Alkylation of histidine with maleimido-compounds

Abstract

Introduction of the maleimide function via a spacer into histidine-containing peptides was found to produce ring closure by nucleophilic addition of the Nim-imino function of the histidine side-chain to the activated double bond of the maleimide. As an intramolecular cyclization reaction it proceeds at remarkably higher rates than the bimolecular alkylation of histidine derivatives with N-ethyl-maleimide. Correspondingly, in the case of the histidine-peptides examined only mixtures of the cyclic isomeric compounds were isolated and structurally characterized by 1H-NMR analysis. As expected, prevention of this reaction in histidine-containing maleoyl-peptides can be achieved by Nim-protection of the imidazole group. However, upon removal of this protection, the reaction takes place again, thus remarkably hampering the usefulness of the maleimide/thiol addition principle in conjugate chemistry for peptides. On the other hand this reaction could represent an interesting new approach for the design of cyclic peptidomimetic analogs.