Design, solid-phase synthesis, and evaluation of a phenyl-piperazine-triazine scaffold as α-helix mimetics

Heejo Moon, Woo Sirl Lee, Misook Oh, Huisun Lee, Ji Hoon Lee, Wonpil Im, Hyun Suk Lim

Research output: Contribution to journalArticle

17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)695-701
Number of pages7
JournalACS Combinatorial Science
Volume16
Issue number12
DOIs
StatePublished - Dec 8 2014

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Keywords

  • combinatorial library
  • protein-protein interaction inhibitor
  • solid-phase synthesis
  • α-helix mimetics

ASJC Scopus subject areas

  • Chemistry(all)
  • Medicine(all)

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