Peptide-heterocycle chimera: New classes of more drug-like peptidomimetics by ligations of peptide-bis(electrophiles) with various bis(nucleophiles)

Abstract

Several C-terminal peptidyl-substituted bis- and tris(electrophiles) were prepared by starting from polymeric phosphoranylidenacetates as acyl anion equivalents. After C-acylations with amino acids and peptide elongation, the obtained peptidyl-phosphoranylideneacetate resins were either cleaved oxidatively, delivering peptidyl-diketo esters, or saponified, leading to immediate decarboxylation. The generated peptidyl-phosphorane could be treated with aldehydes to yield peptidyl vinyl ketones or could be cleaved oxidatively to yield peptidyl keto aldehydes. Ligation with various bis(nucleophiles) including hydrazines, hydroxylamine, diamines, amino-thiols, amidines, and guanidines were investigated in the formation of peptide-heterocycle chimera containing pyrazoline, pyrazole, isoxazole, isoxazoline, thiazepine, quinoxaline, and imidazolone heterocycles. Various peptidyl-substituted bis(electrophiles) were generated through C-acylations of polymer-supported phosphorus ylides with standard Fmoc-amino acid building blocks. The peptidyl-bis(electrophiles) were further converted into novel combinations of drug-like heterocycles with peptides by a set of ligation reactions with bis(nucleophiles). © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.