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PubMed2006

Surface-enhanced raman scattering investigations of 4-nitro(pyridine N-oxide) and 4,4'-azobis(pyridine N-oxide) adsorbed on silver colloidal nanoparticles.

A spectroscopic investigation on the adsorption process of 4-nitro(pyridine N-oxide) (NPO) onto silver colloidal nanoparticles has been performed by Raman and UV-visible absorption measurements. Discrepancies between the Raman spectra of NPO in aqueous solution and in Ag hydrosol prompted an extension of the SERS study to include an investigation on the reactivity of this compound in silver colloidal suspension. The data are diagnostic of a reduction of the nitrogroup of NPO with subsequent formation of 4,4'-azobis(pyridine N-oxide) (APO). Hence, the adsorption mechanism and the molecular arrangement of APO adsorbed on the silver surface have been investigated by means of the SERS technique with the help of Density Functional Theoretical calculations of models of APO bound to a silver surface adatom.

Journal Article↗
PubMed1995

Synthesis of pyridine nucleotide analogs using rabbit spleen pyridine nucleotide glycohydrolase and stereospecificity of the transglycosidation reaction.

Seven pyridine nucleotide analogs were synthesized, including nicotinic acid mononucleotide, nicotinic acid-adenine dinucleotide, and nicotinic acid-adenine dinucleotidephosphate, by means of the transglycosidase activity of rabbit spleen pyridine nucleotide glycohydrolase. The velocity ratio of the transglycosidation to the hydrolysis in the presence of 16 mM nicotinamide mononucleotide and 0.3 M nicotinic acid at pH 5.2 was greater than 10 and the transglycosidation/hydrolysis partition ratio was estimated to be (12 +/- 2) x 10(3). The partition ratio values obtained with 3-acetylpyridine and nicotinylglycine were smaller than that with nicotinic acid. Configurational analysis of pyridinium C-N glycosidic linkages of the transglycosidation products by means of 1H-NMR, UV, CD, and paper chromatography indicated that the configuration was completely retained and absolutely beta. Retention of the configuration, together with the substrate specificity of the enzyme for the beta-pyridinium linkage and formation of the intermediary enzyme-phosphoribosyl (or ADP-ribosyl) complex during the enzyme catalysis, indicated that the transglycosidation reaction catalyzed by the enzyme proceeds through the double replacement mechanism.

Animals↗
PubMed2004

The copper(II) complexes di-mu-bromo-bis{[2,6-bis(pyrazol-1-yl)pyridine]perchloratocopper(II)} and [2,6-bis(pyrazol-1-yl)pyridine]dibromocopper(II).

The two title compounds, di-mu-bromo-bis{[2,6-bis(pyrazol-1-yl-kappaN(2))pyridine-kappaN](perchlorato-kappaO)copper(II)}, [Cu(2)Br(2)(ClO(4))(2)(C(11)H(9)N(5))(2)], (I), and [2,6-bis(pyrazol-1-yl)pyridine]dibromocopper(II), [CuBr(2)(C(11)H(9)N(5))], (II), were synthesized by only slight modifications of the same reaction; compound (II) was formed by adding one molar equivalent of pyrazole (C(3)N(2)H(4)) to the reaction mixture of (I). Compound (I) is a bromo-bridged dinuclear copper(II) compound stabilized by weak interactions with the perchlorate anions (ClO(4)(-)), while (II) is a related mononuclear species, which has a distorted square-pyramidal geometry.

Journal Article↗
PubMed2005

Bis(mu-pyridine-2-thiolato)-kappa4S:N;N:S-bis[(pyridine-2-thiolato-kappaS)(2-pyridylphenyl-kappa2N,C2)platinum(III)](Pt-Pt): the non-solvated and acetonitrile-solvated forms.

The title dinuclear platinum(III) complex, [Pt2(C11H8N)2(C5H4NS)4], forms two crystal structures, viz. the non-solvated and acetonitrile-solvated (C2H3N) forms. For both forms, two (2-pyridylphenyl)platinum units are bridged by two pyridine-2-thiolate (pyt) anions in a head-to-tail configuration, and the other two pyridine-2-thiolate anions occupy the axial position, coordinated through their S atoms. The most remarkable difference between the two forms is the orientation of the axial monodentate ligands. Those for the solvated form are located over the 2-pyridylphenyl ligands, being related by a twofold axis which lies through the centre of the Pt-Pt bond, while the axial pyt ligands for the non-solvated form are oriented irregularly, which is attributable to the dimeric arrangement in the crystal.

Journal Article↗
PubMed1985

Effects of oximes, diacetylmonoxime, pyridine-2-aldoxime, and pyridine-2-aldoxime methochloride, on the electrical and mechanical activities of guinea pig cardiac ventricular muscles.

Effects of 3 oximes, diacetylmonoxime (DAM), pyridine-2-aldoxime (PAM) and pyridine-2-aldoxime methochloride (2-PAM), on the normal electrical and mechanical activities and on the slow response action potentials were examined in the guinea pig ventricular muscles. DAM and long-term exposure to high concentrations of PAM produced decreases in contractile force, action potential duration and slow response action potentials, whereas 2-PAM and low concentrations of PAM tended to increase these parameters. Thus, these 3 oximes did not act uniformly on cardiac muscle. It was speculated that DAM and high concentrations of PAM may act as slow channel inhibitors, whereas 2-PAM and low concentrations of PAM may act as slow channel activators.

Action Potentials↗
PubMed1989

Cardiovascular effects of the new cardiotonic agent 1,2-dihydro-6-methyl-2-oxo-5-(imidazo[1,2-a]pyridin-6-yl)-3-pyridine carbonitrile hydrochloride monohydrate. 1st communication: studies on isolated guinea pig cardiac muscles.

Cardiotonic effects and the mechanism of action of 1,2-dihydro-6-methyl-2-oxo-5-(imidazo[1,2-a]pyridin-6-yl)-3-pyridine carbonitrile hydrochloride monohydrate (E-1020), a new cardiotonic agent, were investigated in vitro. E-1020 (10(-7)-10(-4) mol/l) produced a concentration-dependent positive inotropic effect in papillary muscles. E-1020 also caused an increase in contractile force in the right atria which was accompanied by small increases in spontaneous beating rate. The inotropic effect of E-1020 on papillary muscles was not altered by treatment with beta-adrenoceptor or histamine H2-receptor blockade, but was attenuated by the muscarinic agonist, carbachol. E-1020, like isoprenaline (isoproterenol, Iso), restored the contraction of papillary muscles which had been arrested in a high-potassium solution. The inotropic response of papillary muscles to Iso was potentiated by pretreatment with E-1020 at a minimally-effective inotropic concentration (3 x 10(-7) mol/l). E-1020 did not affect the activity of dog kidney Na+, K+-ATPase. On the other hand, the compound specifically inhibited the cyclic AMP-specific isoenzyme (fraction III) of phosphodiesterase and caused an elevation of cyclic AMP content in guinea pig hearts. These results indicate that E-1020 is a potent cardiotonic agent with a minor chronotropic effect and that its inotropic action is mainly mediated by the rise in cardiac cyclic AMP content due to the inhibition of cyclic AMP-specific phosphodiesterase.

Adrenergic beta-Antagonists↗
PubMed1989

Cardiovascular effects of the new cardiotonic agent 1,2-dihydro-6-methyl-2-oxo-5-(imidazo[1,2-a]pyridin-6-yl)-3-pyridine carbonitrile hydrochloride monohydrate. 2nd communication: studies in dogs.

The cardiovascular effects of 1,2-dihydro-6-methyl-2-oxo-5-(imidazo[1,2-a]pyridin-6-yl)-3-pyridine carbonitrile hydrochloride monohydrate (E-1020), a new nonglycoside, noncatechol cardiotonic agent, were investigated in dogs. In anesthetized dogs, E-1020 (10-100 micrograms/kg i.v.) dose-relatedly increased cardiac contractility (LV dP/dtmax), enhanced cardiac index and decreased systemic vascular resistance accompanying relatively small reduction in mean aortic pressure and a mild increase in heart rate. Coronary and femoral arterial blood flow were increased by either systemic intravenous or topical administration of E-1020. The degree of increase in myocardial oxygen consumption was only slight (10% at 30 micrograms/kg i.v.). The inotropic effect of E-1020 was not markedly affected by pretreatment with beta-adrenoceptor blockade, reserpine or other cardiotonic agents such as dobutamine or ouabain. In two experimental heart failure models induced by an excessive dose of propranolol or by coronary occlusion following volume-loading, E-1020 (30 micrograms/kg i.v.) rapidly reversed the cardiac depression. In chronically instrumented conscious dogs, E-1020 (30-100 micrograms/kg i.v. or 0.3-10 mg/kg p.o.) produced dose-dependent increases in LV dP/dtmax with minor increases in heart rate. E-1020 did not exacerbate arrhythmias of several experimental models in anesthetized dogs even at high dose of 100 micrograms/kg i.v. These results indicate that E-1020 is an intravenously and orally effective cardiotonic agent with vasodilating property, and that it may be beneficial in the treatment of acute and chronic congestive heart failure.

Anesthesia↗
PubMed1984

The reaction mechanism of the mitochondrial pyridine nucleotide transhydrogenase. A study utilizing arylazido-pyridine nucleotide analogues.

The addition of a purified mitochondrial pyridine nucleotide transhydrogenase enzyme preparation to complex I (NADH-CoQ reductase) results in a significant increase in the NADPH-AcPyAD+ transhydrogenase activity of the complex without influencing the NADH-AcPyAD+ transhydrogenase activity. When subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis in the presence of complex I, the purified transhydrogenase enzyme preparation was found to co-migrate with the Mr = 130,000 (130K) subunit of the NADH-CoQ reductase. Loss of the NADPH-NAD+ transhydrogenase activity of complex I following limited tryptic digestion was associated with a corresponding loss of the 130K subunit from the complex. These results suggest that the 130K subunit of complex I is the specific peptide responsible for the catalysis of the NADPH-NAD+ transhydrogenase activity observed in complex I. Studies have been carried out testing the influence of photoaffinity pyridine nucleotide probes on the NADPH-NAD+ transhydrogenase activity catalyzed at three levels of resolution, i.e. a homogeneous transhydrogenase preparation, a partially resolved membrane preparation (complex I), and an intact mitochondrial membrane preparation (EDTA particles). Such studies have revealed arylazido-beta-alanyl NADP+ (N3'-O-(3-[N-(4-azido-2-nitrophenyl)amino]propionyl)NADP+) to be a potent inhibitor and an active site-directed reagent for NADPH-NAD+ transhydrogenation at all three levels of resolution. On the other hand, arylazido-beta-alanyl NAD+ (A3'-O-(3-[N-(4-azido-2-nitrophenyl)-amino]propionyl)NAD+ does not produce a significant degree of inhibition of NADPH-NAD+ transhydrogenase activities prior to or following photoirradiation. Nevertheless, the NAD+ analogue has been found to specifically label, covalently, the transhydrogenase protein following photoirradiation of an enzyme-analogue mixture. Arylazido-beta-alanyl NAD+ can as well function as a substrate during transhydrogenation by virtue of being able to accept a hydride ion from NADPH. An interpretation of the observed nucleotide photoprobe specificity for interaction at the active site for transhydrogenation is advanced. In this interpretation, an ordered binding of substrate involves an initial NADP(H) (or NADP+ photoprobe) interaction with a hydrophobic region at the transhydrogenation site. This initial reactivity is followed by a positioning of NAD(H) (or the NAD+ photoprobe analogue) above or periphery to the NADP(H) nucleotide present at the active site region. Supportive evidence for this model for transhydrogenation is presented and discussed.

Affinity Labels↗
PubMed1995

Evidence for the presence of two pyridine nucleotide-binding sites on the beta subunit of the Escherichia coli pyridine nucleotide transhydrogenase.

The pyridine nucleotide transhydrogenase of Escherichia coli is composed of two types of subunits, alpha and beta. Trypsin digestion of the purified enzyme generates fragments of the alpha subunit. The beta subunit is uncleaved unless NADP(H) is present (Tong, R.C.W., Glavas, N.A. and Bragg. P.D. (1991) Biochim. Biophys. Acta 1080, 19-28). Purified transhydrogenase bound to either NAD- or NADP-agarose was treated with trypsin. The alpha subunit was cleaved to 16, 29 and 43 kDa fragments in both cases. The beta subunit remained bound to NAD-agarose but was released as two cleavage fragments (25 and 30 kDa) from NADP-agarose. The beta subunit of the transhydrogenase bound to NAD-agarose was cleaved by trypsin in the presence of NADP(H) to yield 25 and 30 kDa fragments of the beta subunit. These results suggest that the beta subunit contains two pyridine nucleotide-binding sites.

Binding Sites↗
PubMed1994

Anticonvulsant activity of pyrrolo[1',2':1,2]imidazo[4,5-b]pyridines, pyrrolo[2',1':2,3]imidazo[4,5-c] pyridines and pyrrolo[2,1-f]purines in DBA/2 mice.

1. The behavioural and anticonvulsant effects of eight pyrroloimidazopyridines (PI1a-d and PI2a-d) and four pyrrolopurines (PP) were studied after intraperitoneal administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. 2. The anticonvulsant effects were evaluated in DBA/2 mice on seizures evoked by means of auditory stimulation (109 dB, 12-16 kHz) in animals placed singly under a perspex dome. 3. Hypothermic activity was observed after the highest doses of the pyrroloderivatives studied. 4. Our study demonstrated that the anticonvulsant effect of pyrroloimidazopyridines (PI1-7,8,8a,9-tetrahydro-6H-pyrrolo-[1',2':1,2]imidazo[4,5-b]pyrid in-6- ones) and pyrrolopurines (PP) was generally better than corresponding pyrrolobenzimidazoles (PB) and pyrroloimidazopyridines (PI2-5,5a,6,7-tetrahydro-8H-pyrrolo[2',1':2,3]imidazo[4,5-c]pyridin-8- ones) and, in some cases, comparable to that of phenytoin and desmethylclobazam. 5. The anticonvulsant potency of the derivatives studied cannot be directly related to their lipophilicity.

Animals↗
PubMed2004

Synthesis, antimicrobial activity and conformational analysis of novel substituted pyridines: BF(3)-promoted reaction of hydrazine with 2-alkoxy pyridines.

Some new 2-alkoxy-3-cyano-4,6-diarylpyridines 3,4 were synthesized by condensation of different alpha,beta-unsaturated ketones 1 with malononitrile 2, followed by cyclization in sodium alkoxide/alcohol system. Lewis acid-catalyzed reaction of 4 with hydrazine afforded the corresponding 1H-pyrazolo[3,4-b]pyridines 5. The potency of the results as antimicrobial agents has been evaluated. The structure of the newly prepared compounds was assessed by microanalysis, IR and NMR spectra. Molecular mechanics (MM2) and semiemperical (AM1) molecular orbital calculations have been performed for the most biologically active compounds 5b and c to get insight into their molecular structures and to learn more about their stable molecular conformations.

Anti-Infective Agents↗
PubMed2005

Inhibitors of type I MetAPs containing pyridine-2-carboxylic acid thiazol-2-ylamide. Part 2: SAR studies on the pyridine ring 3-substituent.

Systematic SAR studies on the pyridine ring 3-substituent of PCAT, an inhibitor of EcMetAP1 and ScMetAP1, revealed that 3-substituents have different selectivity for EcMetAP1 and ScMetAP1. The selective inhibitors of type I MetAP are useful tools for investigating the detailed interactions between the enzymes and their inhibitors. In addition, these findings provide useful information for the design and discovery of more potent inhibitors of type I MetAPs.

Aminopeptidases↗
PubMed2002

2-Amino-1-methyl-6-(5-hydroxy-)phenylimidazo[4,5-b]pyridine (5-OH-PhIP), a biomarker for the genotoxic dose of the heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP).

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a mutagenic and carcinogenic heterocyclic amine formed during ordinary cooking. PhIP is metabolically activated by CYP P450 mediated N-hydroxylation followed by phase II esterification. The ultimate mutagenic metabolite reacts with DNA resulting in formation of adducts, and with proteins and other cellular constituents resulting in unstable products which are degraded to 5-hydroxy-PhIP. Rats were dosed orally with PhIP and urine and faeces were collected to 24, 48 and 72 h. Urine and faeces samples were hydrolysed with glucuronidase/sulfatase in order to release conjugated metabolites, followed by purification on C18 columns. The rats excreted 0.88% of the dose as 5-hydroxy-PhIP with the urine to 24 h and 0.04 and 0.01% to 48 and 72 h, respectively. The amounts of 5-hydroxy-PhIP found in faeces were 0.03, 0.1 and 0% to 24, 48 and 72 h. Urinary excretion of 5-hydroxy-PhIP showed a linear dose-response relationship in rats dosed orally with PhIP. This shows that 5-hydroxy-PhIP is also formed in vivo and that 91% is excreted with the urine in 24 h, indicating the possible use of 5-hydroxy-PhIP as a urinary biomarker for the bioactive dose of PhIP. In a preliminary study, using molecular imprinted polymer a specific sorbent for purification, after enzymatic hydrolysis and purification on a C18 column, we have identified 5-OH-PhIP in a 24-h urine sample from a male volunteer who had ingested a fried beef. This indicates that urinary 5-OH-PhIP could be used as an easily obtainable marker for the genotoxic dose of PhIP in human biomonitoring studies.

Administration, Oral↗
PubMed2001

Comparative molecular field analysis of dopamine D4 receptor antagonists including 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 113), 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]-1H-pyrrolo-[2,3-b]pyridine (L-745,870), and clozapine.

A CoMFA study was undertaken to elucidate the correlation of biological activity and structural parameters of 25 dopamine D4 antagonists. A special point of interest is that we have included the atypical D4 antagonist clozapine as a structural template for all other compounds. After comparing potential protonation sites at semiempirical (AM1) and ab initio (6-31G(d)) levels of theory, possible conformations of the lead compound 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 113) were investigated by systematic semiempirical conformational analysis. The final conformation of FAUC 113, which was used as a template for the other compounds in the dataset, was chosen by clustering and rigid body alignment of all conformations to clozapine. The CoMFA applied on the final alignment resulted in a q2cv of 0.739. To elucidate the influence of the absolute orientation of the molecules within the grid space, the entire dataset was systematically rotated (1296 steps) within the lattice. The Gaussian-shaped distribution of the q2cv values spanned the range of 0.699-0.794 and therefore supports the significance of the analysis.

Clozapine↗
PubMed1990

[The microbiological transformation and degradation of pyridine and alkyl pyridines].

The scientific literary data on the microbiological transformation and degradation of pyridine, methylpyridines (picolines), dimethylpyridines (lutidines) and some ethylpyridines are summarized and analysed in this review. These highly toxic compounds are on the one hand the raw materials for medicinal preparation production with microorganisms, on the other hand they are industrial wastes polluting the environment which may be degraded microbiologically.

Bacteria↗
PubMed1988

Pyridine induction of cytochrome P-450 in the rat: role of P-450j (alcohol-inducible form) in pyridine N-oxidation.

Previous research has shown that pyridine (PY) pretreatment of rabbits elevates total hepatic microsomal cytochrome P-450 content in association with the appearance of intense bands in the region of P-450LM4 and LM3 in the electrophoretic pattern of the microsomes and increased rates of PY N-oxide production and N-nitrosodimethylamine, alcohol and aniline metabolism. In the present study, PY administration (100 mg/kg i.p., 4 days) to rats was found to elevate hepatic microsomal cytochrome P-450 content approximately 2.5-fold as compared to controls. Sodium dodecylsulfate-polyacrylamide gel electrophoresis revealed a protein band of enhanced intensity migrating in the region of P-450j, the major ethanol-inducible form of rat liver cytochrome P-450. Immunochemical analysis confirmed that the level of immunoreactive P-450j protein was increased in PY-induced microsomes as compared to preparations from control, phenobarbital- or beta-naphthoflavone-induced animals. The rate of PY N-oxide production was enhanced 4-fold in PY-induced microsomes relative to untreated controls and was approximately 1.5- to 2-fold greater than that monitored for either phenobarbital- or beta-naphthoflavone-induced microsomes. When data were normalized for increased P-450 content, an altered substrate specificity was suggested for the PY-induced microsomes. para-Nitrophenol hydroxylase activity, which is exhibited primarily by the ethanol-inducible form of P-450, was elevated approximately 4-fold in PY-induced microsomes relative to uninduced microsomes and, when expressed per nanomol of P-450, was approximately 2- to 3-fold greater in PY-induced preparations as compared to phenobarbital-, beta-naphthoflavone-induced, or uninduced microsomes.(ABSTRACT TRUNCATED AT 250 WORDS)

Aniline Hydroxylase↗
PubMed1998

Inhibitors of farnesyl protein transferase. 4-Amido, 4-carbamoyl, and 4-carboxamido derivatives of 1-(8-chloro-6,11-dihydro-5H-benzo[5,6]- cyclohepta[1,2-b]pyridin-11-yl)piperazine and 1-(3-bromo-8-chloro-6,11- dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)piperazine.

The synthesis of a variety of novel 4-amido, 4-carbamoyl and 4-carboxamido derivatives of 1-(8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl) piperazine to explore the SAR of this series of FPT inhibitors is described. This resulted in the synthesis of the 4- and 3-pyridylacetyl analogues 45a and 50a, respectively, both of which were orally active but were found to be rapidly metabolized in vivo. Identification of the principal metabolites led to the synthesis of a variety of new compounds that would be less readily metabolized, the most interesting of which were the 3- and 4-pyridylacetyl N-oxides 80a and 83a. Novel replacements for the pyridylacetyl moiety were also sought, and this resulted in the discovery of the 4-N-methyl and 4-N-carboxamidopiperidinylacetyl derivatives 135a and 160a, respectively. All of these derivatives exhibited greatly improved pharmacokinetics. The synthesis of the corresponding 3-bromo analogues resulted in the discovery of the 4-pyridylacetyl N-oxides 83b (+/-) and 85b [11S(-)] and the 4-carboxamidopiperidinylacetamido derivative 160b (+/-), all of which exhibited potent FPT inhibition in vitro. All three showed excellent oral bioavailability in vivo in nude mice and cynomolgus monkeys and exhibited excellent antitumor efficacy against a series of tumor cell lines when dosed orally in nude mice.

3T3 Cells↗