Enantiomerically pure 1,4-benzodiazepine-2,5-diones as Hdm2 antagonists

  • Bioorg Med Chem Lett. 2006 Jun 15;16(12):3115-20. doi: 10.1016/j.bmcl.2006.03.067.
Juan Jose Marugan  1 ,  Kristi Leonard ,  Pierre Raboisson ,  Joan M Gushue ,  Raul Calvo ,  Holly K Koblish ,  Jennifer Lattanze ,  Shuyuan Zhao ,  Maxwell D Cummings ,  Mark R Player ,  Carsten Schubert ,  Anna C Maroney ,  Tianbao Lu
Affiliations
  • 1. Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 665 Stockton Drive, Exton, PA 19341, USA. [email protected]
PMID: 16630722 DOI: 10.1016/j.bmcl.2006.03.067
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.