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At least 91 records · Page 5Linked to original sources
PubMed1998

Formation of 4,4-dialkoxycyclohexa-2,5-dienone N-(thiol-S-yl)imine during reaction of 4-alkoxynitrosobenzenes with thiols in alcoholic solvents.

During the interaction of nitrosoarenes with glutathione in aqueous media, intermediate generation of a highly resonance-stabilized sulfenamide cation has been repeatedly suggested. Most intermediates and end products could be explained by reactions of this sulfenamide cation with different nucleophiles such as excess thiol, solvent water, and metabolically produced arylamine. The present paper presents evidence for adduct formation of the sulfenamide cation with solvent alcohol at neutral pH. Sulfenamide cations generated from 4-nitrosophenetole and 4-nitrosoanisole, respectively, are strongly suggested to form the metastable ketals 4-ethoxy-4-methoxycyclohexa-2,5-dienone N-(glutathion-S-yl)imine and 4,4-dimethoxycyclohexa-2,5-dienone N-(glutathion-S-yl)imine, respectively, during reaction with solvent methanol. Reaction of the two sulfenamide cations in ethanol yielded 4,4-diethoxycyclohexa-2, 5-dienone N-(glutathion-S-yl)imine and 4-ethoxy-4-methoxycyclohexa-2, 5-dienone N-(glutathion-S-yl)imine, respectively. Although the metastability of the ketals did not allow isolation of pure solid material, chromatographic and chemical behavior as well as tandem MS fragmentation substantiate a ketal structure of these intermediates. To confirm the proposed structure, new compounds, 2, 6-dimethyl-4-nitrosophenetole, 2,6-dimethyl-4-nitrophenetole, 2, 6-dimethyl-4-phenetidine, and N-(glutathion-S-yl)-N-hydroxy-4-aminoacetophenone, were synthesized and included in supportive experiments. In summary, the detection of ketals corroborates once more the occurrence of a sulfenamide cation which obviously not only reacts with soft nucleophiles such as GSH but, to a limited extent, also reacts with hard nucleophiles. The toxicological significance of this result is discussed.

Alcohols↗
PubMed2004

Synthesis, structure and reactivity of palladium(II) complexes of chiral N-heterocyclic carbene-imine and -amine hybrid ligands.

The synthesis and structures of chiral N-heterocyclic carbene (NHC)-N-donor complexes of silver(I) and palladium(II) are reported. The X-ray structure of an NHC-imine silver(I) complex [((nPr)CN(CHPh))AgBr](2) exhibits an Ag(2)Br(2) dimer motif where the imine group is not coordinated to the silver atom. Reaction between 2 and [PdCl(2)(MeCN)(2)] gives the palladium(II) complex [(kappa(2)-(nPr)CN(CHPh))PdCl(2)](3) that contains a chelating NHC-imine ligand as shown by single-crystal X-ray diffraction. Slow hydrolysis of related complexes [(kappa(2)-(nPr)CN(CHPh))PdCl(2)](3) and [(kappa(2)-((Ph)(2)CH)CN(CHPh))PdCl(2)](4) using triethylammonium chloride and water lead to the precipitation of single crystals of insoluble NHC-amino palladium(II) complexes [(kappa(2)-(nPr)CN(H(2)))PdCl(2)](6) and [(kappa(2)-((Ph)(2)CH)CN(H(2)))PdCl(2)](7), respectively. In the solid state, complexes 6 and 7 both exhibit intermolecular hydrogen bonding between chlorine and an amino-hydrogen atom resulting in an infinite chain structure. Substitution of an amino hydrogen for an ethyl group gives the soluble complex [(kappa(2)-(iPr)CN((H)Et))PdCl(2)](12). Reaction between two equivalents of 2 and [PdCl(2)(MeCN)(2)] gives the di-NHC complex [(kappa(1)-(nPr)CN(CHPh))(2)PdCl(2)](5) that does not contain a coordinated imine as shown by single crystal X-ray diffraction. Conproportionation between 5 and an equivalent of [PdCl(2)(MeCN)(2)] to does not occur at temperatures up to 100 degrees C in CD(3)CN.

Journal Article↗
PubMed2004

Catechol imine ligands: from helicates to supramolecular tetrahedra.

Di- and tricatechol imines are easily accessible by condensation of appropriate amines with 2,3-dihydroxybenzaldehyde. Dicatechol imines can be used for the alkali metal template-directed self-assembly of dinuclear triple-stranded helicates or meso-helicates with high diastereoselectivity. Tricatechol imines lead in self-assembly processes to metallosupramolecular 4 [ratio] 4 tetrahedra with a huge internal cavity, which is able to encapsulate guest species. Hereby the special features of the imine unit can be used to control the outcome of the self-assembly process.

Journal Article↗
PubMed1986

Structure-activity relationships in the mutagenicity of N-substituted derivatives of phenanthrene-9,10-imine.

A series of K-region, N-substituted phenanthrene imines were tested for mutagenicity in Salmonella typhimurium TA100. All chemicals were mutagenic in the absence of an exogenous metabolic activation system. The apparent decay times of the mutagenic species in diffusion plates and their alkylating activities were also measured. The unsubstituted phenanthrene-9,10-imine was approximately 70-fold more mutagenic than the corresponding phenanthrene-9,10-oxide. N-substitution with electron-releasing groups resulted in chemicals that were more mutagenic than those substituted with electron-withdrawing groups. The mutagenic activity of the latter group of chemicals was comparable with that of phenanthrene-9,10-oxide. Except for N-chlorophenanthrene imine, both alkylation of p-nitrothiophenol and apparent decay times in diffusion plates were inversely correlated with mutagenicity. It is hypothesized that reactivity towards p-nitrothiophenol (alkylating activity) and mutagenicity reflect different reactions, in contrast to other chemical mutagens. The results suggest that the high potency of phenanthrene imines as mutagens is possibly due to DNA binding via an aziridinium ion rather than a carbonium ion.

Alkylating Agents↗
PubMed2002

Setting the stage for new catalytic functions in designed proteins--exploring the imine pathway in the efficient decarboxylation of oxaloacetate by an Arg-Lys site in a four-helix bundle protein scaffold.

Fourteen 42-residue polypeptides have been designed to identify reactive sites for the catalysis of the decarboxylation of oxaloacetate, a chemical transformation that proceeds through the formation of an imine intermediate. The sequences fold into helix-loop-helix motifs and dimerize to four-helix bundles. The catalytically active lysine residues were incorporated in several surface exposed positions, but also in positions characterised by hydrophobic properties to reduce their pKa values. The molecular environments of the Lys residues were systematically varied, to find which residues were able to stabilise and bind the imine intermediate in the decarboxylation reaction. A two-residue Arg-Lys site formed the main component of the reactive site of the helix-loop-helix dimer Decarb-K34_R33, which obeyed saturation kinetics in catalysing the reaction with a kcat/KM of 0.59 M-1S-1. The rate constant measured was nearly three orders of magnitude larger than the second-order rate constant of the butylamine-catalysed reaction (0.0011 M-1S-1), and four orders of magnitude larger than the pseudo first-order rate constant of the uncatalyzed reaction (1.3 x 10(-5) s(-1)). The sequence of Decarb-K34_R33 contained only a single lysine residue. It was flanked by an arginine in the preceding position in the sequence. A flanking Arg residue provided more efficient catalysis than a flanking Lys or Gln residue. Arginines in flanking positions in the helix, in positions four residues before or after the Lys in the sequence, are not as important in catalysis as the Arg of the Arg-Lys pair. The effect of pKa on the catalytic efficiency of the Lys residue in the decarboxylation reaction is well known. The identification of the role of the flanking Arg residue in catalysing decarboxylation, its optimal position, and the importance of conformational stability reported here sets the stage for developing a number of catalytic systems that depend on the formation of imine intermediates, but that lead to different reaction products.

Amino Acid Sequence↗
PubMed1987

Role of hepatic microsomal and purified cytochrome P-450 in one-electron reduction of two quinone imines and concomitant reduction of molecular oxygen.

The possible role of cytochrome P-450 in one-electron reduction of quinoid compounds as well as in the formation of reduced oxygen species was investigated in hepatic microsomal and reconstituted systems of purified cytochrome P-450 and purified NADPH-cytochrome P-450 reductase using electron spin resonance (ESR) methods. Two compounds were selected as model compounds: N-acetyl-parabenzoquinone imine (NAPQI) and 3,5-dimethyl-N-acetyl-para-benzoquinone imine (3,5-dimethyl-NAPQI). Both compounds could be reduced by oxyhaemoglobin, the semiquinones formed were detectable by ESR and did not reduce molecular oxygen. Both NAPQI and 3,5-dimethyl-NAPQI underwent one-electron reduction in microsomal systems and in fully reconstituted systems of cytochrome P-450 and NADPH-cytochrome P-450 reductase under anaerobic and aerobic conditions. In both incubation systems the semiquinone formation was diminished under aerobic circumstances and concomitant reduction of oxygen occurred, leading to the formation of hydrogen peroxide and hydroxyl free radicals. Both the reduction of the quinone imines and the reduction of oxygen were found to be cytochrome P-450 dependent. Both activities of cytochrome P-450 may also be involved in the bioactivation of other compounds with quinoid structural elements, like many chemotherapeutic agents.

Animals↗
PubMed2006

C-Branched pyrrolidines from 2-C-acetylmethyl-glycosylazides. Reduction of imines formed by monosaccharide ring opening.

Reduction of the protected 2-C-acetylmethyl-beta-glucopyranosyl azide derivative 1 produced the corresponding beta-glucosylamine 3. Rather than forming a conformationally strained 1,2-trans-fused bicyclic imine, we propose that the beta-glycosylamine underwent anomerization to an acyclic imine (4) followed by an intramolecular ring closure by the 5-hydroxy group. The resultant 2-C-acetylmethyl-alpha-glucopyranosylamine 5, which possesses the 1,2-cis-configuration was immediately converted to a bicyclic imine (2) in excellent yield. Attempts to selectively reduce the C=N double bond of 2 using sodium borohydride and cyanoborohydride failed to produce bicyclic amine 6. Instead, compound 6 underwent another ring-opening elimination and further reduction to produce a C-branched pyrrolidine (8) in good yield. Catalytic hydrogenation of 1 and 2 also provided the C-branched pyrrolidine (10).

Azides↗
PubMed2005

Metabolic activation of the nontricyclic antidepressant trazodone to electrophilic quinone-imine and epoxide intermediates in human liver microsomes and recombinant P4503A4.

Therapy with the antidepressant trazodone has been associated with several cases of idiosyncratic hepatotoxicity. While the mechanism of hepatotoxicity remains unknown, it is possible that reactive metabolites of trazodone play a causative role. Studies were initiated to determine whether trazodone undergoes bioactivation in human liver microsomes to electrophilic intermediates. LC/MS/MS analysis of incubations containing trazodone and NADPH-supplemented microsomes or recombinant P4503A4 in the presence of glutathione revealed the formation of conjugates derived from the addition of the sulfydryl nucleophile to mono-hydroxylated- and hydrated-trazodone metabolites. Product ion spectra suggested that mono-hydroxylation and sulfydryl conjugation occurred on the 3-chlorophenyl-ring, whereas hydration and subsequent sulfydryl conjugation had occurred on the triazolopyridinone ring system. These findings are consistent with bioactivation sequences involving: (1) aromatic hydroxylation of the 3-chlorophenyl-ring in trazodone followed by the two-electron oxidation of this metabolite to a reactive quinone-imine intermediate, which reacts with glutathione in a 1,4-Michael fashion and (2) oxidation of the pyridinone ring to an electrophilic epoxide, ring opening of which, by glutathione or water generates the corresponding hydrated-trazodone-thiol conjugate or the stable diol metabolite, respectively. The pathway involving trazodone bioactivation to the quinone-imine has also been observed with many para-hydroxyanilines including the structurally related antidepressant nefazodone. It is proposed that the quinone-imine and/or the epoxide intermediate(s) may represent a rate-limiting step in the initiation of trazodone-mediated hepatotoxicity.

Antidepressive Agents, Second-Generation↗
PubMed2005

Enantioselective reduction of imines catalyzed by a rhenium(V)-oxo complex.

An air- and moisture-tolerant enantioselective hydrosilylation of N-phosphinyl imines employing a chiral Re(V)-oxo complex as a catalyst is described. The chiral catalyst is a cyanobis(oxazoline) (CNbox)-ligated rhenium-oxo complex of the general formula (CNbox)Re(O)Cl2(OPPh3). Using this catalyst, a wide range of aromatic imines (including cyclic, acyclic, and heteroaromatic), alpha-iminoesters, and alpha,beta-unsaturated imines are reduced with good to excellent enantioselectivities.

Catalysis↗
PubMed2005

Reduction of imines by hydroxycyclopentadienyl ruthenium hydride: intramolecular trapping evidence for hydride and proton transfer outside the coordination sphere of the metal.

Reduction of imines by [2,5-Ph2-3,4-Tol2(eta(5)-C4COH)]Ru(CO)2H (2) produces kinetically stable ruthenium amine complexes. Reduction of an imine by 2 in the presence of an external amine trap gives only the complex of the newly generated amine. Reaction of 2 with H2N-p-C6H4N=CHPh (11), which contains an intramolecular amine trap, gave a 1:1 mixture of [2,5-Ph2-3,4-Tol2(eta(4)-C4CO)](CO)2RuNH(CH2Ph)(C6H4-p-NH2) (8), formed by coordination of the newly generated amine to the ruthenium center, and [2,5-Ph2-3,4-Tol2(eta(4)-C4CO)](CO)2RuNH2C6H4-p-NHCH2Ph (9), formed by coordination of the amine already present in the substrate. These results require transfer of hydrogen to the imine outside the coordination sphere of the metal to give a coordinatively unsaturated intermediate that can be trapped inside the initial solvent cage. Amine diffusion from the solvent cage must be much slower than coordination to the metal center. Mechanisms requiring prior coordination of the substrate to ruthenium would have led only to 8 and can be eliminated.

Crystallography, X-Ray↗
PubMed2006

Asymmetric Friedel-crafts reaction of indoles with imines by an organic catalyst.

In this communication, we report an asymmetric Friedel-Crafts reaction of indoles with imines catalyzed by a bifunctional cinchona alkaloid catalyst. This is the first efficient organocatalytic asymmetric Friedel-Crafts reaction of indoles with imines. This reaction is operationally simple and, unprecedentedly, affords high enantioselectivity for a wide range of indoles and both aryl and alkyl imines. This establishes a direct, convergent, and versatile approach to optically active 3-indolyl methanamines, a structural motif embedded in numerous indole alkaloids and synthetic indole derivatives.

Catalysis↗
PubMed2004

Mild and selective reduction of imines: formation of an unsymmetrical macrocycle.

During investigations of 5, a [3 + 3] Schiff-base macrocycle with six imines, a partially reduced Schiff-base macrocycle, 6, possessing one CH(2)NH and five imine groups was obtained. Control experiments and deuterium labeling indicate that the macrocycle is reduced by a benzimidazoline generated during the reaction. Benzimidazolines may be convenient reagents for the mild and selective reduction of imines.

Cyclization↗
PubMed2005

Copper-catalyzed cross-coupling of imines, acid chlorides, and organostannanes: a multicomponent synthesis of alpha-substituted amides.

A copper-catalyzed cross-coupling of organotin reagents with imines and acid chlorides is reported. The reaction proceeds efficiently with a range of vinyl-, alkyl-, aryl- and heteroaryl-substituted organostannanes as well as a diverse set of imines of non-enolizable aldehydes. Use of chloroformates also allows for the formation of N-protected alpha-substituted amines. This chemistry has been applied to the synthesis of isoquinoline alkaloid derivatives through the activation of cyclic imines.

Alkaloids↗
PubMed1990

Structure-activity relationships in mutagenicity and in nucleophilic ring opening of N-(arylmethyl)phenanthrene 9,10-imines.

Ten derivatives of N-benzylphenanthrene 9,10-imine with different substituents on the phenyl ring were synthesized and subjected to mutagenicity tests in Salmonella typhimurium TA100. While electron donating groups were found to enhance the biological activity, electron attracting and bulky substituents lowered the mutagenic potency. A similar dependence on the electronic structure was observed in triethylamine/acetonitrile-promoted interaction of the title imines and 4-nitrothiophenol. This similarity suggests that both biochemical and chemical processes involve mechanisms in which protonation of the aziridine nitrogen is rate controlling, and the attack of the cellular or model nucleophile is a fast step. In contrast to these processes, the reaction of the imines with 4-nitrothiophenol in the presence of 1,5-diazabicyclo[4.3.0] non-5-ene proved to proceed by an SN2 mechanism and to be enhanced by electron attracting substituents.

Chemical Phenomena↗
PubMed2004

Bioactivation of the nontricyclic antidepressant nefazodone to a reactive quinone-imine species in human liver microsomes and recombinant cytochrome P450 3A4.

The therapeutic benefits of the antidepressant nefazodone have been hampered by several cases of acute hepatotoxicity/liver failure. Although the mechanism of hepatotoxicity remains unknown, it is possible that reactive metabolites of nefazodone play a causative role. Studies were initiated to determine whether nefazodone undergoes bioactivation in human liver microsomes to electrophilic intermediates. Following incubation of nefazodone with microsomes or recombinant P4503A4 in the presence of sulfydryl nucleophiles, conjugates derived from the addition of thiol to a monohydroxylated nefazodone metabolite were observed. Product ion spectra suggested that hydroxylation and sulfydryl conjugation occurred on the 3-chlorophenylpiperazine-ring, consistent with a bioactivation pathway involving initial formation of p-hydroxynefazodone, followed by its two-electron oxidation to the reactive quinone-imine intermediate. The formation of novel N-dearylated nefazodone metabolites was also discernible in these incubations, and 2-chloro-1,4-benzoquinone, a by-product of N-dearylation, was trapped with glutathione to afford the corresponding hydroquinone-sulfydryl adduct. Nefazodone also displayed NADPH-, time-, and concentration-dependent inactivation of P4503A4 activity, suggesting that reactive metabolites derived from nefazodone bioactivation are capable of covalently modifying P4503A4. A causative role for 2-chloro-1,4-benzoquinone and/or the quinone-imine intermediate(s) in nefazodone hepatotoxicity is speculated. Although the antianxiety agent buspirone, which contains a pyrimidine ring in place of the 3-chlorophenyl-ring, also generated p-hydroxybuspirone in liver microsomes, no sulfydryl conjugates of this metabolite were observed. This finding is consistent with the proposal that two-electron oxidation of p-hydroxybuspirone to the corresponding quinone-imine is less favorable due to differences in the protonation state at physiological pH and due to weaker resonance stabilization of the oxidation products as predicted from ab initio measurements.

Antidepressive Agents, Second-Generation↗
PubMed2001

Protective activity of aromatic amines and imines against oxidative nerve cell death.

Oxidative stress is a widespread phenomenon in the pathology of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Neuronal cell death due to oxidative stress may causally contribute to the pathogeneses of these diseases. Therefore, neuroprotective antioxidants are considered to be a promising approach to slow down disease progression. We have investigated different aromatic amine and imine compounds for neuroprotective antioxidant functions in cell culture, and found that these compounds possess excellent cytoprotective potential in diverse paradigms of oxidative neuronal cell death, including clonal cell lines, primary cerebellar neurons, and organotypic hippocampal slice cultures. Aromatic amines and imines are effective against oxidative glutamate toxicity, glutathione depletion, and hydrogen peroxide toxicity. Their mode of action as direct antioxidants was experimentally confirmed by electron spin resonance spectroscopy, cell-free brain lipid peroxidation assays, and intracellular peroxide measurements. With half-maximal effective concentrations of 20-75 nM in different neuroprotection experiments, the aromatic imines phenothiazine, phenoxazine, and iminostilbene proved to be about two orders of magnitude more effective than common phenolic antioxidants. This remarkable efficacy could be directly correlated to calculated properties of the compounds by means of a novel, quantitative structure-activity relationship model. We conclude that bridged bisarylimines with a single free NH-bond, such as iminostilbene, are superior neuroprotective antioxidants, and may be promising lead structures for rational drug development.

Amines↗
PubMed1985

The toxicity of acetaminophen and N-acetyl-p-benzoquinone imine in isolated hepatocytes is associated with thiol depletion and increased cytosolic Ca2+.

The effects of acetaminophen and its major toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI), have been investigated in hepatocytes isolated from 3-methylcholanthrene-pretreated and -untreated rats, respectively. The two compounds produced qualitatively similar changes although the quinone imine was toxic with shorter incubations periods and at lower doses. Both agents caused an elevation of cytosolic Ca2+, assessed by phosphorylase a activity, which was accompanied by the concomitant appearance of plasma membrane blebs. A loss of mitochondrial Ca2+ was also observed. This disruption of Ca2+ homeostasis always preceded cell death. Studies with NAPQI showed that low doses were able to cause complete Ca2+ release from isolated liver mitochondria which was accompanied by pyridine nucleotide oxidation and preceded membrane damage. NAPQI also produced a rapid, dose-dependent depletion of both cytosolic and mitochondrial reduced glutathione as well as a loss of protein-bound SH groups. This loss of protein thiols may have been responsible for the observed inhibition of the high-affinity Ca2+-ATPase activity of the plasma membrane fraction isolated from NAPQI-treated cells. In addition, NAPQI inhibited microsomal Ca2+ uptake which would further contribute to the elevation in cytosolic Ca2+. Our results suggest that acetaminophen and N-acetyl-p-benzoquinone imine exert their cytotoxic effects via a disruption of Ca2+ homeostasis secondary to the depletion of soluble and protein-bound thiols. This mechanism may prove to be of general applicability to a variety of hepatotoxins.

Acetaminophen↗
PubMed1985

Peroxidase-catalyzed O-demethylation reactions. Quinone-imine formation from 9-methoxyellipticine derivatives.

Despite numerous reports on the N-demethylation reactions catalyzed by peroxidases, to our knowledge, O-demethylation reactions with the same enzymes seem to be still a questionable matter. Unexpectedly, a peroxidase system (horseradish peroxidase and hydrogen peroxide) is able to effect the O-demethylation of the cytotoxic agents 9-methoxyellipticine and N2-methyl-9-methoxyellipticinium acetate. The reaction leads directly to the formation of the corresponding quinone-imine derivatives with the concomitant formation of one molecule of methanol per molecule of methoxy compound. One hydrogen peroxide molecule is consumed during the process. Experiments in H218O-enriched water clearly indicate that 18O is nearly quantitatively incorporated in the carbonyl group of the generated quinone-imine compound with the concomitant elimination of the methoxy group as methanol. So this peroxidase-catalyzed apparent O-demethylation in fact implies an oxidative demethoxylation step. This enzymatic reaction exhibits normal Michaelis-Menten saturation kinetics. Like the 9-hydroxylated ellipticines, both the 9-methoxylated ellipticines show a good affinity for the peroxidase itself (Km approximately 10 microM) but are slowly transformed to the corresponding quinone-imines. The Vmax values for methoxylated ellipticines are 10(-1)-10(-3) lower than those for hydroxylated compounds. This new route for the in vitro formation of electrophilic derivatives from the cytotoxic 9-methoxyellipticine and N2-methyl-9-methoxyellipticinium might be considered as a novel possible metabolic pathway for these drugs, especially if we bear in mind the "bio-oxidative alkylation" process previously described for at least one of the corresponding hydroxylated ellipticine derivatives (see Bernadou, J., Meunier, B., Meunier, G., Auclair, C., and Paoletti, C. (1984) Proc. Natl. Acad. Sci. U.S.A. 81, 1297-1301; and Monsarrat, B., Maftouh, M., Meunier, G., Dugué, B., Bernadou, J., Armand, J. P., Picard-Fraire, C., Meunier, B., and Paoletti, C. (1983) Biochem. Pharmacol. 32, 3887-3890).

Alkaloids↗