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

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http://pubman.mpdl.mpg.de/cone/persons/resource/persons78902

Wolf,  Siglinde
Holak, Tad / NMR Spectroscopy, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons78123

Holak,  Tad
Holak, Tad / NMR Spectroscopy, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Wang, W., Cao, H., Wolf, S., Camacho-Horvitz, M. S., Holak, T., & Domling, A. (2013). Benzimidazole-2-one: A novel anchoring principle for antagonizing p53-Mdm2. BIOORGANIC & MEDICINAL CHEMISTRY, 21(14), 3982-3995. doi:10.1016/j.bmc.2012.06.020.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0014-4594-8
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-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.