Design, Solid-Phase Synthesis, and Evaluation of a Phenyl-Piperazine-Triazine Scaffold as α-Helix Mimetics

alpha-Helices play a critical role in mediating many protein-protein interactions (PPIs) as recognition motifs. Therefore, there is a considerable interest in developing small molecules that can mimic helical peptide segments to modulate alpha-helix-mediated PPIs. Due to the relatively low aqueous solubility and synthetic difficulty of most current alpha-helix mimetic small molecules, one important goal in this area is to develop small molecules with favorable physicochemical properties and ease of synthesis. Here we designed phenyl-piperazine-triazine-based alpha-helix mimetics that possess improved water solubility and excellent synthetic accessibility. We developed a facile solid-phase synthetic route that allows for rapid creation of a large, diverse combinatorial library of alpha-helix mimetics. Further, we identified a selective inhibitor of the Mcl-1/BH3 interaction by screening a focused library of phenyl-piperazine-triazines, demonstrating that the scaffold is able to serve as functional mimetics of alpha-helical peptides. We believe that our phenyl-piperazine-triazine-based alpha-helix mimetics, along with the facile and divergent solid-phase synthetic method, have great potential as powerful tools for discovering potent inhibitors of given alpha-helix-mediated PPIs.