MDM2-p53 protein-protein interaction inhibitors: a-ring substituted isoindolinones

  • Bioorg Med Chem Lett. 2011 Oct 1;21(19):5916-9. doi: 10.1016/j.bmcl.2011.07.084.
Anna F Watson  1 ,  Junfeng Liu ,  Karim Bennaceur ,  Catherine J Drummond ,  Jane A Endicott ,  Bernard T Golding ,  Roger J Griffin ,  Karen Haggerty ,  Xiaohong Lu ,  James M McDonnell ,  David R Newell ,  Martin E M Noble ,  Charlotte H Revill ,  Christiane Riedinger ,  Qing Xu ,  Yan Zhao ,  John Lunec ,  Ian R Hardcastle
Affiliations
  • 1. Newcastle Cancer Centre at the Northern Institute for Cancer Research and School of Chemistry, Bedson Building, Newcastle University, Newcastle, NE1 7RU, UK.
PMID: 21875801 DOI: 10.1016/j.bmcl.2011.07.084
Abstract

Structure-activity relationships for the MDM2-p53 inhibitory activity of a series of A-ring substituted 2-N-benzyl-3-(4-chlorophenyl)-3-(1-(hydroxymethyl)cyclopropyl)methoxy)isoindolinones have been investigated, giving rise to compounds with improved potency over their unsubstituted counterparts. Isoindolinone A-ring substitution with a 4-chloro group for the 4-nitrobenzyl, 4-bromobenzyl and 4-cyanobenzyl derivatives (10a-c) and substitution with a 6-tert-butyl group for the 4-nitrobenzyl derivative (10j) were found to confer additional potency. Resolution of the enantiomers of 10a showed that potent MDM2-p53 activity resided in the (-)-enantiomer ((-)-10a; IC(50)=44 ± 6 nM). The cellular activity of key compounds has been examined in cell lines with defined p53 and MDM2 status. Compounds 10a and (-)-10a increase p53 protein levels, activate p53-dependent MDM2 and p21 transcription in MDM2 amplified cells, and show improved selectivity for growth inhibition in wild type p53 cell lines over the parent compound.