N-alkylated oligoamide α-helical proteomimetics

Generic approaches for the design and synthesis of small molecule inhibitors of protein-protein interactions (PPIs) represent a key objective in modern chemical biology. Within this context, the α-helix mediated PPIs have received considerable attention as targets for inhibition using small molecules, foldamers and proteomimetics. This manuscript describes a novel N-alkylated aromatic oligoamide proteomimetic scaffold and its solid-phase synthesis - the first time such an approach has been used for proteomimetics. The utility of these scaffolds as proteomimetics is exemplified through the identification of potent μM inhibitors of the p53-hDM2 helix mediated PPI - a key oncogenic target.