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At least 235 records · Page 13Linked to original sources
PubMed1999

Specific IgG response to monomeric and polymeric diphenylmethane diisocyanate conjugates in subjects with respiratory reactions to isocyanates.

BACKGROUND: Isocyanates are a frequent cause of occupational asthma and can also induce hypersensitivity pneumonitis. OBJECTIVES: It is still unclear whether antibodies to diphenylmethane diisocyanate (MDI), which are elicited in some subjects with these conditions, are specific for this type of isocyanate. Moreover, preparation of conjugates to human serum albumin (HSA) with the polymeric formulation rather than monomeric MDI might result in improved detection of antibodies. METHODS: We addressed these issues by testing the sera of 13 subjects with asthma (n = 12) and hypersensitivity pneumonitis (n = 1) induced by MDI (n = 4 or 5, see below) by comparing them with sera obtained from subjects with occupational asthma caused by toluene diisocyanate (TDI; n = 5) and hexamethylene diisocyanate (HDI; n = 2). Conjugate preparations were compared by using SDS-PAGE, absorbance spectral analysis, and isolectric focusing. Immunologic screening was done by ELISA. RESULTS: Specific IgG antibodies that recognize MDI-HSA conjugates were detected in all but 1 of the MDI-exposed workers and could not be found in TDI-exposed and HDI-exposed workers. The levels of specific IgG antibodies were more elevated when tested against the HSA conjugates formed with polymeric MDI compared with the HSA conjugates formed with monomeric MDI. CONCLUSION: This study shows that specific IgG antibodies to MDI appear to be specific for MDI without cross-reactivity with TDI and HDI and higher by use of polymeric rather than monomeric MDI-HSA test antigens.

Adult↗
PubMedDate not supplied

Use of hexyl isocyanate antigen to detect antibodies to hexamethylene diisocyanate (HDI) in sensitized guinea pigs and in a sensitized worker.

Hypersensitivity to hexamethylene diisocyanate (HDI) has been reported following occupational exposure. Diagnosis of sensitivity is usually made from clinical evaluation of symptomatology. An in vitro serologic assay for HDI sensitivity was developed by immunizing guinea pigs with HDI and with hexyl isocyanate (HMI). Animals injected intradermally with HMI produced hapten-specific antibodies whereas guinea pigs injected with HDI produced antibodies specific for larger determinants which included the HDI hapten. The larger determinants were assumed to be composed of portions of "self" molecules which reacted in vivo with HDI. Serum albumin appeared to be one such molecule. No cross reactions were noted between antibodies to HDI and another widely used industrial isocyanate, toluene diisocyanate (TDI). Antigens effective in detecting antibodies to HDI or HMI were tested for ability to detect reaginic antibodies in a worker with clinical "HDI" asthma. Using a radioimmunoassay (RAST), antibodies reacted with conjugates containing either HDI or HMI as haptens. In addition, the prevalance of HDI polyisocyanates (Desmodur N) in spray paints prompted its use as a hapten. Antibodies reacted with Desmodur N antigen conjugates in RAST. RAST inhibition further indicated that Desmodur N antigen reacted more readily with the patient's antibodies than did HDI or HMI antigens. These results suggest that the patient may have been exposed to HDI polyisocyanates in spray paint application. Use of Rast inhibition for diagnosis of sensitivity may indicate the precise sensitizing agent within a mixture.

Animals↗
PubMed2002

Two rotors potential scans and vibrational assignments for dihalomethylsulfonyl isocyanates.

The conformational behavior and structural stability of dichloro and difluoromethyl-sulfonyl isocyanates were investigated by quantum mechanical DFT and ab initio calculations. The 6-311 + + G** basis set was employed to include polarization and diffuse functions in the calculation at B3LYP and MP2 levels. The molecules were found to exist in a mixture of trans-gauche and gauche-gauche conformations at ambient temperatures. From the calculations the isocyanate NCO moiety was predicted to nearly eclipse one of the sulfony S=O bonds in the two stable conformers of both molecules. The potential scans for the rotations of the two NCO and CX2H rotors were calculated from which the rotational barriers could be estimated. The vibrational frequencies, potential energy distributions, IR intensities as well as depolarization ratios were calculated.

Isocyanates↗
PubMed2002

4-Nitro-7-piperazino-2,1,3-benzoxadiazole as a reagent for monitoring of airborne isocyanates by liquid chromatography.

4-Nitro-7-piperazino-2,1,3-benzoxadiazole (NBDPZ) is presented as a new reagent for the determination of mono- and diisocyanates in air samples. NBDPZ readily reacts with the airborne analytes, thus yielding the corresponding urea derivatives, which are subsequently separated by means of reversed-phase liquid chromatography. On a phenyl-modified stationary phase, excellent baseline separation for numerous mono- and diisocyanate derivatives is obtained. Both diode array and fluorescence detection are performed with limits of detection of 11-35 and 5-9 nmol/L for the individual derivatives, respectively. In contrast to established derivatizing agents for the analysis of isocyanates, NBDPZ provides for increased selectivity due to the favorable detection wavelengths in the visible range (UV/visible, absorption maximums approximately 480 nm; fluorescence, excitation maximums approximately 470 nm, emission maximums approximately 535 nm). In addition, the high molar absorptivities of the reagent and the derivatives provide excellent sensitivity that is superior to most literature-known methods. Finally, air sampling methods comprising both the use of impingers and test tubes are developed and successfully applied to the determination of isocyanates in gaseous samples. Excellent recovery reaching values of >90% is observed for each of the two techniques investigated.

Air Pollutants↗
PubMedDate not supplied

Solid-phase synthesis of oxazolidinones by cycloaddition of resin-bound epoxides with isocyanates.

The first solid-phase synthesis of oxazolidinones by cycloaddition of resin-bound epoxides with isocyanates is described. Synthesis of the title compounds was achieved by alkylation of resin-bound carbamates with glycidyl tosylate, followed by cycloaddition of the resulting epoxides with isocyanates at elevated temperature in high yields and purity. Because N-aryloxazolidinones have been known to possess various biological activities, this method is useful from the viewpoint of drug discovery.

Epoxy Compounds↗
PubMed2006

Enantioselective rhodium-catalyzed [2+2+2] cycloaddition of alkenyl isocyanates and terminal alkynes: application to the total synthesis of (+)-lasubine II.

The use of TADDOL-based phosphoramidite ligands on rhodium allows for the incorporation of terminal alkynes in the [2+2+2] cycloaddition with alkenyl isocyanates. Terminal aliphatic alkynes provide bicyclic lactams, while the use of aryl alkynes provides complementary access to vinylogous amides. Product selectivity seems to be governed by a combination of electronics and sterics, with smaller and/or more electron-deficient substituents favoring lactam formation. The use of homologous alkenyl isocyanates leads to an expedient asymmetric total synthesis of the alkaloid lasubine II.

Alkenes↗
PubMed2000

Reactions of 2-amino-2-thiazolines with isocyanates and isothiocyanates. Chemical and computational studies on the regioselectivity, adduct rearrangement, and mechanistic pathways.

2-Amino-2-thiazoline derivatives bearing alkyl or aryl substituents at exocyclic nitrogen have been condensed with different isocyanates and isothiocyanates. The addition occurs at ring endocyclic nitrogen in a regiospecific manner to afford kinetic and enthalpy-favored adducts. The unequivocal assignment of these structures has been confirmed by X-ray diffraction analyses of several compounds. The endo adducts do not rearrange on heating with the sole exception of adducts in which the exocyclic nitrogen remains unsubstituted. Trapping experiments in the presence of other isocyanates or isothiocyanates produce the formation of new endo adducts by acyl exchange in the reaction mixture. Semiempirical PM3 calculations full corroborate the higher stability of endo or exo adducts depending on the substitution pattern. The formation of adducts is compatible with a stepwise reaction mechanism, for which semiempirical transition structures could be located in the potential energy surface, and the global energetics of the process have been determined. The formation of the endo adducts proceeds with a smaller activation barrier.

Crystallography, X-Ray↗
PubMed2005

Ultrathin coatings from isocyanate terminated star PEG prepolymers: patterning of proteins on the layers.

This study presents the easy and fast patterning of low molecular weight molecules that act as binding partners for proteins on Star PEG coatings. These coatings are prepared from isocyanate terminated star shaped prepolymers and form a highly cross-linked network on the substrate in which the stars are connected via urea groups and free amino groups are present. Streptavidin has been patterned on these layers by microcontact printing (muCP) of an amino reactive biotin derivative and consecutive binding of streptavidin to the biotin. Patterns of Ni(2+)-nitriltriacetic acid (NTA) receptors have been prepared by printing amino functional NTA molecules in freshly prepared Star PEG layers that still contain amino reactive isocyanate groups. Complexation of the NTA groups with Ni(II) ions enabled the binding of His-tag enhanced green fluorescent protein (EGFP) in the desired pattern on the substrates. Since the unmodified Star PEG layers prevent unspecific protein adsorption, His-EGFP could selectively be bound to the sample by immersion into crude, nonpurified His-tag EGFP containing cell lysate.

Biotin↗
PubMedDate not supplied

Carbamoylation of peptides and proteins in vitro by S-(N-methylcarbamoyl)glutathione and S-(N-methylcarbamoyl)cysteine, two electrophilic S-linked conjugates of methyl isocyanate.

The reactivity toward peptides and proteins of S-(N-methylcarbamoyl)glutathione (SMG), the glutathione conjugate of methyl isocyanate, and the corresponding cysteine adduct, S-(N-methylcarbamoyl)cysteine (SMC), was investigated with the aid of in vitro model systems. Incubation of SMC or a trideuteriomethyl analogue of SMC with either the reduced or oxidized forms of oxytocin afforded similar mixtures of mono-, bis- and tris-N-methylcarbamoylated peptides. Structure elucidation of the mono and bis adducts by fast atom bombardment tandem mass spectrometry indicated that carbamoylation of oxytocin occurred preferentially at Cys-6 and that Cys-1 and/or Tyr-2 were secondary sites of modification. Upon incubation of S-[N-([14C]methyl)carbamoyl]glutathione (14C-SMG) with native bovine serum albumin (BSA), radioactivity became bound covalently to the protein in a time- and concentration-dependent fashion. "Blocking" of the lone Cys-34 thiol group of BSA in the form of a disulfide prior to exposure of the protein to 14C-SMG failed to decrease significantly the extent or time course of this covalent binding. It is concluded that carbamate thioester conjugates of MIC are reactive, carbamoylating entities which can donate the elements of MIC to nucleophilic functionalities on peptides and proteins. Free thiols appear to be preferred sites for such carbamoylation processes, a phenomenon that may have important toxicological consequences in the pathology of tissue lesions induced by MIC and related isocyanates.

Cyanates↗
PubMedDate not supplied

Oxidative conversion by rat liver microsomes of 2-naphthyl isothiocyanate to 2-naphthyl isocyanate, a genotoxicant.

The present study investigated the oxidative metabolism of 2-naphthyl isothiocyanate catalyzed by rat liver microsomes. Incubation of 2-naphthyl isothiocyanate, microsomes, and NADPH yielded either N,N'-di-2-naphthylurea or, on inclusion of 2-aminofluorene in the incubations, N-2-naphthyl-N'-2-fluorenylurea. These ureas were formed by the production of 2-naphthyl isocyanate, which reacted with its hydrolysis product, 2-aminonaphthalene, to yield the symmetrical urea or, with 2-aminofluorene, to form the mixed urea. Formation of N,N'-di-2-naphthylthiourea was also observed, since 2-aminonaphthalene reacted with the substrate. Urea formation was dependent on microsomes, NADPH, and O2. Use of microsomes from rats previously treated with Aroclor increased urea formation > or = 10-fold. The enzyme activity was inhibited by alpha-naphthoflavone, flavone, or CO and slightly inhibited by metyrapone, 7-ethoxycoumarin, or SKF-525A. It was not inhibited by methimazole or paraoxon. These data are consistent with a cytochrome P-450-dependent, oxidative desulfuration of the isothiocyanate to yield an isocyanate.

1-Naphthylisothiocyanate↗
PubMedDate not supplied

Studies on the metabolic fate of caracemide, an experimental antitumor agent, in the rat. Evidence for the release of methyl isocyanate in vivo.

Following administration to rats of a single ip dose (6.6 mg kg-1) of the investigational antitumor agent caracemide (N-acetyl-N,O-bis[methylcarbamoyl]hydroxylamine), the mercapturic acid derivative N-acetyl-S-(N-methylcarbamoyl)cysteine (AMCC) was identified in urine by thermospray LC-MS. Quantification of this conjugate was carried out by stable isotope dilution thermospray LC-MS, which indicated that the fraction of the caracemide dose recovered as AMCC in 24-h urine collections was 54.0 +/- 5.5% (n = 4). Since AMCC is known to represent a major urinary metabolite of methyl isocyanate (MIC) in the rat, the results of this study support the contention that caracemide yields MIC as a toxic intermediate in vivo. Furthermore, with the aid of a specifically deuterium-labeled analog of caracemide ([carbamoyloxy-C2H3]caracemide), it was shown that the methylcarbamoyl group of AMCC derived from both the O-methylcarbamoyl (72%) and N-methylcarbamoyl (28%) side chains of the drug. In view of these findings, it is concluded that caracemide acts as a latent form of MIC in vivo and that this reactive isocyanate (or labile S-linked conjugates thereof) may contribute to the antitumor properties and/or adverse side-effects of caracemide.

Acetylcysteine↗
PubMed2002

Glutathione-dependent metabolism of the antitumor agent sulofenur. Evidence for the formation of p-chlorophenyl isocyanate as a reactive intermediate.

The antitumor agent sulofenur (LY186641), which has shown promising activity against a wide range of cancers, causes hemolytic anemia and methemoglobinemia at dose-limiting toxicities. The antitumor and toxicological mechanism(s) of action of the drug is (are) not well understood, but unlike other antineoplastic agents, sulofenur does not interfere with DNA, RNA, or protein synthesis, or with polynucleotide function. In the present study, we evaluated the hypothesis that sulofenur undergoes bioactivation in vivo to generate p-chlorophenyl isocyanate (CPIC), which could carbamoylate biological macromolecules directly or form a conjugate with glutathione (GSH) which would serve as a latent form of CPIC. The objectives of this study, therefore, were to determine if the GSH and N-acetylcysteine conjugates of CPIC were excreted into bile and urine, respectively, after an i.p. dose of sulofenur to rats. In addition, the chemical stability and thiol exchange properties of these S-linked conjugates were determined. The results of this study indicate that sulofenur does undergo metabolism in vivo to yield the GSH conjugate of CPIC, and that this conjugation reaction is reversible and subject to thiol exchange in buffered aqueous solution (pH 7.4, 37 degrees C). In contrast, sulofenur itself was stable under these same conditions, even in the presence of GSH and glutathione-S-transferase (GST), thus raising the possibility that bioactivation of sulofenur is necessary for liberation of CPIC. These findings suggest that the generation of this isocyanate in vivo and subsequent carbamoylation of biological macromolecules may play a role in the toxicity and/or antitumor activity of sulofenur and related diarylsulfonylureas.

Animals↗
PubMedDate not supplied

Enzyme induction and comparative oxidative desulfuration of isothiocyanates to isocyanates.

Enzyme induction of oxidative metabolism of isothiocyanates to isocyanates by rat liver microsomes and comparative metabolic conversion of some isothiocyanates were investigated. Metabolic activity was assayed by trapping the isocyanate metabolites from isothiocyanates with the inclusion of 2-aminofluorene to form the respective mixed ureas as previously described for the 2-naphthyl isothiocyanate. Male F344 rats were fed either a conventional grain diet for induction with Aroclor 1254 or AIN 76A diet without antioxidant beginning 2 weeks before treatment with Aroclor 1254, beta-naphthoflavone, isosafrole, or phenobarbital. Enzymes responsible for the metabolism of 1- and 2-naphthyl isothiocyanate were inducible by all four agents, Aroclor being the best under the current induction protocol and metabolic conversion assay procedure. On the other hand, enzymes responsible for the metabolism of benzyl isothiocyanate were induced only by Aroclor and, to a lesser extent, by phenobarbital. For the comparative metabolic conversion studies, using the microsomes from Aroclor-treated rats fed a conventional grain diet, the rates of metabolic conversion followed the order of 1-naphthyl > > phenyl > benzyl and phenethyl > > propyl, ethyl, and methyl isothiocyanates.

Animals↗
PubMed1999

Determination of hexamethylene diisocyanate-based isocyanates in spray-painting operations. Part 2. Comparison of high performance liquid chromatography with capillary zone electrophoresis.

A capillary zone electrophoresis (CZE) approach was developed for the determination of hexamethylene diisocyanate (HDI) monomer and HDI-based oligomers. A comparison of CZE with high performance liquid chromatography (HPLC) indicates that the CZE separation completely isolates isocyanates from excess solvent, derivatizing reagent and pigment while offering a fivefold increase in sensitivity. The CZE approach allows for the quantification of HDI monomer and oligomer within a 1 min time window under the run conditions selected. For the determination of HDI-based oligomer, provided that the relative response with respect to HDI monomer is calculated, there is no significant difference (p < 0.05, n = 10) in the isocyanate air concentration when using either HPLC or CZE. The results are significant because they indicate that CZE has advantages for the determination of both HDI-based oligomer and HDI monomer generated during spray-painting operations.

Air Pollutants, Occupational↗
PubMed2000

Determination of airborne methyl isocyanate as dibutylamine or 1-(2-methoxyphenyl)piperazine derivatives by liquid and gas chromatography.

The usefulness of a glass fibre filter method to collect airborne methyl isocyanate (MIC) was studied in laboratory experiments and in a workplace during manufacture of mineral wool insulation material. Filter collection was based on derivatisation in situ with 1-(2-methoxyphenyl)piperazine (2MP). 2MP impinger sampling was also evaluated in the workplace. Impinger sampling with dibutylamine (DBA) was used as an independent method. The samples were analysed by liquid and gas chromatography using various detection techniques: mass spectrometry, ultraviolet and electrochemical detection (LC-MS, LC-UV, LC-EchD and GC-MS). The sampling efficiency of 2MP filters for MIC varied with the origin of the glass fibre filter. Two Whatman filters (diameter 25 mm) with altogether 21 mumol of 2MP collected 100% of 9.8 micrograms of MIC during 30 min at an airflow rate of 1 l min-1. The workplace measurements were performed at two concentration levels, 0.003 and 0.09 mg m-3. The theoretical amounts of derivatisation reagent were 42 mumol (2MP filter), 52 mumol (2MP impinger) and 100 mumol (DBA). MIC concentrations were 20% lower by the 2MP methods compared with the DBA method (statistically significant difference). Breakthrough was 6% for the DBA method and 9% for the 2MP impinger method. To trap both MIC and isocyanic acid, which was also present in the workplace samples, a tenfold molar amount of 2MP reagent was used. The precision of sample preparation, expressed as relative standard deviation, was 3.5% (0.17 microgram ml-1, n = 6). The precision of sampling in the workplace was 15% (0.002 mg m-3, n = 6). The limit of quantification was 0.0006 mg m-3 for 30 l of air by the 2MP impinger method and 0.03-0.05 mg m-3 by the 2MP filter method. Hence, airborne MIC can be determined using 2MP as derivatisation reagent. Impinger sampling is preferable when low concentration levels are expected.

Air Pollutants, Occupational↗
PubMed2002

Development of a diffusive sampling method for determination of methyl isocyanate in air.

A diffusive sampling method for determination of methyl isocyanate in air has been developed. A glass fibre filter impregnated with 1-(2-methoxyphenyl)piperazine in a commercially available diffusive sampling device was used to collect methyl isocyanate and the derivative formed was analysed with LC-MS/MS. The sampling rate was determined to be 15.6 ml min(-1), with a relative standard deviation of 7.3%. The sampler was validated for sampling periods from 15 min to 8 h, for relative humidities from 20% to 80% and for concentrations from I to 46 microg m(-3). A field validation was also made and the diffusive sampling results showed no difference compared to a pumped reference method. The impregnated filters have to be stored apart from the diffusive sampler housing and loaded into the sampler prior to each sampling.

Air Pollution, Indoor↗
PubMed2004

An exploratory study of ring closures of aryl radicals onto cyclopropyl- and oxiranyl-isocyanate acceptors.

The idea that ring closures of C-centred radicals onto isocyanates could be made permanent by designing the cyclised radical to undergo a rapid onward beta-scission, was investigated for the 2-(2-isocyanato)cyclopropylphenyl and 2-(2-isocyanato)oxiranylphenyl radicals. The radical precursors, trans- and cis-1-bromo-(2-isocyanatocyclopropyl)benzene and (2-bromophenyl)-3-isocyanatooxirane, were prepared from the corresponding bromophenylcyclopropane and bromophenyloxirane carboxylic acids via Curtius rearrangements of the derived azides. The structure of the trans-2-(2-isocyanato)cyclopropylphenyl radical prevents cyclization, however, it was shown that isomerisation to the analogous cis-radical occurred, probably by scission of the disubstituted cyclopropane bond followed by internal rotation of the resulting resonance stabilised diradical. It was found, however, that the main product from homolytic reactions of both trans- and cis-isocyanatocyclopropyl compounds, with tributyltin hydride and tris(trimethylsilyl)silane, was the direct reduction product, trans-(2-isocyanatocyclopropyl)benzene. Only traces of cyclised products, that were probably 4,5-dihydrobenzo[c]azepin-1-one from the cyclopropane precursor and 5H-6-oxa-8-azabenzocyclohepten-9-one from the oxirane precursor, were detected. We conclude, therefore, that the rate of cyclization onto isocyanate acceptor groups must be slower in these systems than hex-5-enyl cyclization or that the reverse ring-opening process must be faster than for analogous radicals.

Cyclization↗