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PubMed2005

Formation of inter- and intrastrand imine type DNA-DNA cross-links through secondary reactions of aldehydic adducts.

Acrolein-derived DNA adducts of guanine have previously been detected in tissues of several species, including humans, and have been shown to be mutagenic in mammalian cells and potentially carcinogenic in higher organisms. In duplex DNA, the predominant acrolein-derived lesion, gamma-hydroxy-1,N2-propanodeoxyguanosine (gamma-HOPdG), exists in an equilibrated mixture of ring-opened and ring-closed forms. We have previously shown that the acyclic form can undergo secondary chemical reactions to form both interstrand DNA-DNA cross-links in a CpG sequence context and DNA-protein and DNA-peptide cross-links. Investigations using duplex DNAs containing gamma-HOPdG in a CpG sequence context reversibly created at least two cross-linked species: an imine, which is a minor species but could be readily reduced by NaBH4, and a major heat labile, nonreducible species that we formulate as a carbinolamine cross-link. The DNA came to equilibrium over several days with the carbinolamine species being significantly more abundant than the reducible imine. In an effort to find other types of DNA-DNA cross-links, we have developed a high throughput screen to evaluate the effects of DNA sequence and lesion structure on the formation of reducible interstrand and intrastrand cross-links. These data reveal that four different lesions, two involving deoxyguanosine and two involving deoxyadenosine, can react with nearby bases to form inter- and intrastrand DNA cross-links.

Aldehydes↗

PubMed2003

Chiral phosphine Lewis base catalyzed asymmetric aza-Baylis-Hillman reaction of N-sulfonated imines with methyl vinyl ketone and phenyl acrylate.

In the aza-Baylis-Hillman reaction of N-sulfonated imines with methyl vinyl ketone (MVK) promoted by chiral phosphine Lewis base: (R)-2'-diphenylphosphanyl-[1,1']binaphthalenyl-2-ol (10 mol%), the aza-Baylis-Hillman adducts 1 were obtained in good yields with high ee (70-94% ee) at -30 degrees C in THF. In CH2Cl2 upon heating at 40 degrees C, the aza-Baylis-Hillman reaction of N-sulfonated imines with phenyl acrylate gave the adducts 2 in high yields (60-97%) with moderate ee (52-77%).

Journal Article↗

PubMed2004

Thione complexes of Rh(I): a first comparison with the bonding and catalytic activity of related carbene and imine compounds.

Heterocyclic mono(thione), trans-bis(thione), cis-bis(thione), trans-(carbene-thione), cis-(carbene-thione), trans-(phosphine-thione) and mono(imine) complexes of rhodium(I) have been prepared and fully characterised. Chloro(eta(4)-1,5-cyclooctadiene)(L)rhodium(I)(1a, L = 1,3-diisopropyl-4,5-dimethyl-2,3-dihydro-1H-imidazol-2-thione; 1b L = 1,3,4,5-tetramethyl-2,3-dihydro-1H-imidazol-2-thione) appear as isomers at room temperature due to slow coordination exchange on the S-donor atom. In the three structures determined, the substituent on the sulfur appears syn to Cl. Hindered rotation about the Rh-carbene bond is revealed in the NMR spectra of seven new complexes with isopropyl substituents on the heterocyclic carbene ligands. The trans influence of the thione ligands is smaller than that of carbenes but larger than that shown by imines and chloride. Thione complexes are better catalyst precursors than the carbene complexes for the hydroformylation of 1-hexene under the chosen reaction conditions: 80 degrees C, 8 MPa CO-H2(1:1), 16 h, 1:1000 catalyst to 1-hexene ratio.

Journal Article↗

PubMed1993

Evidence for covalent binding of acyl glucuronides to serum albumin via an imine mechanism as revealed by tandem mass spectrometry.

Acyl glucuronide metabolites of bilirubin and many drugs can react with serum albumin in vivo to form covalent adducts. Such adducts may be responsible for some toxic effects of carboxylic nonsteroidal antiinflammatory agents. The mechanism of formation of the adducts and their chemical structures are unknown. In this paper we describe the use of tandem mass spectrometry to locate binding sites and elucidate the binding mechanism involved in the formation of covalent adducts from tolmetin glucuronide and albumin in vitro. Human serum albumin and excess tolmetin glucuronide were coincubated in the presence of sodium cyanoborohydride to trap imine intermediates. The total protein product was reduced, carboxymethylated, and digested with trypsin. Six tolmetin-containing peptides (indicated by absorbance at 313 nm) were isolated by high-pressure liquid chromatography and analyzed by liquid secondary-ion mass spectrometry and collision-induced dissociation, using a four-sector tandem mass spectrometer. All six peptides contained tolmetin linked covalently via a glucuronic acid to protein lysine groups. Major attachment sites on the protein were Lys-195, -199, and -525; minor sites were identified as Lys-137, -351, and -541. Our results show unambiguously that the glucuronic acid moiety of acyl glucuronides can be retained within the structure when these reactive metabolites bind covalently to proteins, and they suggest that acyl migration followed by Schiff base (imine) formation is a credible mechanism for the generation of covalent adducts in vivo.

Acylation↗

PubMed1995

Antibiotic activity of isoxazolylnaphthoquinone imines on mice infected with Staphylococcus aureus.

The antibiotic activity of new synthetic isoxazolylnaphthoquinone imines was studied. Pseudomonas aeruginosa ATCC 27853 and Escherichia coli ATCC 25922 were resistant to the four compounds studied (MIC > 128 micrograms ml-1), but Staphylococcus aureus ATCC 25923, ATCC 29213 and 30 clinical isolates of Staph. aureus were inhibited by 2-hydroxy-N-(3,4-dimethyl-5-isoxazolyl)-1,4-naphthoquinone-4-imine (I). This compound diminished bloodstream infection of mice injected i.m. with Staph. aureus; septicaemia decayed significantly when I was applied at the beginning of the infection while when I was given 3 d after bacterial challenge, a significant protection was afforded. Bactericidal activity in serum increased during the 5 h after I was administered i.p. The acetyl derivative of I had a high MIC but when inoculated orally in mice decreased the Staph. aureus counts in circulation. This protection occurred only when the schedule of administration started close to the bacterial challenge. Antibiotic activity in vivo may be associated with in vitro effects.

Animals↗

PubMed1996

Nitric oxide-donating properties of mesoionic 3-aryl substituted oxatriazole-5-imine derivatives.

1. The nitric oxide (NO)-releasing properties of two new mesoionic 3-aryl substituted oxatriazole-5-imine derivatives (GEA 3162 and GEA 3175) were characterized and compared with the known NO-donors 3-morpholino-sydnonimine (SIN-1) and S-nitroso-N-acetylpenicillamine (SNAP). 2. GEA 3162, GEA 3175, SIN-1 and SNAP inhibited adenosine 5'-diphosphate-induced platelet aggregation (IC50 values 0.18, 0.39, 3.73 and 2.12 microM, respectively). All four compounds induced a dose-dependent and more than 4 fold increase in cyclic GMP in platelets. The increase in cyclic GMP concentration was potentiated more than 1.5 fold by a phosphodiesterase inhibitor, zaprinast (10 microM) and inhibited 38-97% by oxyhaemoglobin (10-45 microM). 3. All of the four compounds studied converted oxyhaemoglobin to methaemoglobin and formed a paramagnetic NO-haemoglobin complex. All but GEA 3175 formed nitrite and nitrate in phosphate buffer. During a 40 min incubation, GEA 3162, SIN-1 and SNAP (100 microM) produced 50-70 microM NO2- + NO3- as determined by high performance liquid chromatography. The release of NO and NO2 by GEA 3175 was increased 140 fold in the presence of human plasma (0.14 and 19.7 ppb in the absence and presence of 1% human plasma, respectively) as analyzed by ozone chemiluminescence. 4. The results suggest that the mesoionic 3-aryl substituted oxatriazole-5-imine derivatives GEA 3162 and GEA 3175 as well as SIN-1 and SNAP release nitric oxide.

Blood Platelets↗

PubMed1978

Comparison of pseudorabies virus inactivated by bromo-ethylene-imine, 60Co irradiation, and acridine dye in immune assay systems.

Pseudorabies virus infections among animals, especially swine, have become prevalent in the United States in the past few years. The disease in swine is now economically important. Test systems and antigens are being developed for use in control and disease suppression efforts. Pseudorabies virus was inactivated by three methods: chemically, with bromo-ethylene-imine; physically, with 60Co irradiation; and chemically and physically, with 3,9-diaminoacridine dye followed by exposure to white visible light. The antigenicities of the preparations were determined in the presence of specific antibody in immunodiffusion tests and through immunoelectrophoresis. The latter technique permitted quantitation of either antigen or antibody. In the electrophoretic patterns, the antigenic mass in bromo-ethylene-imine preparations was estimated to be 42 mg/ml, the same as in the untreated control material. After 60Co irradiation, 22 mg/ml was present, in comparison with 50 mg/ml in the untreated control antigen. In contrast, 67 mg/ml was present in the acridine dye-light-treated preparation, in comparison with 58 mg/ml in the untreated control material. A possible explanation for the acridine dye-light-treated preparation values is that photodynamic inactivation interferes with viral maturation during the replicative cycle within cells, with a resulting production of a greater amount of antigen, at least some of which is in the form of defective particles.

Acridines↗

PubMed2006

Investigations on the toxicological profile of functionalized fifth-generation poly (propylene imine) dendrimer.

Dendrimers have generated tremendous interest in the field of drug delivery. Despite indications of their utility as drug carriers, the inherent cytotoxicity associated with polycationic dendrimers acts as a limiting factor to their clinical applications. Many functionalization strategies have been adopted to mask peripheral amines in order to overcome this limitation. The object of the present investigation was to evaluate the effect of functionalization on the toxicological profile of fifth-generation poly(propylene imine) dendrimer (PPI-5.0G). Four forms of functionalized dendrimers, including protected glycine and phenylalanine, and mannose and lactose functionalized poly(propylene imine) (PPI) dendrimer, were synthesized as prospective drug carriers. These dendrimeric systems were evaluated for haemolytic toxicity, cytotoxicity, immunogenicity and haematological parameters. PPI-5.0G demonstrated a positive charge-based time- and concentration-dependent toxicity profile. Functionalization greatly improved the toxicity profile of the parent dendrimer. Hence it is proposed that these functionalized forms of PPI dendrimer have great potential as bio-compatible drug vehicles.

Animals↗

PubMed2006

[Synthesis and characterization of chitosan-imine-palladacycle].

Chitosan was grafted with salicylaldehyde to obtain Schiff base. The Schiff base reacted with Li2 PdCl4 in methanol to synthesize chitosan-imine-palladacycle. The structure of chitosan, schiffbase and chitosan-imine-palladacycle was characterized by IR, XRD, DTA-TG, fluorescence and XPS. According to the results of analysis, the structure of Schiff base and chitosanimine-palladacycle can be inferred.

English Abstract↗

PubMed2002

Catalytic enantioselective addition of propionate units to imines: an efficient synthesis of anti-alpha-methyl-beta-amino acid derivatives.

Optically active anti-alpha-methyl-beta-amino acid derivatives have been prepared based on catalytic enantioselective addition of propionate units to simple and inert imines using a chiral zirconium complex. High reactivity and selectivity with wide substrate scope were attained by using a new chiral ligand, (R)-6,6'-bis(pentafluoroethyl)-1,1'-bi-2-naphthol ((R)-6,6'-C(2)F(5)BINOL). The reactions using geometrically isomeric ketene silyl acetals gave excellent anti-selectivity with high enantiomeric excess in both cases. Synthetic utility of this reaction has been demonstrated by the preparation of various anti-alpha-methyl-beta-amino acid and trans-3,4-disubstituted beta-lactam derivatives.

Amino Acids↗

PubMed1993

New NO-donors with antithrombotic activities and vasodilating activities, III: 3,4-disubstituted N-nitroso-5-sydnone imines.

38 title compounds have been synthesized. They bear a wide variety in substituents including alkyl-, aryl-, arylalkyl-, and styryl groups. The anti-platelet activities elucidated in the Born-test with collagen cover more than two orders of magnitude (IC50 = 0.3-45 mumol/L). These effects depend on the presence of the N-NO-group. This is shown by comparison with the corresponding sydnone imines, sydnone cyanimines, and sydnones. The most suitable substituents were phenylethyl, styryl, and hexyl at either position of the molecule. Seven compounds, most of them styryl derivatives, have IC50 values below 1 mumol/L. It is suggested that the differences in activity are connected with the ability of the compounds to bind to the platelet membrane.

Animals↗

PubMed1984

The in vitro trypanocidal activity of N-substituted p-benzoquinone imines: assessment of biochemical structure-activity relationships using the Hansch approach.

It has previously been found that naphthoquinones can potentiate the rate of hydrogen peroxide production by mitochondrial preparations of Trypanosoma brucei brucei and that organisms treated with naphthoquinones are more susceptible to lysis, especially in the presence of compounds such as heme, which promote the homolytic cleavage of hydrogen peroxide. We have evaluated the lytic effect of various N-substituted p-benzoquinone imines both in vitro and in vivo and have attempted to correlate their structure with trypanocidal activity using the Hansch approach. While none of the compounds tested proved to be active in vivo, all caused the lysis of trypanosomes in vitro. The parameters that correlated best with trypanocidal activity were the conditional redox potential, the lipophilicity of the substituent attached to the nitrogen atom and the number of active hydrogens on the quinonoid ring. These findings suggest two possible modes of action, which may in fact be related. Conjugate nucleophilic addition and/or oxidative damage could be responsible for lysis of the parasites. These same compounds were previously found to be active against the ascitic sarcoma 180 in mice. The strong correlation between antineoplastic activity in vivo and trypanocidal activity in vitro suggests a similar mode of action in both cases. Further studies aimed at developing a quinonelike compound that will be active against trypanosomes in vivo are now in progress.

Animals↗

PubMed2006

Characterization of the structure and reactivity of monocopper-oxygen complexes supported by beta-diketiminate and anilido-imine ligands.

Copper-oxygen complexes supported by beta-diketiminate and anilido-imine ligands have recently been reported (Aboelella et al., J Am Chem Soc 2004, 126, 16896; Reynolds et al., Inorg Chem 2005, 44, 6989) as potential biomimetic models for dopamine beta-monooxygenase (DbetaM) and peptidylglycine alpha-hydroxylating monooxygenase (PHM). However, in contrast to the enzymatic systems, these complexes fail to exhibit C--H hydroxylation activity (Reynolds et al., Chem Commun 2005, 2014). Quantum chemical characterization of the 1:1 Cu-O(2) model adducts and related species (Cu(III)-hydroperoxide, Cu(III)-oxo, and Cu(III)-hydroxide) indicates that the 1:1 Cu-O(2) adducts are unreactive toward substrates because of the weakness of the O--H bond that would be formed upon hydrogen-atom abstraction. This in turn is ascribed to the 1:1 adducts having both low reduction potentials and basicities. Cu(III)-oxo species on the other hand, determined to be intermediate between Cu(III)-oxo and Cu(II)-oxyl in character, are shown to be far more reactive toward substrates. Based on these results, design strategies for new DbetaM and PHM biomimetic ligands are proposed: new ligands should be made less electron rich so as to favor end-on dioxygen coordination in the 1:1 Cu-O(2) adducts. Comparison of the relative reactivities of the various copper-oxygen complexes as hydroxylating agents provides support for a Cu(II)-superoxide species as the intermediate responsible for substrate hydroxylation in DbetaM and PHM, and suggests that a Cu(III)-oxo intermediate would be competent in this process as well.

Binding Sites↗

PubMed1982

Phosphorus--nitrogen compounds XXIII: Oncolytic phosphorylated imines.

A series of 15 amidine, iminopiperidine, iso(thio)urea, and guanidine derivatives and six 2,5-dihydro-1,3,5,2-triazaphosphorines were synthesized. Most of the compounds were tested for ability to react with L-cysteine and for antitumor activity against sarcoma 180 and P-388 murine tumor systems. Three acyclic phosphorylated imines and one triazaphosphorine showed activity in the former model to indicate that the P(O)N = C grouping serves as an oncolytic moiety. All agents condensed with L-cysteine with the active antitumor compounds displaying a tendency for relatively higher reactivity with this amino acid.

Animals↗

PubMed2006

Poly(ether imide) membranes modified with poly(ethylene imine) as potential carriers for epidermal substitutes.

Poly(ether imide) (PEI) membranes were modified with a linear low-molecular weight (PETIM_0.6) and a branched high-molecular weight poly(ethylene imine) (PETIM_60). The membrane surfaces became more hydrophilic and the zeta potentials were shifted from negative to positive zeta values after immobilisation of both PETIM. These measurements also indicated the presence of a swollen surface layer in the case of PETIM_60, while a regular structuring of the surface was observed with scanning force microscopy for PETIM_0.6. A human keratinocyte cell line HaCaT was cultured on the different membranes. It was found that HaCaT cell growth was stimulated by PETIM_0.6. Cells reached earlier confluence on this substratum, while their growth was inhibited on a PEI membrane modified with PETIM_60, which makes PEI membranes modified with PETIM_0.6 a promising material for in vitro culture of epidermal transplants.

Adult↗

PubMed1998

Asymmetric imine-ene reactions: diastereofacial selective reactions with chiral glyoxylate-derived alpha-imino esters and asymmetric catalysis of enantiofacial selective reactions with prochiral alpha-imino esters.

The diastereofacial selective "imine-ene" reactions with alpha-imino esters, prepared from (-)-8-phenylmenthyl glyoxylate, are shown to provide an efficient entry to the asymmetric synthesis of alpha-amino acids. The feasibility study of the asymmetric catalysis is also reported on the enantiofacial selective ene reactions with prochiral alpha-imino esters.

Amino Acids↗

PubMed1990

Interactions between N-acetyl-p-benzoquinone imine and fluorescent calcium probes: implications for mechanistic toxicology.

Intracellular free calcium ([Ca2+]i) homeostasis has been implicated as an early target in both cellular necrosis and apoptosis. In this study, we have used peripheral blood mononuclear cells (PBMC) as target cells to investigate the effects of several reactive metabolites associated with drug toxicity on [Ca2+]i in order to delineate further early events in cytotoxicity. Compounds implicated in both drug-induced necrosis (N-acetyl-p-benzoquinone imine; NAPQI) and drug hypersensitivity (sulfamethoxazole hydroxylamine; SMX-HA) were examined and their effects on [Ca2+]i compared with those of the T cell mitogen phytohemagglutinin (PHA; 1.5 micrograms/ml) and the calcium ionophore ionomycin (2.5 microM). PHA and ionomycin produced characteristic elevations in [Ca2+]i as monitored by an increase in the fluorescence of fluo-3-loaded cells. SMX-HA did not significantly affect [Ca2+]i at concentrations previously shown to be cytotoxic to PBMC (100 and 500 microM), suggesting that Ca2+ homeostasis is not an early target for SMX-HA toxicity. Addition of NAPQI (250 microM) to fluo-3-loaded cells produced a marked decrease in fluorescence which was not reversed by ionomycin. Conversely, addition of NAPQI to cells loaded with indo-1 resulted in a rapid increase in fluorescence. This effect, however, was found to be attributable to NAPQI addition per se rather than to an increase in [Ca2+]i. HPLC and fluorescence analysis of samples generated from the decomposition of NAPQI revealed the presence of several products which fluoresced intensely at the excitation/emission wavelength pairs of a number of fluorescent probes commonly used to monitor [Ca2+]i.(ABSTRACT TRUNCATED AT 250 WORDS)

Aniline Compounds↗

PubMed1984

Cytotoxic effects of N-acetyl-p-benzoquinone imine, a common arylating intermediate of paracetamol and N-hydroxyparacetamol.

The cytotoxic effects of N-acetyl-p-benzoquinone imine (NAPQI), a postulated ultimate reactive metabolite of paracetamol (pHAA), was studied in suspensions of isolated rat hepatocytes. Incubation of cells for 10-300 min with 0.1-0.5 mM NAPQI led to concentration dependent cell damage, as determined by increased trypan blue exclusion, lactate dehydrogenase release and glutathione (GSH) depletion. NAPQI and N-hydroxyparacetamol (N-OH-pHAA), a postulated proximate metabolite of pHAA, caused cytotoxic effects in the same concentration range. In contrast, no toxic effects of pHAA (less than or equal to 20 mM) could be demonstrated. With the short half-life of NAPQI, less than 0.5% of the NAPQI added is expected to be left in the incubation medium after a 2 min incubated period. Nevertheless, 10-120 min (depending on the concentration of NAPQI) elapsed before the cells responded with increased membrane permeability. Clearly, the initial damage caused by NAPQI must be followed by subsequent cellular steps before toxicity becomes apparent. The addition of N-acetylcysteine, GSH or ascorbate during the NAPQI exposure period fully protected the hepatocytes from NAPQI damage. Lesser effects were demonstrated when these agents were added after the 5 min NAPQI exposure period. The results presented in this study further support the hypothesis that NAPQI is the ultimate reactive formed from pHAA.

Acetaminophen↗