Synthesis and Application of Functionalized Bis-Peptides Through Hindered Amide Bond Formation

摘要

This work presents significant advances towards installing chemical functionality within bis-peptide scaffolds, an important milestone towards designer, functional macromolecules for our group. First was the discovery of acyl-transfer coupling, a new synthetic route to assemble extremely hindered peptide bonds which were not previously accessible through conventional means. A novel amino-anhydride intermediate and five-membered ring acyl-transfer mechanism is postulated and multiple supporting pieces of evidence are presented. Applying this chemistry to the bis-amino acid building blocks developed in our group, the first functionalized bis-peptides were created which are oligomeric, diketopiperazine-based peptidomimetics. The first application for this new class of macromolecules was to mimic the bound conformation of the p53 ƒÑ-helical domain to its binding partner hDM2. Further structure and function optimization and characterization of the compound¡¦s biological effects showed these bis-peptides to be potent inhibitors of this protein-protein interaction, be cell-permeable and elicit a surprising biological response with human liver cancer cells.