title: Enantiomerically pure 1,4-benzodiazepine-2,5-diones as Hdm2 antagonists.
abstract: The 1,4-benzodiazepine-2,5-dione is a suitable template to disrupt the interaction between p53 and Hdm2. The development of an enantioselective synthesis disclosed the stereochemistry of the active enantiomer. An in vitro p53 peptide displacement assay identified active compounds. These activities were confirmed in several cell-based assays including induction of the p53 regulated gene (PIG-3) and caspase activity.
authors.affiliation: Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 665 Stockton Drive, Exton, PA 19341, USA. jmaruga@prdus.jnj.com
authors.forename: Juan Jose
authors.initials: JJ
authors.lastname: Marugan
authors.forename: Kristi
authors.initials: K
authors.lastname: Leonard
authors.forename: Pierre
authors.initials: P
authors.lastname: Raboisson
authors.forename: Joan M
authors.initials: JM
authors.lastname: Gushue
authors.forename: Raul
authors.initials: R
authors.lastname: Calvo
authors.forename: Holly K
authors.initials: HK
authors.lastname: Koblish
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lattanze
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Zhao
authors.forename: Maxwell D
authors.initials: MD
authors.lastname: Cummings
authors.forename: Mark R
authors.initials: MR
authors.lastname: Player
authors.forename: Carsten
authors.initials: C
authors.lastname: Schubert
authors.forename: Anna C
authors.initials: AC
authors.lastname: Maroney
authors.forename: Tianbao
authors.initials: T
authors.lastname: Lu
mesh_terms: D001569:Benzodiazepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D016159:Tumor Suppressor Protein p53; D001569:Benzodiazepines; D051736:Proto-Oncogene Proteins c-mdm2; D020169:Caspases