Benzimidazole-2-one: A novel anchoring principle for antagonizing p53-Mdm2

Wei Wang, Haiping Cao, Siglinde Wolf, Miguel S Camacho-Horvitz, Tad A Holak, Alexander Dömling*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

16 Citations (Scopus)

Abstract

Herein we propose the benzimidazole-2-one substructure as a suitable tryptophan mimic and thus a reasonable starting point for the design of p53 Mdm2 antagonists. We devise a short multicomponent reaction route to hitherto unknown 2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamides by reacting mono N-carbamate protected phenylenediamine in a Ugi-3CR followed by base induced cyclisation. Our preliminary synthesis and screening results are presented here. The finding of the benzimidazolone moiety as a tryptophan replacement in mdm2 is significant as it offers access to novel scaffolds with potentially higher selectivity and potency and improved biological activities. Observing low μM affinities to mdm2 by NMR and fluorescence polarization we conclude that the 2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamide scaffold might be a good starting point to further optimize the affinities to Mdm2.

Original languageEnglish
Pages (from-to)3982-3995
Number of pages14
JournalBioorganic & Medicinal Chemistry
Volume21
Issue number14
DOIs
Publication statusPublished - 15-Jul-2013

Keywords

  • Protein-protein interaction
  • ANCHOR
  • Tryptophan
  • Multicomponent reaction
  • Ugi
  • p53 mdm2
  • Selectivity
  • SUPPRESSOR TRANSACTIVATION DOMAIN
  • PROTEIN-PROTEIN INTERACTIONS
  • 3-COMPONENT REACTION
  • DRUG DISCOVERY
  • NMR
  • P53
  • INHIBITORS
  • MDM2
  • POTENT
  • DERIVATIVES

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