COPPER-MEDIATED OXIDATIVE C-TERMINAL N-DEALKYLATION OF PEPTIDE-DERIVED LIGANDS - A POSSIBLE MODEL FOR ENZYMATIC GENERATION OF DESGLYCINE PEPTIDE AMIDES

A number of Cu(II) complexes of peptide derivatives that coordinate via N-deprotonation at the C-terminal amino acid residue have been characterized by titrimetry and the Cu(III)-Cu(II) electrochemical potentials. Reaction of these complexes with persulfate induces oxidative decarboxylation and hydrolysis of the resulting N-acyiimines to carboxamide and either HCHO, CH3CHO, or acetonedepending on the identity of the C-terminal residue (Gly, Ala, or Aib, respectively). For complexes with Cu(III)-Cu(II) potentials of +1.4 V vs NHE or lower, reaction with IrCl62- results in C-N dehydrogenation at the C-terminus, giving (after hydrolysis) carboxamide and either glyoxylic or pyruvic acid for C-terminal Gly or Ala. In the case of C-terminal Aib, Ir(IV) oxidation results in a very slow production of acetone. Complexes with Ep above +1.5 V do not react with IrCl62-, and sarcosine-terminal complexes, as well as those containing phenolate ligation, are inert to both persulfate and Ir(IV). The optimal complex studied here for investigating the mechanism of C-N dehydrogenation was picolinyl-Aib-Ala (Ep = +0.882 vs NHE), in which case the Ir(IV)-mediated cleavage to pyruvic acid and picolinyl-Aib-NH2 proceeds via a Cu(III) intermediate. The same transformation could be effected electrochemically. The C-terminal oxidative N-dealkylation reaction, induced by Cu(III), has not been previously observed and may be a relevant model for the copper enzyme peptidyl α-amidating monooxygenase, which is responsible for conversion of glycine-extended peptide prohormones to the biologically active peptide carboxamides. © 1990, American Chemical Society. All rights reserved.