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

被引：19

作者：

Wang, Wei ^{[1
,2
,3
]}

Cao, Haiping ^{[1
]}

Wolf, Siglinde ^{[4
]}

Camacho-Horvitz, Miguel S. ^{[5
]}

Holak, Tad A. ^{[4
,6
]}

Domling, Alexander ^{[1
,7
]}

机构：

[1] Univ Pittsburgh, Pittsburgh, PA 15213 USA

[2] Minist Educ, Key Lab Combinatorial Biosynth & Drug Discovery, Wuhan 430071, Peoples R China

[3] Wuhan Univ, Sch Pharmaceut Sci, Wuhan 430071, Peoples R China

[4] Max Planck Inst Biochem, D-82152 Martinsried, Germany

[5] Pittsburgh Allderdice High Sch, Pittsburgh, PA 15217 USA

[6] Jagiellonian Univ, Fac Chem, PL-30060 Krakow, Poland

[7] Univ Groningen, NL-9713 AV Groningen, Netherlands

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2013年 / 21卷 / 14期

基金：

美国国家科学基金会;

关键词：

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;

D O I：

10.1016/j.bmc.2012.06.020

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：3982 / 3995

页数：14

共 54 条

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