title: Structure-based design, synthesis, and biological evaluation of novel 1,4-diazepines as HDM2 antagonists.
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.
authors.affiliation: Department of Medicinal Chemistry, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 665 Stockton Drive, Exton, PA 19341, USA.
authors.forename: Pierre
authors.initials: P
authors.lastname: Raboisson
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Marugán
authors.forename: Carsten
authors.initials: C
authors.lastname: Schubert
authors.forename: Holly K
authors.initials: HK
authors.lastname: Koblish
authors.forename: Tianbao
authors.initials: T
authors.lastname: Lu
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Zhao
authors.forename: Mark R
authors.initials: MR
authors.lastname: Player
authors.forename: Anna C
authors.initials: AC
authors.lastname: Maroney
authors.forename: Rolanda L
authors.initials: RL
authors.lastname: Reed
authors.forename: Norman D
authors.initials: ND
authors.lastname: Huebert
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lattanze
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Parks
authors.forename: Maxwell D
authors.initials: MD
authors.lastname: Cummings
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001381:Azepines / Q000138:chemical synthesis* / Q000494:pharmacology; D018938:Caco-2 Cells; D018360:Crystallography, X-Ray; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; D008024:Ligands; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2