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PubMed2006

On the preparation of coordination polymers by controlled thermal decomposition: synthesis, crystal structures, and thermal properties of zinc halide pyrazine coordination compounds.

The five zinc(II) halide pyrazine coordination compounds poly-bis(mu2-pyrazine)-dichloro-zinc(II) (I), poly-(mu2-pyrazine-N,N')-dichloro-zinc(II) (II), poly-bis(mu2-pyrazine-N,N')-dibromo-zinc(II) (III), catena-(mu2-pyrazine-N,N')-dibromo-zinc(II) (IV), and catena-(mu-pyrazine)-diiodo-zinc(II) (V) were prepared by the reaction of ZnX2 (X = Cl, Br, I) with pyrazine in acetonitrile. In the crystal structure of compound I, the zinc atoms are coordinated by two chlorine atoms and two pyrazine ligands within distorted tetrahedra. The zinc atoms are linked by the N-donor ligands into layers. The crystal structure of compound III is very similar to that of compound I. The structure of compound III was originally reported in space group Ccca with similar a and b axes, but it was proved that the correct space group is I4/mmm. Ligand-poor compound V is isotypic to compound IV, in which ZnX2 units (X = Br, I) are connected by the pyrazine ligands into chains. It was originally reported in the noncentrosymmetric space group P2(1), but we found that the correct space group is P2(1)/m. If ligand-rich 1:2 compounds I and III are heated in a thermobalance, different mass steps are observed. We have proven that in the first step, ligand-poor compounds II and IV are formed in quantitative yields. On further heating, a second mass step occurs that leads to the formation of two new compounds of composition (ZnCl2)2(pyrazine) (VI) and (ZnBr2)2(pyrazine) (VII). However, the mass step is not well-resolved. and the new compounds are not phase-pure after the thermal event. If ligand-poor 1:1 compound V is investigated by thermogravimetry, a not-well-resolved single mass step is observed in which new ligand-poor 2:1 compound (ZnI2)2(pyrazine) (VIII) is formed. On further heating, all 2:1 compounds lose their remaining ligands and transform into the pure zinc(II) halides.

Journal Article↗
PubMed1993

Induction of rat liver microsomal epoxide hydrolase by thiazole and pyrazine: hydrolysis of 2-cyanoethylene oxide.

Liver microsomal epoxide hydrolase (mEH) is active in the detoxification of epoxide-containing carcinogens. The effects of thiazole and pyrazine, constituents of tobacco and tobacco smoke as well as of a variety of foods, on the expression and regulation of mEH were examined in rats (200 mg/kg body wt/day, i.p., 1-3 days). Immunoblot analyses using rabbit anti-rat mEH antibody revealed a significant increase in mEH levels in hepatic microsomes isolated from either thiazole- or pyrazine-treated animals. Another protein (approximately 43 kd) cross-reacting with polyclonal mEH antibody was found to be increased concomitantly following pyrazine treatment. Northern and slot blot analyses showed substantial increases in mEH mRNA following either thiazole or pyrazine treatment. The level of mEH mRNA increased 17-fold at 24 h following thiazole treatment, relative to control. Approximately 20- and 16-fold increases in mEH mRNA were also observed at 48 and 72 h respectively following treatment with pyrazine. The level of polymerase chain reaction (PCR)-amplified mEH DNA derived from poly(A)+ RNA was clearly elevated following either thiazole or pyrazine treatment relative to that from untreated animals. Both sense and antisense strands of PCR-amplified mEH DNA were cloned into an M13mp19 phage vector in order to examine the nucleotide sequences of PCR-amplified mEH DNA derived from the poly(A)+ RNA isolated from thiazole- or pyrazine-treated animals. Sequence analyses revealed that the sequence of PCR-amplified DNA from the induced mRNA was identical to that published for mEH cDNA. Epoxide hydrolase activity toward the hydrolysis of 2-cyanoethylene oxide (CEO), the epoxide metabolite of the rat carcinogen acrylonitrile, was not significant in hepatic microsomes from untreated rats, but was substantially induced by treatment with thiazole or pyrazine. Microsomal hydrolysis activity was heat-sensitive and potently inhibited by 1,1,1-trichloropropene-2,3-oxide, indicating that mEH was the catalyst. The Vmax for the hydrolysis of CEO by hepatic microsomes from thiazole-treated rats (13.4 nmol/min/mg protein) was 1.5-fold greater than that with microsomes from pyrazine-treated rats, whereas similar Km values (approximately 1 mM) were observed for both microsomal preparations. These kinetic data correlate well with the increases in mEH mRNA observed after administration of thiazole or pyrazine to rats. These results provide evidence that administration of thiazole or pyrazine induces mEH with a large increase in mEH mRNA, and that the induced mEH catalyzes the hydrolysis of CEO.

Animals↗
PubMed2003

Growth and angiogenesis are inhibited in vivo in developing tissues by pyrazine and its derivatives.

Sidestream cigarette smoke solution was previously screened to identify the groups of chemicals in smoke that inhibit growth and angiogenesis in the chick chorioallantoic membrane (CAM). Pyrazine and several pyrazine derivatives were identified as a major chemical group in this screen. In the current study, purified pyrazine and six pyrazine derivatives identified in the screen were tested in dose response experiments to measure their effects on CAM growth, embryo growth, and angiogenesis. Chemicals or control medium were placed on CAMs in ovo on day 5 of development, and results were evaluated on day 6. Of the chemicals tested, pyrazine was the most potent and inhibited both CAM and embryo growth at picomolar doses. 2-Ethylpyrazine and 2,3-dimethylpyrazine were inhibitory at nanomolar doses. Inhibition of growth by pyrazine was correlated with inhibition of DNA synthesis. The pattern of blood vessel development in CAMs was disturbed by micromolar doses of pyrazine and 2,3-dimethylpyrazine. Migration of mesodermal blood vessels to the ectoderm of CAMs and their subsequent differentiation into the capillary plexus was impaired by nanomolar doses of pyrazine. In summary, these data show that pyrazine and some of its derivatives inhibit growth and certain processes important in angiogenesis at very low doses. Since pyrazine and some of its derivatives are considered safe food additives, further toxicological testing of pyrazine, in particular on developing tissues, should be done to fully evaluate its safety as a consumer product additive.

Allantois↗
PubMed1988

Disposition and metabolism of the antitumor agent pyrazine-2-diazohydroxide in mouse and beagle dog.

The pharmacokinetics and metabolism of pyrazine-2-diazohydroxide have been studied in the beagle dog and mouse. When pyrazine-2-diazohydroxide was administered to beagle dogs at a dose of 18.6 mg/kg (428 mg/m2) by i.v. bolus, the plasma half-life (t1/2) was 7.3 min, the apparent volume of distribution (Vd) 577 ml/kg, and the total body clearance (Cl) 55 ml/min per kg. In mice given pyrazine-2-diazohydroxide by i.v. bolus at 100 mg/kg (428 mg/m2), the t1/2 was 5.8 min, the Vd 250 ml/kg, and the Cl 30 ml/min per kg. When [2-14C]pyrazine-2-diazohydroxide was infused i.v. to mice at 100 mg/kg over 8 h, the Cl for parent drug was 122 ml/min per kg. The major product formed from pyrazine-2-diazohydroxide was 2-hydroxypyrazine, which accounted for 80% of the total radioactivity in the plasma after a 6-h drug infusion. There were three other metabolites in plasma, two more polar than pyrazine-2-diazohydroxide, which accounted for 7% of the radioactivity, and one less polar, which accounted for 5% of the radioactivity. Following an i.v. bolus dose of [2-14C]pyrazine-2-diazohydroxide, 79% of the radioactivity was excreted in the urine in 24 h, 3% in the feces, and 0.4% in the expired air; 18% remained in the carcass. The liver and kidney showed the highest tissue levels of radioactivity. 2-Hydroxypyrazine accounted for 45% of the urinary radioactivity, pyrazine-2-diazohydroxide for 14%, and a glucuronide or sulfate conjugate of 2-hydroxypyrazine for 17%. Twenty-four percent of the radioactivity eluted near the void volume on high-performance liquid chromatography and was not identified.

Animals↗
PubMed2004

Pyrazine derivatives in cigarette smoke inhibit hamster oviductal functioning.

BACKGROUND: Our past studies have shown that cigarette smoke inhibits oviductal functioning in vivo and in vitro. The goals in this study were to identify pyrazine derivatives in cigarette smoke solutions that inhibit ciliary beat frequency, oocyte pickup rate, and infundibular smooth muscle contraction in the hamster oviduct and to determine their lowest observable adverse effect levels (LOAELs) using in vitro bioassays. METHODS: MS smoke solutions were fractionated using solid phase extraction cartridges and the fractions were both tested on the hamster oviduct in vitro and analyzed by gas chromatography-mass spectrometry to identify individual pyrazine derivatives. Commercial pyrazine standards were purchased, assayed for purity, and tested in dose-response studies on hamster oviducts. The LOAEL and efficacy were determined for each compound in the in vitro bioassays. Statistical significance was determined using the Student's t-Test where p < 0.05. RESULTS: The LOAELs for the most inhibitory pyrazine derivatives in the ciliary beat frequency, oocyte pickup rate, and infundibular smooth muscle contraction assays were as follows: for pyrazine (1 picomolar, 10 picomolar, and 1 nanomolar); for 2-methylpyrazine (1 picomolar, 10 picomolar, and 10 picomolar); and for 2-ethylpyrazine (1 picomolar, 10 picomolar, and 1 picomolar). Six of the seven pyrazine derivatives tested (pyrazine, 2-methylpyrazine, 2-ethylpyrazine, 2-methoxy-3-methylpyrazine, 2,5-dimethylpyrazine, and 2,3,5-trimethylpyrazine) were inhibitory in picomolar or nanomolar doses in all three bioassays, while the seventh derivative, 2,6-dimethylpyrazine, had LOAELs in the nanomolar to micromolar range. CONCLUSION: This work shows that very low doses of pyrazines significantly inhibit proper oviductal functioning, raising questions regarding the safety of these compounds in cigarettes and other consumer products.

Animals↗
PubMed1988

In vitro cytotoxicity of pyrazine-2-diazohydroxide: specificity for hypoxic cells and effects of microsomal coincubation.

The antitumor drug pyrazine-2-diazohydroxide exhibits cytotoxicity to A204 tumor cells in vitro under acid conditions. The IC50 with a 1 hr drug exposure at pH of 7.4 was 61 micrograms/ml and at pH of 6.0 it was 31 micrograms/ml. It is suggested that the increased cytotoxicity is due to the acid catalyzed formation of a reactive pyrizinyldiazonium ion from pyrazine-2-diazohydroxide. Pyrazine-2-diazohydroxide is also more cytotoxic to A204 cells under hypoxic conditions in the presence of glucose with an IC50 at pH 7.4 of 22 micrograms/ml. The increased cytotoxicity of pyrazine-2-diazohydroxide under acid and hypoxic conditions may favor selective toxicity to solid tumors in vivo. Coincubation with rat hepatic microsomes increased the cytotoxicity of pyrazine-2-diazohydroxide to A204 cells. The effect did not require NADPH and was not due to formation of metabolites. There was an increased rate of degradation of pyrazine-2-diazohydroxide in the presence of microsomes, presumably with formation of the pyrizinyldiazonium ion. The final degradation product 2-hydroxypyrazine was not cytotoxic to A204 cells. The effect of microsomes on pyrazine-2-diazohydroxide cytotoxicity is probably of little in vivo significance.

Animals↗
PubMed1994

Antimutagenicity of Maillard reaction products from amino acid/sugar model systems against 2-amino-3-methylimidazo-[4,5-f]quinoline: the role of pyrazines.

The antimutagenicity of dichloromethane extracts from eight amino acid/sugar model systems was determined using Salmonella typhimurium TA98 against 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ) in the presence of Aroclor 1254-induced rat hepatic S9. The Maillard reaction products in the dichloromethane extracts were then quantified and qualified by capillary gas chromatography and gas chromatography-mass spectrometry, respectively. Pyrazines and furans were found to be the major Maillard reaction products yielded in the extracts. Moreover, the antimutagenicity of dichloromethane extracts correlated positively with the total amounts of pyrazines and furans. To elucidate the mechanism of antimutagenicity of dichloromethane extracts, the inhibitory effect of pyrazines on ethoxycoumarin deethylase activity in Aroclor 1254-induced hepatic microsomes was examined. We also studied the effects of pyrazines on IQ metabolism by Aroclor 1254-induced microsomes using high-performance liquid chromatography. The antimutagenicity of pyrazines correlated positively with both the inhibition of cytochrome P-450 IA2-linked ethoxycoumarin deethylase in hepatic microsomes and the inhibition of N-hydroxy-IQ formation from IQ metabolism by hepatic microsomes. Thus we concluded that pyrazines in dichloromethane extracts from eight amino acid/sugar model systems play an important role in the antimutagenicity of IQ. Moreover, we concluded that the modifying effect of pyrazines on the mutagenicity of IQ is mediated through interaction with microsomal activating enzymes to inhibit the major active metabolite in N-hydroxy-IQ formation.

Amino Acids↗
PubMed1981

Perception of odors of simple pyrazines by young and elderly subjects: a multidimensional analysis.

Ten simple stimuli from the heterocyclic class of nitrogen chemicals known as pyrazines were arranged in a three-dimensional space by INDSCAL using similarity judgments by 12 young and 11 elderly subjects as input. Odor quality at two intensity levels, moderate and strong, was examined. At both concentrations, pyrazines with the highest intrinsic polarity were arranged separate from unsubstituted pyrazines as well as alkyl pyrazines with a single alkyl moiety or any substitution pattern wherein alkyl groups are geometrically opposite. Use of the pattern recognition procedure ADAPT in conjunction with PREFMAP and canonical correlation procedures pointed to the relationship of three variables to olfactory quality: (1) the presence of oxygen atoms, (2) the environment associated with a substructure of the pyrazines and (3) stimulus concentration. Six of the elderly subjects showed a possible loss in the ability to discriminate among the pyrazines at the moderate intensity level.

Adult↗
PubMed1999

Participation of the pyrazine cation radical in the formation of mutagens in the reaction of glucose/glycine/creatinine.

Two classes of the free radical Maillard intermediates, the pyrazine cation radical and the carbon-centered radicals, are detected in the reaction of Glc (glucose)/Gly (glycine) by electron spin resonance and spin trapping technique. Profile of the generation of the pyrazine cation radical in the reaction with different ratios of the reactants was found to be similar to that of the formation of mutagens in the subsequent reaction with creatinine. By contrast, profile of the generation of the carbon-centered radicals was not consistent with that of the mutagen formation. Thiol antioxidants and unsaturated fatty acids (or their esters) effectively scavenged the pyrazine cation radical generated in the reaction of Glc/Gly, and inhibited the formation of the mutagens in the reaction of Glc/Gly and creatinine. Ethanol, a sulfide and a saturated fatty acid were not effective to scavenge the pyrazine cation radical and did not inhibit the mutagen formation. The pyrazine cation radical rather than the carbon-centered radicals may play an important role in the mutagen formation. Thiol antioxidants and unsaturated fatty acids can be evaluated as inhibitors of the pyrazine cation radical-derived formation of the mutagens.

Cations↗
PubMed2000

Effect of food reductones on the generation of the pyrazine cation radical and on the formation of the mutagens in the reaction of glucose, glycine and creatinine.

One of the possible pathways of the formation of mutagens in heated foods is through the pyrazine cation radical generated in the early stage of the Maillard reaction. The aim of the present study was to elucidate how food reductones contribute to the pyrazine cation radical generation in the reaction of glucose (Glc) and glycine (Gly), and to the formation of the mutagens in the reaction of Glc, Gly and creatinine. Electron spin resonance (ESR) studies showed that fragrant reductones, 2,5-dimethyl-4-hydroxy-3(2H)-furanone (DMHF) and 4-hydroxy-2(or 5)-ethyl-5(or 2)-methyl-3(2H)-furanone (HEMF), generated in the Maillard reactions, enhanced the generation of the pyrazine cation radical in the reaction of Glc and Gly, and the reaction of DMHF or HEMF with Gly generated a larger amount of the pyrazine cation radical than the reaction of Glc and Gly, indicating that the furanones were intermediates of the pyrazine cation radical. By contrast, food antioxidants, ascorbic acid and erythorbic acid, effectively scavenged the pyrazine cation radical generated in the reaction of Glc and Gly. DMHF and HEMF were not effective to modulate the mutagen formation in the reaction of Glc, Gly and creatinine, and the mutagenicity produced in the reaction of DMHF or HEMF, Gly and creatinine was lower than that produced in the reaction of Glc, Gly and creatinine. On the other hand, ascorbic acid and erythorbic acid were effective to decrease the mutagen formation in the reaction of Glc, Gly and creatinine.

Animals↗
PubMed2003

Synthesis, complexation, and coordination oligomerization of 1,8-pyrazine-capped 5,12-dioxocyclams.

(Methyl)(methoxy)-5,12-dioxocyclam 1 was alkylated on the secondary amines (capped) with 2,6-bis(bromomethyl)pyrazine. The resulting macrocycle was complexed to copper(II) to produce a five-coordinate complex 5a which was fully characterized by a range of spectroscopic methods (IR, UV-vis, ESR) as well as by X-ray crystallography. The structure of this complex is similar to the previously reported pyridine complex, with the five-coordinate copper having distorted square pyramidal geometry and a Cu-Pz bond length of 2.125 A. Attempts to prepare this same complex under microwave irradiation instead produced a trinuclear complex 6a having an octahedral copper(II) center complexed to two pyrazine-cyclam copper units through the amide carbonyl oxygen and the methoxyl group oxygen of the cyclam unit. The X-ray crystal structure of the trinuclear complex showed extensive distortion in the cyclam rings. The remote nitrogen of pyrazine-cyclam complex 5a was capable of coordinating an additional metal. Treatment with RuCl(2)(DMSO)(4) or Rh(2)(OAc)(4), respectively, produced trimetallic Cu-Ru-Cu complex 7 or tetrametallic Cu-Rh-Rh-Cu complex 8. The latter was fully characterized, including an X-ray crystal structure, and had two pyrazine-cyclam complexes bridged by a Rh(2)(OAc)(4) unit through the remote pyrazine nitrogens. There was little distortion in the pyrazine-cyclam copper units as compared to complex 5a: the four metals were collinear, and the two cyclam units were eclipsed. All of the copper complexes were subjected to cyclic voltametry measurements, and no reversible redox changes were observed. Magnetic measurements of 6a and 8 showed the copper atoms to be weakly antiferromagnetically coupled.

Bridged-Ring Compounds↗