Aromatic Oligoamide Foldamers with a "Wet Edge" as Inhibitors of the α-Helix-Mediated p53-hDM2 Protein-Protein Interaction

This paper describes the design, synthesis and structural analysis of a 3‐O‐alkylated aromatic oligoamide that incorporates an additional hydrophilic 6‐O‐alkyl substituent in the central monomer. This oligomer exhibits low μM inhibitory potency against the p53–hDM2 interaction compared with its unfunctionalised counterpart and significantly improved solubility. A 3‐O‐alkylated aromatic oligoamide foldamer incorporating an additional and hydrophilic 6‐O‐alkyl substituent in the central monomer is shown to have improved solubility, adopt an active binding conformation and disrupt the p53–hDM2 interaction.