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Bioorg Med Chem Lett ; 15(7): 1857-61, 2005 Apr 01.
Article in English | 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.


Subject(s)
Antineoplastic Agents/pharmacology , Azepines/chemical synthesis , Nuclear Proteins/metabolism , Proto-Oncogene Proteins/metabolism , Azepines/pharmacology , Caco-2 Cells , Crystallography, X-Ray , Humans , Inhibitory Concentration 50 , Ligands , Nuclear Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins c-mdm2 , Structure-Activity Relationship , Tumor Cells, Cultured , Tumor Suppressor Protein p53/metabolism
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