非表示:
キーワード:
SUPPRESSOR TRANSACTIVATION DOMAIN; PROTEIN-PROTEIN INTERACTIONS;
3-COMPONENT REACTION; DRUG DISCOVERY; NMR; P53; INHIBITORS; MDM2;
POTENT; DERIVATIVESProtein-protein interaction; ANCHOR; Tryptophan; Multicomponent
reaction; Ugi; p53 mdm2; Selectivity;
要旨:
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-benzoidlimidazol-1-yl)acetamides by reacting mono N-carbamate protected phenylenediamine in a Ugi-3 CR 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 mu M 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. (C) 2012 Elsevier Ltd. All rights reserved.
