Structure-based design, synthesis, and biological evaluation of novel 1,4-diazepines as HDM2 antagonists.
Bioorg Med Chem Lett
; 15(7): 1857-61, 2005 Apr 01.
Article
em En
| MEDLINE
| ID: mdl-15780621
ABSTRACT
Crystallographic analysis of ligands bound to HDM2 suggested that 7-substituted 1,4-diazepine-2,5-diones could mimic the alpha-helix of p53 peptide and may represent a promising scaffold to develop HDM2-p53 antagonists. To verify this hypothesis, we synthesized and biologically evaluated 5-[(3S)-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-2,5-dioxo-7-phenyl-1,4-diazepin-1-yl]valeric acid (10) and 5-[(3S)-7-(2-bromophenyl)-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-2,5-dioxo-1,4-diazepin-1-yl]valeric acid (11). Preliminary in vitro testing shows that 10 and 11 substantially antagonize the binding between HDM2 and p53 with an IC(50) of 13 and 3.6 microM, respectively, validating the modeling predictions. Taken together with the high cell permeability of diazepine 11 determined in CACO-2 cells, these results suggest that 1,4-diazepine-2,5-diones may be useful in the treatment of certain cancers.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Azepinas
/
Proteínas Nucleares
/
Proteínas Proto-Oncogênicas
/
Antineoplásicos
Tipo de estudo:
Evaluation_studies
/
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2005
Tipo de documento:
Article
País de afiliação:
Estados Unidos