-kappaB by high ethanol in rat hepatocytes.

Animals↗
PubMed2000

3,5-Bis

The structure of the title compound, C(10)H(17)N(7)O(2), was determined using a bond-restrained Rietveld refinement which gave bond lengths and angles within the expected ranges. Although the two nearly planar (N,N-dimethylamino)methyleneamino groups are inclined at approximately 46 degrees to the pyrazole ring, the conformations of the two amino chains are different, owing to either a repulsion effect of the pyrazole-methyl group or a short interatomic contact with the nitro group in one of the chains.

Journal Article↗
PubMed2001

5,12-Dimethyl-3,10-diphenyl-1,3,4,8,10,11-hexaazatetracyclo[6.6.1.0(2,6).0(9,13)]pentadeca-2(6),4,9,(13),11-tetraene,a new Tröger's base analogue.

The synthesis of the title Tröger's base analogue, C(23)H(22)N(6), was undertaken in order to study the influence of a methyl substituent on the structure. Minor differences were found in the bond lengths of the title structure in comparison with the values for free pyrazole and for the first pyrazolic Tröger's base reported in the literature. There are two molecules of opposite chirality in the asymmetric unit and the packing in the lattice is characterized by a non-crystallographic n-glide plane relating these molecules.

Journal Article↗
PubMed2003

Dichlorotetrakis(3-phenylpyrazole-kappaN2)copper(II).

In the title compound, [CuCl(2)(C(9)H(8)N(2))(4)], there are two independent molecules in the asymmetric unit. The Cu(2+) ions lie on inversion centres and are octahedrally coordinated by two Cl atoms and four pyrazole N atoms. All pyrazole N-H groups form intramolecular hydrogen bonds, giving rise to five-membered hydrogen-bonded rings incorporating the Cu atoms.

Journal Article↗
PubMed2003

[Complexation du 2-[(5-méthylpyrazolyl)méthyle]benzimidazole par les chlorures de cuivre et de cadmium].

The structures of dichloro[2-[(5-methyl-1H-pyrazol-3-yl-kappaN(2))methyl]-1H-1,3-benzimidazole-kappaN(3)]copper(II), [CuCl(2)(C(12)H(12)N(4))], and di-mu-chloro-bis(chloro[2-[(5-methyl-1H-pyrazol-3-yl-kappaN(2))methyl]-1H-1,3-benzimidazole-kappaN(3)]cadmium(II)), [Cd(2)Cl(4)(C(12)H(12)N(4))(2)], show that these compounds have the structural formula [ML(Cl)(2)](n), where L is 2-[(5-methylpyrazolyl)methyl]benzimidazole. When M is copper, the complex is a monomer (n = 1), with a tetrahedral coordination for the Cu atom. When M is cadmium (n = 2), the complex lies about an inversion centre giving rise to a centrosymmetric dimer in which the Cd atoms are bridged by two chloride ions and are pentacoordinated.

English Abstract↗
PubMed1976

Spectroscopic investigation of binary and ternary coenzyme complexes of yeast alcohol dehydrogenase.

Corrected fluorescence properties of yeast alcohol dehydrogenase and its coenzyme complexes have been investigated as a function of temperature. Dissociation constants have been obtained for binary and ternary complexes of NAD and NADH by following the enhancement of NADH fluorescence or the quenching of the protein fluorescence. It is found that the presence of pyrazole increases the affinity of NAD to the enzyme approximately 100-fold. The formation of the ternary enzyme - NAD - pyrazole complex is accompanied by a large change in the ultraviolet absorption properties, with a new band in the 290-nm region. Significant optical changes also accompany the formation of the ternary enzyme-NADH-acetamide complex. The possible origin for the quenching of the protein fluorescence upon coenzyme binding is discussed, and it is suggested that a coenzyme-induced conformational change can cause it. Thermodynamic parameters associated with NAD and NADH binding have been evaluated on the basis of the change of the dissociation constants with temperature. Optical and thermodynamic properties of binary and ternary complexes of yeast alcohol dehydrogenase are compared with the analogous properties of horse liver alcohol dehydrogenase.

Alcohol Oxidoreductases↗
PubMed1986

Venous blood levels of inhaled trichloroethylene in female rats and changes induced by interacting agents.

The concentration from inhalation of trichloroethylene (TCE) in venous blood from female rats was studied. Exposure consisted of 200, 400 and 500 ppm for 6 hrs, or 50 and 100 ppm for 2 hrs. In each experiment, 1 rat was exposed at a constant concentration of TCE. Blood samples were obtained from an indwelling jugular cannula throughout the experiment. Combination effects with chloral hydrate (0.2 g/kg), ethanol (0.8 ml/kg), isopropanol (0.8 ml/kg), pyrazole (0.2 g/kg), tetraethylthiuram disulfide (TETD; 0.2 g/kg) or tetrachloroethylene (TTCE; 1 g/kg) given orally were observed. The experimental data on the uptake of TCE in blood were fitted, by use of nonlinear regression analysis, to a simple toxicokinetic model. TETD caused the greatest increase in the steady state concentration of TCE (3.7 X), compared to TCE alone at 200 ppm. Isopropanol, pyrazole and TTCE also produced pronounced effects, but chloral hydrate treatment resulted in no significant change. At 50 and 100 ppm TCE exposure for 2 hrs, a significant increase (almost 3 X) in the steady state concentration of TCE from both ethanol and isopropanol was observed.

Animals↗