Department of Materials and Environmental Chemistry , Stockholm University, SE-106 91 Stockholm, Sweden.
Chem Res Toxicol. 2010 Mar 15;23(3):540-6. doi: 10.1021/tx900278p.
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 above-mentioned 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.
血红蛋白加合物可用作监测异氰酸酯暴露的生物标志物。特别有用的是测量 Hb 中 N-末端缬氨酸的氨基甲酰化，方法是将其作为海因衍生物分离。由于副反应和异氰酸酯起始原料的聚合，从反应性异氰酸酯（特别是二异氰酸酯）合成参考物质一直存在问题。已经开发出一种更简单、更安全、更通用的方法，使用 N-[(4-硝基苯基)氨基甲酸酯]缬氨酸甲酯酰胺（NPCVMA）作为关键前体，合成各种单异氰酸酯和二异氰酸酯的缬氨酸加合物。通过使 NPCVMA 与一系列与异氰酸酯相关的胺反应，无需使用反应性异氰酸酯即可形成氨基甲酰化缬氨酸。在这里合成的氨基甲酰化产物与形成的海因以良好的收率环化。在血液中使用的条件下进行环化测试时，来自苯基异氰酸酯的氨基甲酰化衍生物也显示出定量收率。这种用于制备 N-氨基甲酰化模型化合物的新途径克服了上述合成问题，是一种通用且简化的方法，可使异氰酸酯与 N-末端缬氨酸加合物的参考化合物能够用于生物监测目的。用开发的 LC-MS 条件分析了与异氰酸、甲基异氰酸酯、苯基异氰酸酯和 2,6-甲苯二异氰酸酯加合物相对应的海因的背景水平。
