in vitro reactivity of the antineoplastic drug carmustin and acrolein with model peptides

The in vitro interaction of the antineoplastic drug 1, 3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) and acrolein with model peptides has been investigated in order to provide a detailed description of their electrophilic reactivity towards biological macromolecules. Following incubation with these substances, the modified species were separated by HPLC and identified by fast atom bombardment mass spectrometry, whereas the reactive amino acids within the peptide structure were assigned by tandem mass spectrometry. Incubation with BCNU led essentially to the formation of an N-terminal carbamoyl derivative that slowly decomposed to form three isomeric structures and a very minor ethylated adduct. Alkylation with acrolein gave rise to a mixture of different adducts due to the reaction of both the double bond and the carbonyl group. Two species containing intramolecular cross-links were also observed. These results constitute the prerequisite for in vitro and in vivo studies on the modification of haemoglobin in patients following treatment with antineoplastic drugs. © Munksgaard 1997.