6 research outputs found
Synthetic Approaches To Obtain Amino Acid Adducts of 4,4′-Methylenediphenyl Diisocyanate
4,4′-Methylenediphenyl
diisocyanate (MDI) is the most important
isocyanate used in the chemical industry. Lung sensitization and asthma
are the main types of damage after exposure to MDI. Albumin adducts
of MDI might be involved in the etiology of sensitization reactions.
It is therefore necessary to have sensitive and specific biomarkers
such as blood protein adducts to monitor people exposed to isocyanates.
For the discovery of new isocyanate adducts with blood proteins present
in vivo, new synthetic standards are needed. To achieve this, we developed
five methods to obtain amino acid adducts of MDI. We synthesized and
isolated MDI adducts of aspartic acid, glutamic acid, cysteine, and
valine. The new adducts were characterized by LC-MS/MS and NMR. We
synthesized the corresponding isotope-labeled MDI adducts to develop
analytical methods using LC-MS/MS. Glutathione adducts of isocyanates
are an important way of transportation of the reactive isocyanates
to distant sites from the original site of exposure. Therefore, we
used <i>N</i>-acetyl-cysteine adducts of MDI as reactants: <i>N</i>-acetyl-<i>S</i>-[[4-(4-aminobenzyl)Âphenyl]Âcarbamoyl]-cysteine
(MDI-AcCys) and <i>N</i>-acetyl-<i>S</i>-[[4-(4-acetylaminobenzyl)Âphenyl]Âcarbamoyl]-cysteine
(AcMDI-AcCys). MDI-AcCys or AcMDI-AcCys formed adducts with albumin, <i>N</i><sub>α</sub>-acetyl lysine, and valine. Isotope-labeled
albumin adducts (= <i>d</i><sub>4</sub>-MDI-albumin) were
synthesized from <i>d</i><sub>4</sub>-MDI-AcCys and albumin. <i>d</i><sub>4</sub>-MDI-albumin can be used as an internal standard
to analyze biological samples. Such an internal standard will not
correct only for the extraction recovery of the adducts but also for
the potential variation of the enzymatic digestions used in the procedure
to analyze albumin adducts of MDI. The synthetic procedures described
in this manuscript will be applicable to the synthesis of amino acid
adducts from other isocyanates