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At least 1,081 records · Page 60Linked to original sources
PubMed2003

Stereoselective synthesis of functionalized pyrrolidines by ruthenium porphyrin-catalyzed decomposition of alpha-diazo esters and cascade azomethine ylide formation/1,3-dipolar cycloaddition reactions.

[reaction: see text] Ruthenium porphyrins catalyze three-component coupling reaction of alpha-diazo esters with a series of N-benzylidene imines and alkenes to form functionalized pyrrolidines in excellent diastereoselectivities. The reaction proceeds via a reactive ruthenium-carbene intermediate and its subsequent reaction with imine to generate azomethine ylide, which reacts with alkenes via 1,3-diploar cycloaddition.

Journal Article↗
PubMed2003

Catalytic, three-component assembly reaction for the synthesis of pyrrolidines.

[reaction: see text] Copper(I) salts catalyze the three-component assembly reaction between an alpha-diazo ester, an imine, and various alkenes and alkynes to form substituted pyrrolidines with excellent to good diastereoselectivities in high yields. The transition metal-catalyzed decomposition of the alpha-diazo compound in the presence of the imine likely generates a transient azomethine ylid that undergoes addition with various dipolarophiles in a highly convergent manner.

Journal Article↗
PubMed2004

Enantioselective aza-Henry reaction catalyzed by a bifunctional organocatalyst.

[reaction: see text] The aza-Henry reaction of imines with nitroalkanes was promoted by chiral thiourea with an N,N-dimethylamino group to give beta-nitroamines with good enantioselectivity. Various N-protected imines were examined as substrates. N-Phosphinoylimine gave the best result in terms of chemical yield and enantioselectivity (up to 91% yield, up to 76% ee).

Journal Article↗
PubMed2004

Zn-alkynylide additions to acyl iminiums.

[reaction: see text] A new addition reaction of zinc-alkynylides to N-acyl and N-phosphinoyl iminiums is reported. These can be prepared in situ from imines with acid halides in the presence of a Zn-acetylide. The reaction is general with regard to imine, alkyne, and acid halides, allowing access to a large number of differentially protected propargylic amines.

Journal Article↗
PubMed2005

Lewis base-catalyzed additions of alkynes using trialkoxysilylalkynes.

[reaction: see text]. The Lewis base-catalyzed additions of alkynyl nucleophiles to aldehydes, ketones, and imines is described. Mechanistic studies strongly indicate that the use of new triethoxysilylalkynes facilitates access of a reactive hypervalent silicate intermediate. This activated carbon nucleophile subsequently undergoes rapid addition to carbonyl compounds and imines, thus affording the secondary and tertiary propargyl systems in moderate to high yield.

Journal Article↗
PubMed1999

Hetero [4 + 2] cycloadditions of (trialkylsilyl)vinylketenes. Synthesis of alpha,beta-unsaturated delta-valerolactones and -lactams.

[formula: see text] Hetero Diels-Alder reactions of (trialkylsilyl)vinylketenes (TAS-vinylketenes) with carbonyl and imino dienophiles are described. TAS-vinylketenes participate as electron-rich dienes in [4 + 2] cycloadditions with diethyl ketomalonate to afford alpha,beta-unsaturated delta-valerolactones in good yield. Nonenolizable N-alkyl- and N-(trimethylsilyl)imines combine with TAS-vinylketenes to furnish alpha,beta-unsaturated delta-valerolactams. In contrast to most Diels-Alder reactions involving unactivated imines, these cycloadditions do not require promotion by Lewis acids and in general proceed with a high degree of stereoselectivity.

Cyclization↗
PubMedDate not supplied

On the chemistry of the reaction between N-acetylcysteine and 4-[(4-ethoxyphenyl)imino]-2,5-cyclohexadien-1-one, a 4-ethoxyaniline metabolite formed during peroxidase reactions.

4-Ethoxyaniline (p-phenetidine) is oxidized by peroxidases to form several products, one of which is 4-[(4-ethoxyphenyl)imino]-2,5-cyclohexadien-1-one (1). This compound reacts with N-acetylcysteine (NAC) in methanol-phosphate buffers, generating at least four different products. Four major products, 4-[(4-ethoxyphenyl)amino]phenol (2), 3-(N-acetylcystein-S-yl)-4-[(4-ethoxyphenyl)amino]phenol (3), 2,5-bis(N-acetylcystein-S-yl)-4-[(4-ethoxyphenyl)-amino]phenol (4), and 2,5-bis(N-acetylcystein-S-yl)-4-[(4-ethoxyphenyl)imino]-2,5- cyclohexadien-1-one (5), were isolated and identified by NMR spectroscopy and mass spectrometry. The relative ratio between the formed products depends on the pH, the concentration of NAC, and the reaction time. Compound 2, which is the reduced form of 1, was the dominating product when the reaction took place at pH 3, whereas formation of the mono conjugate (3) was more extensive at a neutral pH. Under alkaline conditions 2 and 3 were oxidized by 1 or O2. The oxidized form of 3 was subsequently attacked by a second molecule of NAC, generating the bis conjugate (4). Unless an excess of NAC was present, compound 4 underwent rapid oxidation to 5. Quinone imines, like 1, generating mono conjugates, which are more reactive than the quinone imines per se, are likely to inflict an increased toxic potential and an increased stress on the endogenous thiol pool, resulting in an overall greater toxicity.

Acetylcysteine↗
PubMedDate not supplied

Identification of a cysteinyl adduct of oxidized 3-methylindole from goat lung and human liver microsomal proteins.

3-Methylindole is a selective pneumotoxin that is oxidized by cytochrome P-450 enzymes to a reactive intermediate. 3-Methyleneidolenine, a methylene imine electrophile, is the postulated reactive intermediate, and it binds to proteins, a reaction that probably initiates the pneumotoxicity of 3-methylindole. Thioether adducts of this electrophile are formed with glutathione in vitro, but the identity of the adducted electrophile with amino acid residues of microsomal proteins had not previously been determined. 3-Methylindole was incubated with NADPH and goat lung or human liver microsomal proteins, and the proteins were hydrolyzed. 3-(Cystein-S-ylmethyl)indole was isolated and identified as the major amino acid adduct of 3-methyleneindolenine, demonstrating that cysteine thiols preferentially attack the exocyclic methylene position and result in a covalently (thioether) attached 3-methylindole residue to these pulmonary and hepatic proteins. These results demonstrate that the putative methylene imine intermediate is indeed the active electrophile that binds to proteins and presumably initiates the toxic events.

Animals↗
PubMed1995

Oxidation versus addition reactions of glutathione during the interactions with quinoid thioethers of 4-(dimethylamino)phenol.

4-(Dimethylamino)phenol (DMAP) is a potent cyanide antidote which forms many equivalents of ferrihemoglobin in vivo and in vitro. During this process formation of phenoxyl radicals was observed which are reduced by ferrohemoglobin, thereby sustaining a catalytic cycle of ferrihemoglobin formation, or which disproportionate to give the quinone imine of DMAP. In the presence of thiols, e.g., glutathione (GSH), formation of 4-(dimethylamino)-2-(glutathion-S-yl)phenol (2-GS-DMAP), 4-(dimethylamino)-2,6-bis(glutathion-S-yl)phenol (2,6-bis-GS-DMAP), and 4-(dimethylamino)-2,3,6-tris(glutathion-S-yl)phenol (2,3,6-tris-GS-DMAP) was observed. While the trisubstituted glutathione conjugate is a stable end product, 2-GS-DMAP and 2,6-bis-GS-DMAP were still reactive and produced ferrihemoglobin. It is concluded that formation of polysubstituted DMAP thioethers is a result of sequential oxidation/addition reactions with quinoid intermediates. Formation of glutathione disulfide (GSSG) was minimal during the interaction of oxidized DMAP or 2-GS-DMAP with glutathione but became significant when oxidized 2,6-bis-GS-DMAP reacted with GSH. Thus it is conceivable that the bulky glutathione substituents in 2,6-bis-GS-DMAP render the addition of a third GSH molecule to the quinone imine derivative more difficult, and other reactions may get a chance. The reaction mechanism of GSSG formation has not been fully resolved, but a radical pathway mechanism involving thiyl radicals is proposed. Oxidation and addition reactions were also observed in the absence of oxygen when ferrihemoglobin served as oxidant. In the presence of oxygen, however, GSSG formation was increased, Partly due to hydrogen peroxide formation, partly due to an additional trapping reaction of the glutathione disulfide radical anion.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminophenols↗
PubMed1995

Reactivity of glutathione adducts of 4-(dimethylamino)phenol. Formation of a highly reactive cyclization product.

During ferrihemoglobin formation, 4-(dimethylamino)phenol (DMAP), a potent cyanide antidote, forms a quinoid compound that is prone to sequential oxidation/addition reactions. In human red cells and hemoglobin solutions fortified with glutathione, a transient adduct has been isolated and identified as 4-(dimethylamino)-2-(glutathion-S-yl)phenol (2-GS-DMAP). This compound still formed ferrihemoglobin but differed from parent DMAP in that the reaction rate was roughly proportional to the oxygen concentration and exhibited a lag phase, pointing to a reactive autoxidation product. The compound was isolated and tentatively identified as an intramolecular cyclization product of 2-GS-DMAP. Formation of this product includes three reaction steps: (1) formation of a quinoid intermediate, (2) addition of the alpha-amino nitrogen atom of the glutamate residue to the aromatic ring, and (3) autoxidation of the cyclization product to give a highly reactive o-quinone imine. The isolated compound existed in two isomeric states (1H-NMR) which upon reduction could be separated by HPLC. The isolated reduced isomers mutually converted into each other. A model compound which was synthesized to mimic the most important structural features, 4-(dimethylamino)-6-[S-(2'-hydroxyethyl)-thio]-N-(2"-phenylethyl)-1,2- quinone imine, had a very similar visible spectum and exhibited an even higher ferrihemoglobin activity than the cyclization product. A similar phenomenon of intramolecular cyclization of a thioether of DMAP had been observed earlier: DMAP covalently bound to the SH groups of the beta-chains in hemoglobin formed a cross-link with the C-terminal histidine residue in the presence of oxygen but not in its absence.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminophenols↗
PubMed2003

Reactivity with Tris(hydroxymethyl)aminomethane confounds immunodetection of acrolein-adducted proteins.

The toxic alpha,beta-unsaturated aldehyde acrolein readily attacks proteins, generating adducts at cysteine, histidine, and lysine residues. In this study, rabbit antiserum was raised against acrolein-modified keyhole limpet hemocyanin in the expectation that it would allow immunodetection of adducted proteins in biological samples. Using slot-blot and enzyme-linked immunosorbent assays, the antiserum detected acrolein-modified protein with high sensitivity and specificity. Adduct immunodetection was strongly inhibited by acrolein-modified polylysine but not polyhistidine. Efforts to develop a Western blotting method for detecting adducted proteins in cell lysates were hampered by irreproducible outcomes, evidently due to adduct instability during SDS-PAGE. Indeed, adducts generated via brief exposure of a model protein to acrolein displayed pH- and concentration-dependent instability to tris(hydroxymethyl)aminomethane (Tris), a nucleophilic buffer used in protein electrophoresis. The effect was most striking when Tris solutions were buffered to pH 8.0 and higher. In contrast, adducts formed during extended exposure to acrolein (> or =60 min) were completely stable to Tris. The time dependence of susceptibility raised the possibility that Tris interfered with specific steps in lysine modification, which involves stepwise Michael addition of two molecules of acrolein to the same residue, followed by condensation and dehydration to form a heterocyclic adduct, N(epsilon)-(3-formyl-3,4-dehydropiperidino)lysine. We hypothesize that carbonyl-retaining Michael adducts may react with Tris by forming imines with the primary amine of the buffer. Consistent with this idea, triethanolamine, a tertiary amine buffer unable to form imines, had no effect on acrolein-adducted protein. These effects of Tris may explain difficulties in the detection of acrolein-adducted proteins during conventional Western blotting procedures.

Acrolein↗
PubMed2004

2,6-diarylaminotetrahydropyrans from reactions of glutaraldehyde with anilines: models for biomolecule cross-linking.

Glutaraldehyde reacts with weakly nucleophilic anilines, e.g., 3-fluoro-4-nitroaniline, which are models for amino groups in DNA, to give meso-2,6-disubstituted tetrahydropyrans, e.g., meso-2,6-di-(3-fluoro-4-nitroanilino)tetrahydropyran, that were characterized spectroscopically and by X-ray crystal structure analysis. This contrasts with the outcome of reactions with more strongly nucleophilic amines, which give rise to N-substituted 1,4-dihydropyridines. The mechanism of formation of the tetrahydropyrans is proposed to involve initial attack of the amine on one of the aldehyde groups of glutaraldehyde to give a carbinolamine intermediate. The ensuing cyclization to a tetrahydropyran, rather than dehydration to an imine leading to a dihydropyridine, is explained as a result of a competition between the lone pair of the amino function of the carbinolamine and the two lone pairs of the hydroxyl group. The formation of the tetrahydropyran is more likely with an amino function of low nucleophilicity, whereas dehydration to an imine leading to a dihydropyridine is favored with an amino function of higher nucleophilicity. The formation of tetrahydropyrans may be relevant to the toxicology of glutaraldehyde by providing a mechanistic basis for DNA adduction or DNA-protein cross-linking.

Aniline Compounds↗
PubMed2006

Stereospecific formation of interstrand carbinolamine DNA cross-links by crotonaldehyde- and acetaldehyde-derived alpha-CH3-gamma-OH-1,N2-propano-2'-deoxyguanosine adducts in the 5'-CpG-3' sequence.

The crotonaldehyde- and acetaldehyde-derived R- and S-alpha-CH3-gamma-OH-1,N2-propanodeoxyguanosine adducts were monitored in single-stranded and duplex oligodeoxynucleotides using NMR spectroscopy. In both instances, the cis and trans diastereomers of the alpha-CH3 and gamma-OH groups underwent slow exchange, with the trans diastereomers being favored. In single-stranded oligodeoxynucleotides, the aldehyde intermediates were not detected spectroscopically, but their presence was revealed through the formation of N-terminal conjugates with the tetrapeptide KWKK. When annealed into 5'-d(GCTAGCXAGTCC)-3'.5'-d(GGACTCYCTAGC)-3' containing the 5'-CpG-3' sequence context (X = R- or S-alpha-CH3-gamma-13C-OH-PdG; Y = 15N2-dG) at pH 7, partial opening of the R- or S-alpha-CH3-gamma-13C-OH-PdG adducts to the corresponding N2-(3-oxo-1-methyl-propyl)-dG aldehydes was observed at temperatures below the T(m) of the duplexes. These aldehydes equilibrated with their geminal diol hydrates; higher temperatures favored the aldehydes. When annealed opposite T, the S-alpha-CH3-gamma-13C-OH-PdG adduct was stable. At 37 degrees C, an interstrand DNA cross-link was observed spectroscopically only for the R-alpha-CH3-gamma-OH-PdG adduct. Molecular modeling predicted that the interstrand cross-link formed by the R-alpha-CH3-gamma-OH-PdG adduct introduced less disruption into the duplex structure than did the cross-link arising from the S-alpha-CH3-gamma-OH-PdG adduct, due to differing orientations of the R- and S-CH3 groups. Modeling also predicted that the alpha-methyl group of the aldehyde arising from the R-alpha-CH3-gamma-OH-PdG adduct is oriented in the 3'-direction in the minor groove, facilitating cross-linking. In contrast, the alpha-methyl group of the aldehyde arising from the S-alpha-CH3-gamma-OH-PdG adduct is oriented in the 5'-direction within the minor groove, potentially hindering cross-linking. NMR revealed that for the R-alpha-CH3-gamma-OH-PdG adduct, the carbinolamine form of the cross-link was favored in duplex DNA with the imine (Schiff base) form of the cross-link remaining below the level of spectroscopic detection. Molecular modeling predicted that the carbinolamine linkage maintained Watson-Crick hydrogen bonding at both of the tandem C.G base pairs. Dehydration of the carbinolamine cross-link to an imine, or cyclization of the latter to form a pyrimidopurinone cross-link, required disruption of Watson-Crick hydrogen bonding at one or both of the cross-linked base pairs.

Acetaldehyde↗
PubMed1998

Evidence supporting the formation of 2,3-epoxy-3-methylindoline: a reactive intermediate of the pneumotoxin 3-methylindole.

The existence of a cytochrome P450-dependent 2,3-epoxide of the potent pneumotoxin 3-methylindole was indirectly confirmed using stable isotope techniques and mass spectrometry. Determination of hydride shift and incorporation of labeled oxygen in 3-methyloxindole and 3-hydroxy-3-methyloxindole, metabolites that may be in part dependent on the presence of the epoxide, were utilized as indicators of the epoxide's existence. One mechanism for the formation of 3-methyloxindole involves cytochrome P450-mediated epoxidation followed by ring opening requiring a hydride shift from C-2 to C-3. Through incubations of goat lung microsomes with [2-2H]-3-methylindole, the retention of 2H in 3-methyloxindole was found to be 81%, indicating a majority of the oxindole was produced by the mechanism described above. 3-Hydroxy-3-methylindolenine is an imine reactive intermediate that could be produced by ring opening of the 2,3-epoxide. The imine may be oxidized to 3-hydroxy-3-methyloxindole by the cytosolic enzyme aldehyde oxidase. Activities of this putative detoxification enzyme were determined in both hepatic and pulmonary tissues from goats, rats, mice, and rabbits, but the activities could not be correlated to the relative susceptibilities of the four species to 3-methylindole toxicity. The 18O incorporation into either 3-methyloxindole or 3-hydroxy-3-methyloxindole from both 18O2 and H218O was determined. The 18O incorporation into 3-methyloxindole from 18O2 was 91%, strongly implicating a mechanism requiring cytochrome P450-mediated oxygenation. Incorporation of 18O into 3-hydroxy-3-methyloxindole indicated that the alcohol oxygen originated from molecular oxygen, also implicating an epoxide precursor. These studies demonstrate the existence of two new reactive intermediates of 3-methylindole and describe the mechanisms of their formation and fate.

Aldehyde Oxidase↗
PubMed1998

Iron- and manganese-catalyzed autoxidation of dopamine in the presence of L-cysteine: possible insights into iron- and manganese-mediated dopaminergic neurotoxicity.

Iron(II/III) and manganese(II) both catalyze the autoxidation of the neurotransmitter dopamine (DA) in the presence of L-cysteine (CySH) in buffered aqueous solution at pH 7.4. Fe2+/Fe3+ and CySH together generate the hydroxyl (HO.) and cysteinyl thiyl (CyS.) radicals. DA is oxidized by HO. to DA semiquinone radical species that either react with CyS. to give 5-S-cysteinyldopamine (5-S-CyS-DA), 2-S-CyS-DA, and 6-S-CyS-DA or disproportionate to DA-o-quinone that reacts with CySH to give the same cysteinyl conjugates of DA. The major product of this initial reaction is 5-S-CyS-DA. However, 5-S-CyS-DA can be further oxidized by HO. to an o-quinone (2) that undergoes intramolecular cyclization to an o-quinone imine (3). The latter intermediate is the precursor of the dihydrobenzothiazine (DHBT) 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1, 4-benzothiazine-3-carboxylic acid (DHBT-1) and several other cyclized products. However, cysteinyl conjugates of DA can also be oxidized by HO. in a one-electron abstraction reaction that leads to DA thiyl radicals. Reactions of these radicals with CyS. or DA semiquinone radicals lead to some novel DA disulfides and thioethers, respectively. The Mn(II)-catalyzed oxidation of DA generates DA-o-quinone that is scavenged by CySH to give 5-S-CyS-DA (major initial product) with lower yields of other cysteinyldopamines. Subsequent Mn(II)-catalyzed oxidation of 5-S-CyS-DA gives o-quinone 2 and thence o-quinone imine 3 that serve as the precursors of DHBT-1 and several other DHBTs. Organic or oxygen radicals do not play significant roles in the Mn(II)-catalyzed oxidation of DA in the presence of CySH. Recent studies have demonstrated that DHBT-1 can be accumulated by brain mitochondria and evoke irreversible inhibition of NADH-coenzyme Q reductase (complex I). Furthermore, iron, manganese, and alterations in glutathione and CySH metabolism have been implicated in the selective degeneration of nigrostriatal dopaminergic neurons in idiopathic and chemically induced Parkinson's disease (PD). Because DHBT-1 is formed in both the iron- and manganese-catalyzed oxidation of DA in the presence of CySH and a defect in mitochondrial complex I respiration contributes to dopaminergic neuronal cell death in PD, the results of this investigation are discussed in terms of their possible implications to an understanding of the neuropathological processes in idiopathic and chemically induced parkinsonism.

Chromatography, High Pressure Liquid↗
PubMed2001

Design of expanded bed supports for the recovery of plasmid DNA by anion exchange adsorption.

In this study we detail the rational design of new chromatographic adsorbents tailored for the capture of plasmid DNA. Features present on current chromatographic supports that can significantly enhance plasmid binding capacity have been identified in packed bed chromatography experiments and blueprints for improved expanded bed adsorbents have been put forward. The characterisation and testing of small (20-40 microm) high density (>3.7 g cm(-3)) pellicular expanded bed materials functionalised with various anion exchange structures is presented. In studies with calf thymus DNA, dynamic binding capacities of 1.2 and 3.4 mg ml(-1) were recorded for prototype diethylaminoethyl-and polyethylene imine-linked adsorbents which were respectively 25 and 70 fold higher than those of equivalently derivatised commercial expanded bed materials. The prototype polyethylene imine-coupled material exhibited severe sensitivity to inter-particle bridging by nucleic acid polymers, gave low DNA recoveries (<37%) and proved difficult to regenerate. In contrast, few operational difficulties were experienced with the diethylaminoethyl-linked prototype adsorbent and successful high capacity (>0.8 mg ml(-1)) capture of plasmid DNA from crude neutralised E. coli lysate was demonstrated.

Adsorption↗
PubMed2003

Chiral base-mediated benzylic functionalisation of tricarbonylchromium(0) complexes of benzylamine derivatives.

The novel complex (eta 6-benzylamine)tricarbonylchromium(0) 11 was prepared in up to 66% yield by direct complexation with Cr(CO)6 in refluxing 1,4-dioxane. Imine derivatives of this complex were readily deprotonated at the benzylic position by diamide 5, and the resultant anions reacted regioselectively with electrophiles (Me3SiCl or MeI) to give fairly good yields of products substituted at the benzylic carbon. Products of up to 87% e.e. were obtained in these reactions, with the highest enantioselectivity being derived from the tert-butyl-substituted imine complex 25.

Journal Article↗