Benzophenone semicarbazone protection strategy for synthesis of aza-glycine containing aza-peptides.
Aza-glycine has been incorporated into peptide mimics as a tool for studying the active conformation and characterizing structure-function relationships for activity. Side reactions, such as intramolecular cyclizations to form hydantoins and oxadiazalones, have, however, inhibited efforts to make activated aza-Gly residues in solution using carbamate protection. Herein, we describe efficient incorporation of aza-glycine into aza-peptides using diphenyl hydrazone protection. Hydrazone acylation with p-nitrobenzyl chloroformate provided the protected aza-Gly activated ester, which was used to acylate a set of amino ester and amino acids to provide aza-Gly-Xaa aza-dipeptide fragments for peptide synthesis. Removal of the hydrazone protection was performed under acidic conditions to provide the hydrochloride salt of the aza-Gly residue for subsequent elongation of the aza-peptide chain using standard coupling conditions. A proof of concept for the use of benzophenone protection has been established by the synthesis of an aza-peptide analog of a potent activator of caspase 9 in cancer cells.
Bourguet
Carine B
CB
Département de Chimie, Université de Montréal, C.P.6128. Succursale Centre-Ville. Montréal, Québec, Canada H3C 3J7.
Sabatino
David
D
Lubell
William D
WD
D001372:Aza Compounds; D001577:Benzophenones; D004151:Dipeptides / Q000138:chemical synthesis; D005998:Glycine / Q000031:analogs & derivatives / Q000737:chemistry*; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D012663:Semicarbazides
D001372:Aza Compounds; D001577:Benzophenones; D004151:Dipeptides; D007202:Indicators and Reagents; D010455:Peptides; D012663:Semicarbazides; C010059:carbamylhydrazine; D005998:Glycine