Alkylation of histidine with maleimido-compounds.
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.
Papini
A
A
Max-Planck-Institute for Biochemistry, Martinsried, Federal Republic of Germany.
Rudolph
S
S
Siglmüller
G
G
Musiol
H J
HJ
Göhring
W
W
Moroder
L
L
D000478:Alkylation; D000595:Amino Acid Sequence; D005033:Ethylmaleimide / Q000737:chemistry; D006639:Histidine / Q000737:chemistry*; D007093:Imidazoles / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008301:Maleimides / Q000737:chemistry*; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000737:chemistry
D007093:Imidazoles; D008301:Maleimides; D010456:Peptides, Cyclic; D006639:Histidine; C029899:imidazole; D005033:Ethylmaleimide