title: Design, solid-phase synthesis, and evaluation of a phenyl-piperazine-triazine scaffold as α-helix mimetics.
abstract: α-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 α-helix-mediated PPIs. Due to the relatively low aqueous solubility and synthetic difficulty of most current α-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 α-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 α-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 α-helical peptides. We believe that our phenyl-piperazine-triazine-based α-helix mimetics, along with the facile and divergent solid-phase synthetic method, have great potential as powerful tools for discovering potent inhibitors of given α-helix-mediated PPIs.
authors.affiliation: Department of Chemistry, Pohang University of Science and Technology (POSTECH) , Pohang 790-784, South Korea.
authors.forename: Heejo
authors.initials: H
authors.lastname: Moon
authors.forename: Woo Sirl
authors.initials: WS
authors.lastname: Lee
authors.forename: Misook
authors.initials: M
authors.lastname: Oh
authors.forename: Huisun
authors.initials: H
authors.lastname: Lee
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Lee
authors.forename: Wonpil
authors.initials: W
authors.lastname: Im
authors.forename: Hyun-Suk
authors.initials: HS
authors.lastname: Lim
mesh_terms: D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry; D032701:Biomimetics; D005454:Fluorescence Polarization; D008958:Models, Molecular; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000737:chemistry; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry; D017433:Protein Structure, Secondary; D060327:Solid-Phase Synthesis Techniques / Q000379:methods; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D001565:Benzoates; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010879:Piperazines; D014227:Triazines
keywords: combinatorial library; protein−protein interaction inhibitor; solid-phase synthesis; α-helix mimetics