71921-91-0Relevant academic research and scientific papers
N-methylcarbamoyl adducts at the N-terminal valine of globin in workers exposed to N,N-dimethylformamide
Angerer, Juergen,Goeen, Thomas,Kraemer, Axel,Kaefferlein, Heiko Udo
, p. 309 - 313 (1998)
N,N-dimethylformamide (DMF) is a commonly used industrial solvent. The formation of some metabolites of DMF in humans occurs via N-methylcarbamoylated species (e.g. N-methylcarbamoylated glutathione). The aim of our study was to investigate whether DMF lends to N-methylcarbamoylated adducts at the N-terminal valine of haemoglobin (Hb). Therefore, Hb adduct levels of ten DMF exposed workers and ten controls were analysed by a specific and sensitive detection method using capillary gas chromatography and a mass selective detector (GC/MS). Using this method we were able to show for the first time that Hb adducts are formed during the metabolism of DMF in humans. The general population, however, shows still unidentified background levels of this adduct which are on average lower by a factor of 50. The pathway for the formation of the investigated DMF-Hb adduct in workers exposed to DMF is still unknown. As identical adducts were also found after exposure to methylisocyanate (MIC), our work indicates the formation of MIC during the metabolism of DMF. The formation of Hb adducts with DMF and its relevance for occupational health is a subject of further research.
N-methylcarbamoylated valine of hemoglobin in humans after exposure to N,N-Dimethylformamide: Evidence for the formation of methyl isocyanate?
Kaefferlein,Angerer
, p. 833 - 840 (2001)
N,N-Dimethylformamide (DMF) is reported to cause testicular germ-cell tumors in exposed workers. The reports, however, are not in line with results obtained in animal and in vitro experiments, where DMF was shown not to be mutagenic and also not to be carcinogenic. Considerable interest raised on the formation of a reactive intermediate, presumably methyl isocyanate (MIC), during metabolism of DMF in humans over the last years. We report the formation of N-methylcarbamoylated valine of hemoglobin (Hb) in blood samples from workers exposed to DMF in the polyacrylic fiber industry. N-Methylcarbamoylated Hb was formed by the reaction of MIC with Hb. For this purpose, Hb adducts were monitored by means of a modified Edman degradation involving the release of the N-terminal valine adduct in form of 3-methyl-5-isopropylhydantoin (MIH). For internal standardization of the method, 3-ethyl-5-isopropylhydantoin (EIH) was used. Separation and analysis of MIH and EIH were carried out by gas chromatography and mass spectrometry with electron impact ionization (GC/EIMS). Hb adducts in form of MIH were quantified in blood samples from exposed persons in concentrations between 26.1 and 412.0 nmol of MIH/g of globin. The observed adducts were proven to be identical to those derived from the in situ reaction between Hb and MIC. Taken together with the fact that only N-methylcarbamoylated Hb can undergo ring closure to the corresponding hydantoin, the reaction is indirect evidence for the occurrence of MIC in vivo. The formation of MIC directly in the cell and its possible distribution through the human body may lead to critical effects after exposure to DMF. Adducts were determined not to be totally specific for exposure to DMF since an identical adduct was also found in blood samples from the general population. However, concentrations were lower by a factor of about 100. The sources for background adducts are currently unknown.
Pd-Catalysed oxidative carbonylation of α-amino amides to hydantoins under mild conditions
Botla, Vinayak,Carfagna, Carla,Della Ca, Nicola,Gabriele, Bartolo,Maestri, Giovanni,Mancuso, Raffaella,Montanari, Luca,Motti, Elena,Voronov, Aleksandr
, p. 294 - 297 (2022/01/06)
The first example of palladium-catalysed oxidative carbonylation of unprotected α-amino amides to hydantoins is described here. The selective synthesis of the target compounds was achieved under mild conditions (1 atm of CO), without ligands and bases. The catalytic system overrode the common reaction pathway that usually leads instead to the formation of symmetrical ureas.
3-(Triflyloxy)benzynes Enable the Regiocontrolled Cycloaddition of Cyclic Ureas to Synthesize 1,4-Benzodiazepine Derivatives
Kaneko, Hideki,Ikawa, Takashi,Yamamoto, Yuta,Arulmozhiraja, Sundaram,Tokiwa, Hiroaki,Akai, Shuji
, p. 943 - 948 (2018/02/26)
A versatile synthesis of 1,4-benzodiazepine derivatives through the reaction of various 3-(trifluoromethanesulfonyloxy)benzynes with N -(p -toluenesulfonyl)imidazolidin-2-ones is reported. This reaction system provides a 1,4-benzodiazepine bearing a trifluoromethanesulfonyloxy group as a single regioisomer among the four possible regioisomers.
NOVEL AMIDE DERIVATIVE AND USE THEREOF AS MEDICINE
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Paragraph 0786; 0787; 0788, (2013/03/26)
Provided are a novel low-molecular-weight compound that suppresses production of induction type MMPs, particularly MMP-9, rather than production of hemostatic type MMP-2, as well as a prophylactic/therapeutic drug for autoimmune diseases or osteoarthritis. An amide derivative represented by the following formula (I) wherein each symbol is as defined in the specification, or a pharmacologically acceptable salt thereof.
A new general pathway for synthesis of reference compounds of N-terminal valine-isocyanate adducts
Davies, Ronnie,Rydberg, Per,Westberg, Emelie,Motwani, Hitesh V.,Johnstone, Erik,Toernqvist, Margareta
experimental part, p. 540 - 546 (2011/02/24)
Adducts to Hb could be used as biomarkers to monitor exposure to isocyanates. Particularly useful is the measurement of carbamoylation of N-terminal valines in Hb, after detachment as hydantoins. The synthesis of references from the reactive isocyanates, especially diisocyanates, has been problematic due to side reactions and polymerization of the isocyanate starting material. A simpler, safer, and more general method for the synthesis of valine adducts of isocyanates has been developed using N-[(4-nitrophenyl)-carbamate] valine methylamide (NPCVMA) as the key precursor to adducts of various mono-and diisocyanates of interest. By reacting NPCVMA with a range of isocyanate-related amines, carbamoylated valines are formed without the use of the reactive isocyanates. The carbamoylated products synthesized here were cyclized with good yields of the formed hydantoins. The carbamoylated derivative from phenyl isocyanate also showed quantitative yield in a test with cyclization under the conditions used in blood. This new pathway for the preparation of N-carbamoylated model compounds overcomes the abovementioned problems in the synthesis and is a general and simplified approach, which could make such reference compounds of adducts to N-terminal valine from isocyanates accessible for biomonitoring purposes. The synthesized hydantoins corresponding to adducts from isocyanic acid, methyl isocyanate, phenyl isocyanate, and 2,6-toluene diisocyanate were characterized by LC-MS analysis. The background level of the hydantoin from isocyanic acid in human blood was analyzed with the LC-MS conditions developed.
Formation of N-Acylureas During the Peptide Coupling with the Use of Unsymmetrical Carbodiimides
Izdebski, J.,Pelka, J.,Orlowska, A.
, p. 523 - 528 (2007/10/02)
A study was concucted to determine the effect of alkyl groups of N,N'-dialkylcarbodiimides on the formation of N-acylureas during the peptide coupling.The use of carbodiimides of the structure Bu-t-N=C=N-R, where R=Me, Et and Pr-i, resulted in the formation of two isomeric N-acylureas.The proportion of the two compounds in the mixture was determined by 1H NMR spectroscopy and confirmed by chromatographic isolation.It was established that it is the least hindered O-acylurea nitrogen atom that attacks intramolecularly the amino acid activated by the unsymmetrical carbodiimide to form the major rearrangement product. Key words: carbodiimide, coupling reagent, peptide synthesis
