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

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.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0014-4594-8 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0014-4595-6
Genre: Journal Article

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 Creators:
Wang, Wei1, Author
Cao, Haiping1, Author
Wolf, Siglinde2, Author              
Camacho-Horvitz, Miguel S.1, Author
Holak, Tad2, Author              
Domling, Alexander1, Author
Affiliations:
1external, ou_persistent22              
2Holak, Tad / NMR Spectroscopy, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565154              

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Free keywords: 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;
 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.

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Language(s): eng - English
 Dates: 2013
 Publication Status: Published in print
 Pages: 14
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000320838200002
DOI: 10.1016/j.bmc.2012.06.020
 Degree: -

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Title: BIOORGANIC & MEDICINAL CHEMISTRY
Source Genre: Journal
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Publ. Info: THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND : PERGAMON-ELSEVIER SCIENCE LTD
Pages: - Volume / Issue: 21 (14) Sequence Number: - Start / End Page: 3982 - 3995 Identifier: ISSN: 0968-0896