Details

Autor(en) / Beteiligte

• Watson, Anna F.
• Liu, Junfeng
• Bennaceur, Karim
• Drummond, Catherine J.
• Endicott, Jane A.
• Golding, Bernard T.
• Griffin, Roger J.
• Haggerty, Karen
• Lu, Xiaohong
• McDonnell, James M.
• Newell, David R.
• Noble, Martin E.M.
• Revill, Charlotte H.
• Riedinger, Christiane
• Xu, Qing
• Zhao, Yan
• Lunec, John
• Hardcastle, Ian R.

Titel

MDM2-p53 protein–protein interaction inhibitors: A-ring substituted isoindolinones

Ist Teil von

• Bioorganic & medicinal chemistry letters, 2011-10, Vol.21 (19), p.5916-5919

Ort / Verlag

Amsterdam: Elsevier Ltd

Erscheinungsjahr

2011

Quelle

Elsevier ScienceDirect Journals

Beschreibungen/Notizen

• 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.