Determination of S-[2-carboxy-1-(1H-imidazol-4-yl)ethyl]glutathione, a novel metabolite of L-histidine, in tissue extracts from sunlight-irradiated rat by capillary electrophoresis.

Exposure of the skin to sunlight results in an increase in the content of epidermal urocanic acid, a key metabolite of L-histidine, and some portions of the metabolite penetrate into the body fluid. S-[2-Carboxy-1-(1H-imidazol-4-yl)ethyl]glutathione (GS(CIE)), an adduct of glutathione and urocanic acid, was proposed to be an origin of a urinary compound, S-[2-carboxy-1-(1 H-imidazol-4-yl)ethyl]-L-cysteine (Cys(CIE)). Various catabolites of Cys(CIE) were also isolated from human urine previously. However, no direct evidence to show the existence of GS(CIE) as a biological material had been found. By using capillary electrophoresis, the glutathione adduct has now been found in the extracts of rat tissues from the kidney, liver, skin and blood when the rat was kept under conditions of sunlight irradiation after the fur on the dorsal skin had been clipped. On the other hand, no or a trace of GS(CIE) was determined in rat tissue extracts when the animal was kept indoor in usual manner. The glutathione adduct was isolated from the kidney extract of the sunlight-irradiated rat using ion-exchangers and high-voltage paper electrophoresis, and determined by fast-atom-bombardment mass spectrometry. These results indicate that GS(CIE) formation actually occurs in the body and that the formation is accelerated by exposing the rat to sunlight irradiation. From these findings, we propose an alternative pathway of histidine metabolism which is initiated by the adduction of urocanic acid to glutathione to form GS(CIE) and terminates with the formation of the urinary compounds via Cys(CIE).     

High functionalization of 5-nitro-1H-imidazole derivatives: the TDAE approach

We report herein the synthesis of substituted 2-[4-(1,2-dimethyl-5-nitro-1H-imidazol-4-yl)phenyl]-1-arylethanols, ethyl 3-[4-(1,2-dimethyl-5-nitro-1H-imidazol-4-yl)-phenyl]-2-hydroxypropanoate and 2-[4-(1,2-dimethyl-5-nitro-1H-imidazol-4-yl)benzyl]-2-hydroxy-acenaphthylen-1(2H)-one from the reactions of 4-[4-(chloromethyl)phenyl]-1,2-dimethyl-5-nitro-1H-imidazole with various aromatic carbonyl and a-carbonyl ester derivatives using tetrakis(dimethylamino)ethylene (TDAE) methodology.     

Direct access to 4-carboxy-1,8-naphthyridines and related compounds through Pfitzinger-type chemistry

The 4-carboxy-1,8-naphthyrid-2-yl moiety is a useful ligand component in that it promotes lower energy electronic absorption in its metal complexes and also provides a useful tether for anchoring the ligand to a semiconductor surface. The synthon [2-(pivaloylamino)pyrid-3-yl]oxoacetic acid ethyl ester can be easily obtained in two steps from 2-aminopyridine. The Pfitzinger-type condensation of this molecule with a 2-acetylazaaromatic species in ethanolic KOH, after acidification, directly provides bi- and tridentate ligands containing the 4-carboxy-1,8-naphthyrid-2-yl moiety.     

Synthesis of substituted 1-[2-(adamantan-1-yl)ethyl]piperidines

Quaternary 1-[2-(adamantan-1-yl)ethyl]pyridinium bromides were reduced with sodium tetrahydridoborate in ethanol, and hydroarylation of the resulting 1-[2-(adamantan-1-yl)ethyl]-1,2,3,6-tetrahydropyridines with benzene in trifluoromethanesulfonic acid afforded phenylpiperidines with preferentially equatorial orientation of the phenyl substituent.     

Determination of the antiallergenic agent, N-[4-(1H-imidazol-1-yl)butyl]-2-(1-methylethyl)-11-oxo-11H- pyrido [2,1-b]quinazoline-8-carboxamide, in plasma by reversed-phase high-performance liquid chromatographic analysis using fluorometric detection

A rapid, sensitive and selective high-performance liquid chromatographic (HPLC) assay was developed for the determination of the antiallergenic compound N-[4-(1H-imidazol-1-yl)butyl]-2-(1-methylethyl)-11-oxo-11H-pyrido[ 2,1-b] quinazoline-8-carboxamide (I), and its major metabolite, 2-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b] quinazoline-8-carboxylic acid (I-A), in plasma. The assay involves precipitation of the plasma proteins with acetonitrile--methanol (9:1), followed by the analysis of an aliquot of the protein-free filtrate by reversed-phase ion-pair HPLC with fluorescence detection for quantitation. The analogous compound, N-[6-(1H-imidazol-1-yl)hexyl]-2-(1-methylethyl)-11-oxo-11H-pyrido [2,1-b]-quinazoline-8-carboxamide (II), is used as the internal standard. The overall recovery of compounds I and I-A from plasma is 107.0 +/- 8.6% and 107.0 +/- 10.0%, respectively. The sensitivity limits of quantitation are 20 ng of I, and 10 ng of I-A per ml of plasma using a 0.5-ml aliquot. The assay was used to monitor the plasma concentrations of I and of I-A in a dog following a 5 mg/kg intravenous infusion of I . 2HCl, a 10 mg/kg oral dose of I . 2HCl and of metabolite I-A.     

A dedicated glutathione S-transferase mediates carbon-sulfur bond formation in gliotoxin biosynthesis

Gliotoxin is a virulence factor of the human pathogen Aspergillus fumigatus , the leading cause of invasive aspergillosis. Its toxicity is mediated by the unusual transannular disulfide bridge of the epidithiodiketopiperazine (ETP) scaffold. Here we disclose the critical role of a specialized glutathione S-transferase (GST), GliG, in enzymatic sulfurization. Furthermore, we show that bishydroxylation of the diketopiperazine by the oxygenase GliC is a prerequisite for glutathione adduct formation. This is the first report of the involvement of a GST in enzymatic C-S bond formation in microbial secondary metabolism.     

Self-assembly of 2D-->2D interpenetrating coordination polymers showing polyrotaxane- and polycatenane-like motifs: influence of various ligands on topological structural diversity

A series of mixed-ligand coordination complexes, namely, [Cd 2(bimb) 2(L (1)) 2] ( 1), [Cd(bpimb) 0.5(L (2))(H 2O)] ( 2), [Zn 5(bpib) 2(L (3)) 4(OH) 2(H 2O) 2] ( 3), [Zn(bpib) 0.5(L (4))] ( 4), and [Cd(bib)(L (4))] ( 5), where bimb = 1,4-bis((1 H-imidazol-1-yl)methyl)benzene, bpimb = 1,4-bis((2-(pyridin-2-yl)-1 H-imidazol-1-yl)methyl)benzene, bpib = 1,4-bis(2-(pyridin-2-yl)-1 H-imidazol-1-yl)butane, bib = 1,4-bis(1 H-imidazol-1-yl)butane, H 2L (1) = 4-((4-(dihydroxymethyl)phenoxy)methyl)benzoic acid, H 2L (2) = 4,4'-methylenebis(oxy)dibenzoic acid, H 2L (3) = 3,3'-methylenebis(oxy)dibenzoic acid, and H 2L (4) = 4,4'-(2,2'-oxybis(ethane-2,1-diyl)bis(oxy))dibenzoic acid, have been synthesized under hydrothermal conditions. Their structures have been determined by single-crystal X-ray diffraction analyses and further characterized by elemental analyses, IR spectra, and thermogravimetric (TG) analyses. In 1, (L (1)) (2-) anions link the metal-neutral ligand subunits to generate a 2-fold parallel interpenetrating net with the 6 (3) topology. In 2- 4, neutral ligands connect the various metal-carboxylic ligand subunits to give a 2-fold parallel interpenetrating net with (4,4) topology in 2, a 2-fold parallel interpenetrating net with (3,6)-connected topology in 3, and a 3-fold parallel interpenetrating net with (4,4) topology in 4. Compounds 1- 4 display both polyrotaxane and polycatenane characters. Compound 5 is a 5-fold parallel interpenetrating net with (4,4) topology. By careful inspection of these structures, we find that different topological structures showing both polyrotaxane and polycatenane characters have been achieved with increase of the carboxylic ligand length. It is believed that various carboxylic ligands and N-donor ligands with different coordination modes and conformations are important for the formation of the different structures. In addition, the luminescent properties of these compounds are discussed.     

Synthesis of ethyl ({[adamantan-1(2)-ylalkyl]-carbamothioyl}amino)acetates

Reactions of adamantan-1(2)-amines and adamantan-1(2)-ylalkanamines with ethyl isothiocyanatoacetate afforded ethyl ({[adamantan-1(2)-ylalkyl]carbamothioyl}amino)acetates in 85–95% yields. The hydrolysis of ethyl {[(adamantan-2-yl)carbamothioyl]amino}acetate in alkaline medium resulted in the formation of {[(adamantan-2-yl)carbamothioyl]amino}acetic acid in a virtually quantitative yield.     

Bronsted acidic ionic liquid catalyzed an eco-friendly and efficient procedure for synthesis of 2,4,5-trisubstituted imidazole derivatives under ultrasound irradiation and optimal conditions

Research on Chemical Intermediates - 2-[(1H-imidazol-3-ium-3-yl)methyl]-4-{bis[3-((1H-imidazol-3-ium-3-yl) methyl-(4-hydroxyphenyl]methylene}cyclohexa-2,5-dienone trihydrogen sulfate...     

Kine-substitution in the N-[ω-(5-bromouracil-1-yl)alkyl]alkylamine series

In the reaction of N-[2-(5-bromouracil-1-yl)ethyl]alkylamines with alkylamines at 40 °C kine-substitution takes place with the formation of N-[2-(6-alkylamino-uracil-1-yl)ethyl]alkylamines.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1260–1261, September, 1984.     

Thiolytic chemistry of alternative precursors to the major metabolite of the cancer chemopreventive oltipraz

The compounds 7-methyl-6,8-bis(methyldisulfanyl)pyrrolo[1,2-a]pyrazine (5; "bis disulfide") and methanethiosulfonic acid S-((6-(methanesulfonylsulfanyl)-7-methyl)pyrrolo[1,2-a]pyrazin-8-yl) ester (6; "bis methanesulfonic acid thioester") have been synthesized to serve as alternative precursors to the major metabolite, 4, of the cancer chemopreventive oltipraz, 1, to test whether they possess similar biological activities. In the present work the mechanisms by which these compounds react with glutathione have been investigated in order to validate the assumption that they would be chemically competent in the presence of the biological thiols to give the oltipraz metabolite. A kinetic and product study was carried out in mainly aqueous media, 相似文献   

New self-assemblies with zinc meso-tetra[3-(1H-imidazol-1-yl)phenyl] porphyrin for use in supramolecular solar cells

In this work, a new zinc meso-tetra[3-(1H-imidazol-1-yl)phenyl]porphyrin (ZnP) was synthesized. Further, the porphyrin ZnP was immobilized by metal-ligand axial coordination (ZnP-A) and a metal-ligand edged binding approach (ZnP-Zn-A) on the nanostructured TiO₂ electrode surface modified with coordinating ligand functionality, isonicotinic acid (A). The performances of the assemblies-sensitized solar cells were performed under irradiance of 100 mW?cm^?2 AM 1.5G sunlight. Photo-electrochemical studies reveal significantly improved performance of the assembly ZnP-A. These assemblies can afford a fertile base for further design and fabrication of new supramolecular solar cells in future.     

Synthesis of some new pyrimidine selanyl derivatives

The targeted synthesis of 2-(methylsulfanyl)-6-(furan-2-yl)-4(3H)-selenoxo -pyrimidine-5-carbonitrile failed due to the formation 1-methyl-2-methylsulfanyl-6-oxo -4-(furan-2-yl)-1,6-dihydropyrimidine-5-carbonitrile. A new series of 5,6,7,8-tetrahydro-1-benzo thieno[2,3-d]pyrimidine-4-yl substituted selanyl derivatives were prepared by the reaction of sodium diselenide with 4-chloro-5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidine followed by the reaction with chloroacetic acid derivatives such as ethyl chloroacetate, chloroacetamide or chloroacetonitrile. Hydrazinolysis of ethyl (5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidine- 4-ylselanyl)acetate with hydrazine hydrate gave the corresponding hydrazino derivative. The latter reacted with ethyl acetoacetate, acetylacetone, diethyl malonate, ethoxymethylenemalononitrile or ethyl 2-cyano-3-ethoxyacetate to afford 5-methyl-2-[2-(5,6,7,8-tetrahydro-1-benzothieno [2,3-d]pyrimidine-4-ylselanyl)acetyl]-2,4-dihydropyrazol-3-one, 1-(3,5-dimethylpyrazol-1-yl)-2- (5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidin-4-ylselanyl)ethanone, 1-[2-(5,6,7,8-tetrahydro -1-benzothieno[2,3-d]pyrimidine-4-ylselanyl)acetyl]-2,4-dihydropyrazolidine-3,5-dione and 5-Amino-1-[2-(5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidin-4-ylselanyl)acetyl]-1H-pyrazol -4-yl substituted carbonitrile or ethyl carboxylate, respectively. The structure of the novel compounds was confirmed by spectroscopic tools (IR, ¹H NMR ¹³C NMR and mass spectra) and elemental analysis.     

Synthesis of new polydentate tweezers ligands of amido-amine type

A series of new tweezers amido-amine ligands containing pyrrole, bipyrrole, and dipyrrolylmethane fragments were synthesized by reaction of 2-thioxothiazolidin-3-yl derivatives of α-pyrrolecarboxylic acids {5-[1-(5-carboxy-3-methyl-4-phenyl-1H-pyrrol-2-yl)-1-methylethyl]-4-methyl-3-phenyl-1H-pyrrole-2-carboxylic acid, 5-[(5-carboxy-3-methyl-4-phenyl-1H-pyrrol-2-yl)phenylmethyl]-4-methyl-3-phenyl-1H-pyrrole-2-carboxylic acid, 5-(5-carboxy-3-methyl-4-phenyl-1H-pyrrol-2-yl)-4-methyl-3-phenyl-1H-pyrrole-2-carboxylic acid, and 3,4-dimethyl-pyrrole-2,5-dicarboxylic acid} with o-phenylenediamine. All compounds obtained were characterized by elemental analysis, NMR and mass spectra.     

Novel malonamide derivatives as alpha v beta 3 antagonists. Syntheses and evaluation of 3-(3-indolin-1-yl-3-oxopropanoyl)aminopropanoic acids on vitronectin interaction with alpha v beta 3.

In attempt to find novel integrin alphavbeta3 antagonists, we selected SC65811 and its guanidine analogue (1) as lead compounds. Modification of the glycine part of SC65811 led to a new series of malonamide derivatives that exhibited alphavbeta3 inhibitory activity. Among them, (R,S)-3-[3-[6-(3-benzylureido)indolin-1-yl]-3-oxopropanoylamino]-3- (pyridin-3-yl)propanoic acid (43a) showed not only potent activity with an IC50 value of 3.0 nM but also good selectivity for alphavbeta3 relative to alphaIIbbeta3, alpha5beta1, and alphavbeta5 with IC50 values of 19,000, 11,000, and 14 nM, respectively. Furthermore, optimization of 43a led to the most potent alphavbeta3 antagonist, (R,S)-3-(3-[6-[(4,5-dihydro-1H-imidazol-2-yl)amino]indolin-1-yl]-3-oxopropanoylamino)-3-(quinolin-3-yl)propanoic acid (431) with an IC50 value of 0.42 nM. The synthesis and the structure-activity relationships of these malonamide derivatives are presented.     

New 4-quinaldinol derivatives XVII. 2-Methyl-3-(3-chloro-2-buten-1-yl)-4-hydroxyquinoline-6-carboxylic acid and some of its transformations

1-(2-Methyl-4-hydroxy-6-carboxy-3-quinolinyl)-3-butanone and 1-(2-methyl-4-chloro-6-carboxy-3-quinolinyl)-3-butanone were obtained by the acid hydrolysis of 2-methyl-3-(3-chloro-2-buten-1-yl)-4-hydroxy(chloro)quinoline-6-carboxylic acids and their esters.See [6] for communication XVI.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1681–1682, December, 1971.     

Synthesis and reactions of 3-(3-ethoxycarbonyl-1-phenyl-1<Emphasis Type="Italic">H</Emphasis>-pyrazol-4-yl)propenic acid

The reaction of ethyl 4-formyl-1-phenyl-1H-pyrazole-3-carboxylate with the malonic acid led to the formation (2E)-3-(3-ethoxycarbonyl-1-phenyl-1H-pyrazol-4-yl)propenic acid. In reactions of this acid chloride with 4-amino-5-aryl(hetaryl)-4H-1,2,4-triazole-3-thiols were obtained ethyl 4-[(E)-2-{3-aryl(hetaryl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl}ethenyl]-1-phenyl-1H-pyrazoe-3-carboxylates, with 5-aryltetrazoles, ethyl 4-[(E)-2-(5-aryl-1,3,4-oxadiazol-2-yl)-ethenyl]-1-phenyl-1H-pyrazole-3-carboxylates, with 1-(2-hydroxy-3,5-dimethylphenyl) followed by the Baker-Venkataraman rearrangement and the cyclization, ethyl 4-[(E)-2-(6,8-dimethyl-4-oxo-4Hchromen-2-yl)ethenyl]-1-phenyl-1H-pyrazole-3-carboxylate.     

Synthesis of the optical isomers of 4-[1-(4-tert-butylphenyl)-2-oxo- pyrrolidine-4-yl]methyloxybenzoic acid (S-2) and their biological evaluation as antilipidemic agent

The enantiomers of (+/-)-4-[1-(4-tert-butylphenyl)-2-oxo-pyrrolidine- 4-yl]methyloxybenzoic acid (S-2), a new antilipidemic agent having dual action on the plasma triglyceride (TG) and cholesterol (Cho) lowering effects, were prepared via separation by Chiralcel OJ column chromatography of their methyl ester and also by the same method as the described racemate's synthesis from optically active 1-(4-tert-butylphenyl)-2-oxo-pyrrolidine-4-carboxylic acid respectively. These optically active carboxylic acids were prepared by the resolution of diastereomeric N-[(S)-(-)-[4-methyl-(alpha-methyl)benzyl]]-1-(4-tert-butylphenyl)-2-oxo - pyrrolidine-4-carboxyamide using silica gel column chromatography, followed by deamination with N2O4. The absolute configurations for the enantiomers of S-2 were indirectly determined using X-ray analysis of the 4-bromo-2-fluorobenzamide of the (+)-4-[1-(4-tert-butylphenyl)-2- oxo-pyrrolidine-4-yl]-methyloxybenzoic acid. S-2 and its enantiomers showed an essentially equipotent activity on the fatty acid- and sterol-biosynthesis inhibition in vitro. On the other hand, in the in vivo activity, (S)-(+)-4-[1-(4-tert-butylphenyl)-2-oxo-pyrrolidine- 4-yl]methyloxybenzoic acid (S-2E) was superior in the lowering abilities of the plasma TG and phospholipid(PL) and was chosen as a candidate for a novel antilipidemic agent. The difference in the in vivo activity among S-2 and its enantiomers was explained from the pharmacokinetics after administration p.o.     

Synthesis of 3-amino-3,4-dihydroquinazolin-4-one derivatives from anthranilic acid hydrazide and dicarboxylic acids

Treatment of anthranilic acid hydrazide with 2 equiv of ethoxalyl chloride gave the corresponding diester which underwent cyclization in acetic anhydride to produce ethyl 3-(ethoxalylamino)-4-oxo-3,4-dihydroquinazoline-2-carboxylate. Acylation of anthranilic acid hydrazide first with succinic anhydride and then with ethoxalyl chloride led to the formation of 4-[2-(2-{[ethoxy(oxo)acetyl]amino}benzoyl)hydrazino]-4-oxobutanoic acid whose cyclization in acetic acid afforded N-(2-ethoxycarbonyl-4-oxo-3,4-dihydroquinazolin-3-yl)succinamic acid, while in acetic anhydride ethyl 3-(2,5-dioxopyrrolidin-1-yl)-4-oxo-3,4-dihydroquinazoline-2-carboxylate was obtained. The latter was brought into reactions with amines and hydrazine hydrate and alkaline hydrolysis. Acylation of 2-[2-(2-aminobenzoyl)hydrazinocarbonyl]benzoic acid with ethoxalyl chloride gave ethyl N-[2-(phthalimidocarbamoyl)phenyl]oxamate, and with succinic anhydride, 3-[4-oxo-3-phthalimido-3,4-dihydroquinazolin-2-yl]propionic acid. 4-[2-(2-Aminobenzoyl)hydrazino]-4-oxobutanoic acid reacted with phthalic anhydride in boiling acetic acid to give phthalazino[1,2-b]quinazoline-5,8-dione via elimination of succinic acid residue.     

Kinetics and mechanism of ring transformation of S-[1-(4-methoxyphenyl)pyrrolidin-2-on-3-yl]isothiuronium bromide to 2-methylimino-5-[2-(4-methoxyphenylamino)ethyl]thiazolidin-4-one

The kinetics and mechanism of transformation reaction of S-[1-(4- methoxyphenyl)pyrrolidin-2-one-3-yl]-N-methyl-isothiuronium bromide into 2-methylimino-5-[2-(4-methoxyphenylamino) ethyl)]thiazolidin-4-one have been studied in aqueous solutions of amine buffers (pH 8.1-11.5) and sodium hydroxide solutions (0.005-0.5 mol l-1) at 25 degrees C and at I = 1 mol l-1 at pseudo-first-order reaction conditions. The kinetics observed shows that the transformation reaction is subject to general base, general acid, and hydroxide-ion catalyses. The rate-limiting step of transformation is the splitting-off a proton from the tetrahedral intermediate In. The value of pKa for S-[1-(4-methoxyphenyl)- pyrrolidin-2-one-3-yl]-N-methylisothiuronium bromide has been determined from the kinetic data (pKa = 8.75 +/- 0.10) and by potentiometric titration (pKa = 8.90 +/- 0.05). With increasing pKa value of the acid buffer component, the value of Br?nsted coefficient beta gradually decreases from about 0.7 to almost zero. The value of pKa approximately 10 for the intermediate to base-catalysed transformation has been found from this dependence. In the N-methylpyrrolidine and triethylamine buffers, the rate-limiting step of transformation is changed into ring opening of In-, and the general-base-catalysed reaction changes into a specific-base-catalysed one.