Design of indole- and MCR-based macrocycles as p53-MDM2 antagonists

Constantinos G Neochoritis, Maryam Kazemi Miraki, Eman M M Abdelraheem, Ewa Surmiak, Tryfon Zarganes-Tzitzikas, Beata Łabuzek, Tad A Holak, Alexander Dömling

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Abstract

Macrocycles were designed to antagonize the protein-protein interaction p53-MDM2 based on the three-finger pharmacophore F19W23L25. The synthesis was accomplished by a rapid, one-pot synthesis of indole-based macrocycles based on Ugi macrocyclization. The reaction of 12 different α,ω-amino acids and different indole-3-carboxaldehyde derivatives afforded a unique library of macrocycles otherwise difficult to access. Screening of the library for p53-MDM2 inhibition by fluorescence polarization and 1H,15N HSQC NMR measurements confirm MDM2 binding.

Original languageEnglish
Pages (from-to)513-520
Number of pages8
JournalBeilstein Journal of Organic Chemistry
Volume15
DOIs
Publication statusPublished - 20-Feb-2019

Keywords

  • MULTICOMPONENT REACTIONS
  • ARTIFICIAL MACROCYCLES
  • CONCISE SYNTHESIS
  • INHIBITORS
  • MDM2
  • DISCOVERY
  • DRUGS
  • BIND

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