Enantiomerically pure 1,4-benzodiazepine-2,5-diones as Hdm2 antagonists.
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.
Marugan
Juan Jose
JJ
Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 665 Stockton Drive, Exton, PA 19341, USA. jmaruga@prdus.jnj.com
Leonard
Kristi
K
Raboisson
Pierre
P
Gushue
Joan M
JM
Calvo
Raul
R
Koblish
Holly K
HK
Lattanze
Jennifer
J
Zhao
Shuyuan
S
Cummings
Maxwell D
MD
Player
Mark R
MR
Schubert
Carsten
C
Maroney
Anna C
AC
Lu
Tianbao
T
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
D004791:Enzyme Inhibitors; D016159:Tumor Suppressor Protein p53; D001569:Benzodiazepines; D051736:Proto-Oncogene Proteins c-mdm2; D020169:Caspases