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At least 19 recordsLinked to original sources
PubMed2000

N-acetyltransferase-dependent activation of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine: formation of 2-amino-1-methyl-6-(5-hydroxy)phenylimidazo [4,5-b]pyridine, a possible biomarker for the reactive dose of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.

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 to the ultimate mutagenic metabolite by CYP P450-mediated N-hydroxylation followed by phase II esterification. Incubation of N-hydroxy-PhIP (N-OH-PhIP) with cytosol, acetyl coenzyme A (AcCoA) and 2'-deoxyguanosine for 24 h resulted in the formation of three different adducts:N(2)-(deoxyguanosin-8-yl)-PhIP, N(2)-(guanosin-8-yl)-PhIP and PhIP-xanthine. One additional product, 5-hydroxy-PhIP (5-OH-PhIP), was also identified in the incubation mixtures. 5-hydroxy-PhIP is formed as a degradation product of conjugates formed from N-acetoxy-PhIP and protein, glutathione or buffer constituents. A similar spectrum of products was obtained using 3'-phosphoadenosine-5'-phosphosulfate (PAPS) instead of acetyl CoA. Addition of glutathione (3 mM) to the incubation mixture resulted in a 50% reduction in both adducts and 5-hydroxy-PhIP formation in liver cytosol. The main product detected was PhIP, suggesting glutathione-dependent reduction of the N-acetoxy-PhIP. Addition of glutathione to incubation mixtures from the other cytosolic preparations had less dramatic effects. In addition, increasing the amount of N-OH-PhIP in the incubation mixture resulted in proportional increased amounts of total adducts and 5-OH-PhIP. Incubation of rat and human S9 with PhIP resulted in the formation of only traces of 5-OH-PhIP. Fortification with AcCoA clearly increased the formation of 5-OH-PhIP. Addition of the CYP 450 1A2 inhibitor, furafylline, completely inhibited the formation of 5-OH-PhIP in incubations with human S9. These results indicate that both PhIP adducts and 5-OH-PhIP are formed by similar routes of activation of N-OH-PhIP. 5-OH-PhIP may therefore serve as a biomarker for the formation of the ultimate mutagenic metabolite of PhIP. A rat dosed orally with PhIP excreted 1% of the dose as 5-OH-PhIP in the urine at 24 h and 0.05 and 0.01% at 48 and 72 h, respectively. This shows that 5-OH-PhIP is also formed in vivo and indicates the possible use of 5-OH-PhIP as a urinary biomarker.

Animals↗
PubMed2003

Bis(pyridine)-based bromonium ions. Molecular structures of bis(2,4,6-collidine)bromonium perchlorate and bis(pyridine)bromonium triflate and the mechanism of the reactions of 1,2-bis(2'-pyridylethynyl)benzenebrominum triflate and bis(pyridine)bromonium triflate with acceptor olefins.

1,2-Bis(2'-pyridylethynyl)benzenebromonium triflate (4) and bis(pyridine)bromonium triflate (5) have been prepared and the mechanism of their reaction with various acceptors including eight alkenes of various structure, collidine, and Br(-) are reported. The reaction of 4 with neutral acceptors is second-order overall and involves a preequilibrium dissociation of the bidentate-bound Br(+) to form an unstable monodentate open form (4-op), which reacts with all neutral acceptors at or near the diffusion limit. Br(-) reacts with 4 by a different mechanism involving a direct nucleophilic attack on the Br(+). The reaction of 5 with acceptors proceeds by a dissociative mechanism to reversibly form an unstable intermediate (pyr-Br(+)), which reacts with 4-penten-1-ol, 4-pentenoic acid adamantylidineadamantane and cyclohexene with nearly the same selectivity. The crystal and molecular structures of bis(2,4,6-collidine)bromonium perchlorate (2-ClO(4)) and 5 were determined by X-ray crystallography.

Journal Article↗
PubMed2002

Cooperative ligation, back-bonding, and possible pyridine-pyridine interactions in tetrapyridine-vanadium(II): a visible and X-ray spectroscopic study.

The binding of pyridine by V(II) in aqueous solution shows evidence for the late onset of cooperativity. The K(1) governing formation of [V(py)](2+) (lambda(max) = 404 nm, epsilon(max) = 1.43 +/- 0.3 M(-1) cm(-1)) was determined spectrophotometrically to be 11.0 +/- 0.3 M(-)(1), while K(1) for isonicotinamide was found to be 5.0 +/- 0.1 M(-1). These values are in the low range for 3d M(2+) ions and indicate that V(II).py back-bonding is not significant in the formation of the 1:1 complex. Titration of 10.5 mM V(II) with pyridine in aqueous solution showed an absorption plateau at about 1 M added pyridine, indicating a reaction terminus. Vanadium K-edge EXAFS analysis of 63 mM V(II) in 2 M pyridine solution revealed six first-shell N/O ligands at 2.14 A and 4 +/- 1 pyridine ligands per V(II). UV/vis absorption spectroscopy indicated that the same terminal V(II) species was present in both experiments. Model calculations showed that in the absence of back-bonding only 2.0 +/- 0.2 and 2.4 +/- 0.2 pyridine ligands would be present, respectively. Cooperativity in multistage binding of pyridine by [V(aq)](2+) is thus indicated. XAS K-edge spectroscopy of crystalline [V(O(3)SCF(3))(2)(py)(4)] and of V(II) in 2 M pyridine solution each exhibited the analogous 1s --> (5)E(g) and 1s --> (5)T(2g) transitions, at 5465.5 and 5467.5 eV, and 5465.2 and 5467.4 eV, respectively, consistent with the EXAFS analysis. In contrast, [V(py)(6)](PF(6))(2) and [V(H(2)O)(6)]SO(4) show four 1s --> 3d XAS transitions suggestive of a Jahn-Teller distorted excited state. Comparison of the M(II)[bond]N(py) bond lengths in V(II) and Fe(II) tetrapyridines shows that the V(II)[bond]N(py) distances are about 0.06 A shorter than predicted from ionic radii. For [VX(2)(R-py)(4)] (X = Cl(-), CF(3)SO(3)(-); R = 4-Et, H, 3-EtOOC), the E(1/2) values of the V(II)/V(III) couples correlate linearly with the Hammett sigma values of the R group. These findings indicate that pi back-bonding is important in [V(py)(4)](2+) even though absent in [V(py)](2+). The paramagnetism of [V(O(3)SCF(3))(2)(py)(4)] in CHCl(3), 3.8 +/- 0.2 mu(B), revealed that the onset of back-bonding is not accompanied by a spin change. Analysis of the geometries of V(II) and Fe(II) tetrapyridines indicates that the ubiquitous propeller motif accompanying tetrapyridine ligation may be due to eight dipole interactions arising from the juxtaposed C-H edges and pi clouds of adjoining ligands, worth about -6 kJ each. However, this is not the source of the cooperativity in the binding of multiple pyridines by V(II) because the same interactions are present in the Fe(II)-tetrapyridines, which do not show cooperative ligand binding. Cooperativity in the binding of pyridine by V(II) is then assigned by default to V(II)-pyridine back-bonding, which emerges only after the first pyridine is bound.

Crystallography, X-Ray↗
PubMed1975

Microbial metabolism of the pyridine ring. Metabolic pathways of pyridine biodegradation by soil bacteria.

1. Two bacteria, a Bacillus sp. and a Nocardia sp. (strain Z1) were isolated from soil by enrichment with 0.1 percent (v/v) pyridine and grew rapidly on this compound as sole C, N and energy source. The monohydroxypyridines, tetrahydropyridine, piperidine and some other analogues were not utilized for growth or oxidized by washed suspensions of either bacterium. 2. Cell-free extracts were unable to metabolize pyridine even after supplementation with a variety of cofactors or protecting agents. Treatment of cells with toluene led to rapid loss of the ability to oxidize pyridine. 3. In the presence of 10mM-semicarbazide at pH 6.0, Nocardia Z1 accumulated a semialdehyde idenditied as its 2,4-dinitrophenylhydrazone by chromatography, mixed melting point, mass spectrometry and isotope trapping from [2,6(-14)C]pyridine as glutarate semialdehyde. 4. Extracts of this bacterium prepared from cells grown with pyridine or exposed to the gratuitous inducer 2-picoline, contained high activities of a specific glutarate semialdehyde dehydrogenase. 5. Cells grown with pyridine or glutarate also contained a glutaric dialdehyde dehydrogenase, an acyl-CoA synthetase and elevated amounts of isocitrate lyase but no glutaryl-CoA dehydrogenase. 6. Bacillus 4 accumulated in the presence of 10mM-semicarbazide several acidic carbonyl compounds from pyridine among which was succinate semialdehyde. Extracts of this bacillus after growth of the cells with pyridine contained an inducible succinate semialdehyde dehydrogenase in amounts at least 50-fold over those found in succinate-grown cells. 7. Two mutants of this bacillus, selected for their inability to grow on pyridine were deficient in succinate semialdehyde dehydrogenase. 8. In the presence of 0.2mM-KCN, washed suspensions of Bacillus 4 accumulated formate and possibly formamide from pyridine. The use of [14C]pyridine showed that formate was derived from C-2 of the pyridine ring. 9. The organism had a specific formamide amidohydrolase cleaving formamide quantitatively to formate and NH3. 10. Formate was further oxidized by the particle fraction. There was no soluble formate dehydrogenase in extracts.

Aldehyde Oxidoreductases↗
PubMed1972

Microbial metabolism of the pyridine ring. Formation of pyridinediols (dihydroxypyridines) as intermediates in the degradation of pyridine compounds by micro-organisms.

1. Several species of micro-organisms that were capable of utilizing pyridine compounds as carbon and energy source were isolated from soil and sewage. Compounds degraded included pyridine and the three isomeric hydroxypyridines. 2. Suitable modifications of the cultural conditions led to the accumulation of pyridinediols (dihydroxypyridines), which were isolated and characterized. 3. Three species of Achromobacter produced pyridine-2,5-diol from 2- or 3-hydroxypyridine whereas an uncommon Agrobacterium sp. (N.C.I.B. 10413) produced pyridine-3,4-diol from 4-hydroxypyridine. 4. On the basis of chemical isolation, induction of the necessary enzymes in washed suspensions and the substrate specificity exhibited by the isolated bacteria, the initial transformations proposed are: 2-hydroxypyridine --> pyridine-2,5-diol; 3-hydroxypyridine --> pyridine-2,5-diol and 4-hydroxypyridine --> pyridine-3,4-diol. 5. A selected pyridine-utilizer, Nocardia Z1, did not produce any detectable hydroxy derivative from pyridine, but carried out a slow oxidation of 3-hydroxypyridine to pyridine-2,3-diol and pyridine-3,4-diol. These diols were not further metabolized. 6. Addition of the isomeric hydroxypyridines to a model hydroxylating system resulted in the formation of those diols predicted by theory.

Alcaligenes↗
PubMed1991

Pyridine effects on P450IIE1, IIB and IVB expression in rabbit liver: characterization of high- and low-affinity pyridine N-oxygenases.

The effects of pyridine exposure on expression of cytochromes P450IIE1, IIB and IVB in rabbit hepatic microsomes and their respective role in pyridine N-oxide production has been examined. Immunoblot analysis revealed that pyridine administration caused a substantial increase in P450IIE1 levels, failed to affect P450IIB content and marginally increased the expression of P450IVB. In an effort to implicate specific forms of P450 in pyridine N-oxide production, the kinetics of pyridine N-oxide formation in uninduced and induced rabbit hepatic microsomal preparations were obtained. Pyridine-induced microsomes exhibited a single low Km value of 81 microM with a approximately 2.5-fold increase in Vmax (2.44 nmol/min/mg protein) relative to uninduced microsomes. Interestingly, pyridine N-oxide production in phenobarbital-induced microsomes were also monophasic, exhibiting a single, high Km value of 949 microM and a Vmax of 3.3 nmol/min/mg protein, a approximately 10-fold increase over the uninduced preparations. In contrast, uninduced and isosafrole-induced rabbit hepatic microsomes both exhibited biphasic kinetics; uninduced microsomes gave Km values of 85 and 973 microM, whereas isosafrole-induced microsomes yielded Km values of 229 and 1733 microM, respectively, with a Vmax somewhat less than uninduced microsomes. When kinetic data were normalized for P450 content, a pronounced substrate specificity was detected for both pyridine- and phenobarbital-induced microsomes. para-Nitrophenol hydroxylase activity was enhanced approximately 6-fold in pyridine-induced microsomes consistent with elevated levels of P450IIE1. para-Nitrophenol competitively inhibited (Ki = 13 microM) the production of pyridine N-oxide in pyridine-induced microsomes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Deuterium nuclear magnetic resonance spectroscopy of deuterated pyridine-iron(III) porphyrin complexes. Locations and relaxation times of bound deuterated pyridine resonances.

The first application of deuterium nuclear magnetic resonance spectroscopy (2H NMR) to fully deuterated pyridine (d5-pyridine)-iron(III) porphyrin complexes is described. (1) d5-Pyridine gives very broad 2H NMR signals in the presence of hemin or horseradish peroxidase to which pyridine is hardly (or not) bound, probably due to relatively long electronic relaxation times of the high-spin ferric ions. d5-Pyridine in the presence of horse-heart metmyoglobin gives resolved and less broadened 2H NMR signals, probably due to the relatively short electronic relaxation times of the ferric ion and/or to slow chemical exchange of the ligand. (2) The three resonances of free d5-pyridine coalesce into a single or a double resonance in the presence of a heme octapeptide prepared by trypsin digestion of Candida krusei cytochrome c. Nuclear spin-lattice and spin-spin relaxation times of the d5-pyridine-heme octapeptide complex are markedly shorter than those of free d5-pyridine. These findings are interpreted by the chemical exchange mechanism from the temperature dependences of the relaxation times. Thus, on certain assumptions the residence time of pyridine in the bound state and the exchange rate are estimated as approximately 10(-3) s and approximately 400 s-1, respectively, at 25 degrees C. Since 1H NMR signals of axial ligands of paramagnetic hemoproteins are hard to observe, the usefulness of deuterium magnetic resonance for investigating ligand exchange in the paramagnetic hemoproteins is emphasized.

Chemical Phenomena↗
PubMed1992

[The effect of pyridine and pyridine-N-oxide on the monooxygenase system of rat liver microsomes].

Effects of pyridine and pyridine-N-oxide on the monooxygenase system of rat liver microsomes have been studied. Pyridine (200 mg/kg) increased total cytochrome P-450 content and activated metabolism of some specific substrates 24 hours after injection. There was an increase in the degree of p-nitrophenol and chlorzoxazone hydroxylation due to increasing ethanol-induced cytochrome P-450IIE1 content. Pyridine was also able to induce cytochrome P-450IIB1 in rat microsomes; this reaction was accompanied by acceleration of 7-pentoxyresorufin 0-dealkylation. Cytochrome P-450IA1 appearance in liver microsomes was associated with increasing content of cytochrome P-450IA2. Dealkylation rates for specific substrates (7-ethoxyresorufin and 7-methoxyresorufin) were also increased. Similar to pyridine, pyridine-7-oxide induced cytochromes P-450IIE1, P-450IIB1/B2, and P-450IA1/A2, resulting in activation of specific substrate metabolism. Hence, pyridine and its derivative pyridine-N-oxide can be regarded as effective inducers of cytochrome P-450.

Animals↗
PubMed2004

Theoretical differential Raman scattering cross-sections of totally-symmetric vibrational modes of free pyridine and pyridine-metal cluster complexes.

The differential Raman scattering cross-sections of totally-symmetric vibrational modes for pyridine and pyridine-metal clusters have been calculated by using ab initio and density functional methods. The results are compared with experimental data and a good agreement is obtained. In particular, we can theoretically reproduce the significant changes in the relative Raman intensities of the nu(12) mode in pyridine-metal cluster complexes. We focus on two mechanisms for these Raman intensities changes: (1) the chemical interaction between the pyridine and the metal clusters; and (2) the charge transfer mechanism. For the pyridine-silver cluster complexes, we find that due to the weak bonding, the chemical interaction does not influence the relative intensities of the Raman peaks of the nu(1) and nu(12) modes. However, in the case where the copper or the gold clusters are attached to pyridine, the intensity of the band of the nu(12) mode is weakened significantly. We also find that the charge transfer mechanism increases the asymmetry of the bands of the nu(1) and nu(12) modes on all three metals.

Carbon↗
PubMed1996

Technetium(III), Technetium(II), and Technetium(I) Complexes with Pyridine Ligands. Can Pyridine Coordination Stabilize the Low Oxidation States of Technetium?

The substitution chemistry of TcCl(3)(PPh(3))(2)(CH(3)CN) is rather facile relative to the analogous rhenium complex, since both the chloride and phosphine ligands are easily substituted for various pyridine ligands. Consequently a series of Tc(III) complexes with amine, pyridine, and polypyridyl ligands were prepared and characterized by (1)H NMR and cyclic voltammetry. In addition, the zinc reduction of TcCl(4)(py)(2) in the presence of pyridine results in TcCl(2)(py)(4). Structural and spectroscopic data indicate that this Tc(II) complex exhibits strong metal-pyridine interactions characteristic of low-valent amine complexes of Re(II) and Os(II). For example, a decrease of 0.04 and 0.06 Å is observed for the trans-Tc-N bond length in TcCl(2)(py)(4 )relative to mer-TcCl(3)(pic)(3) and [TcCl(2)(py)(3)(PPh(3))](+), respectively. This ability of pyridine to function both as a strong sigma-donor and moderate pi-acid ligand has resulted in the isolation of technetium complexes in various oxidation states with similar ligand environments. As a result, a structural comparison of [TcCl(2)(py)(3)(PPh(3))](+), TcCl(2)(py)(4), TcCl(tpy)(py)(2), and other known Tc(III) and Tc(II) pyridine complexes is presented. Crystals of [TcCl(2)(py)(3)(PPh(3))]PF(6) are triclinic, with space group P&onemacr;, Z = 2, and lattice parameters a = 12.677(4) Å, b = 13.064(4) Å, c = 13.103(5) Å, alpha = 110.14(3) degrees, beta = 101.12(3) degrees, gamma = 96.61 degrees, V = 1959 Å(3), and R = 0.0615 (R(w) = 0.1148). Crystals of TcCl(2)(py)(4) are tetragonal, with space group I4(1)/acd, Z = 8, and lattice parameters a = 15.641(4) Å, c = 16.845(6) Å, V = 4121 Å(3), and R = 0.0373 (R(w) = 0.0290). Crystals of TcCl(tpy)(py)(2) are orthorhombic, with space group C222(1), Z = 4, and lattice parameters a = 9.359(3) Å, b = 16.088(6) Å, c = 18.367(4) Å, V = 2765 Å(3), and R = 0.0499 (R(w) = 0.0599).

Journal Article↗
PubMed1990

Antimitotic agents: synthesis of imidazo[4,5-c]pyridin-6-ylcarbamates and imidazo[4,5-b]pyridin-5-ylcarbamates.

Cyclization of ethyl 5,6-diamino-4-hydrazinopyridin-2-ylcarbamate (10) with a mixture of CS2 and Et3N in dimethylacetamide gave mainly ethyl 1,4-diamino-2(3H)-thioxoimidazo[4,5-c]pyridin-6-ylcarbamate (15), whereas, in the absence of dimethylacetamide, a double cyclization gave mainly ethyl 5-amino-2(1H)-4-dithioxodiimidazo-[4,5-b:5,4-c]pyridin-7-ylcarb amate (16). Cyclization of the benzylidenehydrazino derivative (6) of 10 with either CS2-Et3N or (EtO)3CH-HCl gave 1-(benzylideneamino)imidazo[4,5-c]pyridines 11 and 7 as major products and 7-(benzylidenehydrazino)imidazo[4,5-b]pyridines 12 and 8 as minor products. Dethiolation of 11 to give 7 and of 12 to give 8 was effected with excess Raney nickel in refluxing ethanol. The benzylidene group of 11 was removed with hydrazine in ethanolic HCl to give 15. This key compound was condensed with benzaldehydes to give 1-benzylideneamino derivatives (20, 21) and alkylated with benzyl halides to give 2-benzylthio derivatives (24-26). In addition, cyclization of ethyl 5,6-diamino-4-(benzylidene-1-methylhydrazino)pyridin-2-ylcarbam ate (30) with (EtO)3CH provided a method for the synthesis of an imidazo[4,5-c]- and -[4,5-b]pyridines gave compounds that inhibited proliferation of growth and caused mitotic arrest against lymphoid leukemia L1210 at micromolar concentrations. However, the more active in vitro compounds (7, 8, 24-26) gave only borderline activity in mice against lymphocytic leukemia P388.

Animals↗
PubMed2003

Synthesis and antiviral activity of novel erythrofuranosyl imidazo[1,2-a]pyridine C-nucleosides constructed via palladium coupling of iodoimidazo[1,2-a]pyridines and dihydrofuran.

2,5,6-Trichloro-1-(beta-d-ribofuranosyl)benzimidazole (TCRB) and certain analogues have shown significant activity against human cytomegalovirus. The metabolic instability of the glycosidic linkage in TCRB prompted us to synthesize the structurally similar imidazo[1,2-a]pyridine erythrofuranosyl C-nucleosides. As an approach to the synthesis of polychlorinated imidazo[1,2-a]pyridine C-3-erythrofuranosides, a palladium-based methodology for coupling 2,3-dihydrofuran with chlorinated 3-iodoimidazo[1,2-a]pyridines was developed and optimized to give 80-90% yields of 2,6-dichloro- and 2,6,7-trichloro-3-(2,3-dideoxy-2,3-didehydro-d/l-erythrofuranosyl)imidazo[1,2-a]pyridine. Dihydroxylation of these didehydro derivatives with osmium tetroxide or with AD-mix alpha gave a mixture of erythrofuranosyl C-nucleosides that were separated by standard and then chiral chromatography. When screened for anti-HCMV and HSV-1 activity, the alpha-d anomer of 2,6,7-trichloro-3-(erythrofuranosyl)imidazo[1,2-a]pyridine proved to be the most active member of the series, while the beta-anomers all proved to be inactive.

Antiviral Agents↗
PubMed1974

Microbial metabolism of the pyridine ring. The metabolism of pyridine-3,4-diol (3,4-dihydroxypyridine) by Agrobacterium sp.

1. Pyridine-3,4-diol (3,4-dihydroxypyridine, 3-hydroxypyrid-4-one), an intermediate in 4-hydroxypyridine metabolism by an Agrobacterium sp (N.C.I.B. 10413), was converted by extracts into 1mol of pyruvate, 2mol of formate and 1mol of NH(3) at pH7.0. 2. Formate, but not the alternative likely product formamide, was further oxidized fivefold faster by 4-hydroxypyridine-grown washed cells than by similar organisms grown on succinate. 3. The oxidation of pyridine-3,4-diol by crude extracts at pH8.5 required 1mol of O(2)/mol of substrate, produced 1mol of acid and led to the formation of formate and a new compound with an extinction maximum of 285nm (Compound I). This step was believed to be mediated by a new labile dioxygenase (t((1/2))=4h at pH7.0, 4 degrees C) cleaving the pyridine ring between C-2 and C-3. 4. Many of the properties of this pyridine-3,4-diol dioxygenase paralleled those of the extradiol (;meta') oxygenases of aromatic-ring cleavage. The extreme lability of the enzyme has so far precluded extensive purification. 5. Compound I showed changes in the u.v.-absorption spectrum with pH but after acidification it was converted into a new product, 3-formylpyruvate, with an extinction maximum now at 279nm. 6. Both Compound I and 3-formylpyruvate were metabolized by extracts but at very different rates. The slower rate of metabolism of Compound I was nevertheless consistent with that of pyridine-3,4-diol metabolism. 7. On acidification Compound I released about 0.65mol of NH(3) and has been identified as 3-formiminopyruvate. 8. 3-Formylpyruvate was hydrolysed to formate and pyruvate (K(m) 2mum) by an acylpyruvate hydrolase active against several other dioxo homologues. The activity of this enzyme was much lower in extracts of succinate-grown cells.

Ammonia↗
PubMed2003

Ruthenium complexes of 2-[(4-(arylamino)phenyl)azo]pyridine formed via regioselective phenyl ring amination of coordinated 2-(phenylazo)pyridine: isolation of products, X-ray structure, and redox and optical properties.

Aromatic ring amination reactions in the ruthenium complex of 2-(phenylazo)pyridine is described. The substitutionally inert cationic brown complex [Ru(pap)(3)](ClO(4))(2) (1) (pap = 2-(phenylazo)pyridine) reacts smoothly with aromatic amines neat and in the presence of air to produce cationic and intense blue complexes [Ru(HL(2))(3)](ClO(4))(2) (2) (HL(2) = 2-[(4-(arylamino)phenyl)azo]pyridine). These were purified on a preparative TLC plate. The X-ray structure of the new and representative complex 2c has been solved to characterize them. The results are compared with those of the starting complex, [Ru(pap)(3)](ClO(4))(2) (1). The transformation 1 --> 2 involves aromatic ring amination at the para carbon (with respect to the diazo function) of the pendant phenyl rings of all three coordinated pap ligands in 1. The transformation is stereoretentive, and the amination reaction is regioselective. The extended ligand HL(2) coordinates as a bidentate ligand and chelates to ruthenium(II) through the pyridine and one of the azo nitrogens. The amine nitrogen of this bears a hydrogen atom and remains uncoordinated. Similarly, the amination reaction on the mixed-ligand complex [Ru(pap)(bpy)(2)](ClO(4))(2) produces the blue complex [Ru(HL(2))(bpy)(2)](ClO(4))(2) (3) as anticipated. The reactions of [RuCl(2)(dmso)(4)] and [Ru(S)(2)(L)(2)](2+) (dmso = dimethyl sulfoxide, S = labile coordinated solvent, L = 2,2'-bipyridine (bpy) and pap) with the preformed HL(2) ligand have been explored. The structure of the representative complex [RuCl(2)(HL(2a))(2)] (5a) is reported. It has the chlorides in trans configuration while the pyridine as well as azo nitrogens are in cis geometry. Optical spectra and redox properties of the newly synthesized complexes are reported. All the ruthenium complexes of HL(2) are characterized by their intense blue solution colors. The lowest energy transitions in these complexes appear near 600 nm, which have been attributed to intraligand charge-transfer transitions. For example, the lowest energy visible range transition in [Ru(HL(2b))(3)](2+) appears at 602 nm and its intensity is 65 510 M(-1) cm(-1). All the tris chelates show multiple-step electron-transfer processes. In [Ru(HL(2))(3)](2+), six reductions waves constitute the complete electron-transfer series. The electrons are believed to be added successively to the three azo functions. In the mixed-ligand chelates [Ru(HL(2))(pap)(2)](2+) and [Ru(HL(2))(bpy)(2)](2+) the reductions due to HL(2), pap, and bpy are observed.

Journal Article↗
PubMed2003

In vivo receptor occupancy of mGlu5 receptor antagonists using the novel radioligand [3H]3-methoxy-5-(pyridin-2-ylethynyl)pyridine).

In vivo receptor occupancy of mGlu5 receptor antagonists was quantified in rat and mouse brain using the mGlu5 receptor selective antagonist [3H]3-methoxy-5-(pyridin-2-ylethynyl)pyridine) ([3H]methoxy-PEPy). Administration of [3H]methoxy-PEPy (50 microCi/kg i.v.) to mGlu5 receptor-deficient mice revealed binding at background levels in forebrain, whereas wild-type mice exhibited 14-fold higher binding in forebrain relative to cerebellum. Systemic administration of the mGlu5 receptor antagonists 2-methyl-6-(phenylethynyl)pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) reduced the binding of [3H]methoxy-PEPy in rats and mice, reflecting mGlu5 receptor occupancy by these compounds. MPEP (10 mg/kg i.p.) and MTEP (3 mg/kg i.p.) maintained >75% receptor occupancy for 2 h in rats, while in mice MPEP and MTEP achieved >75% occupancy for only 30 and 15 min, respectively. Compound levels in plasma were substantially lower in mice suggesting species differences in receptor occupancy result from differences in absorption or metabolism of the compounds. These findings demonstrate that [3H]methoxy-PEPy is useful for determining the occupancy of mGlu5 receptors in the brain.

Animals↗