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

Lookup NU author(s): Dr Karim Bennaceur, Dr Catherine Drummond, Professor Jane Endicott, Professor Bernard Golding, Professor Roger Griffin, Dr Karen Haggerty, Professor Herbie Newell, Professor Martin Noble, Qing Xu, Dr Yan Zhao, Professor John Lunec, Dr Ian Hardcastle

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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; IC50 = 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. (C) 2011 Elsevier Ltd. All rights reserved.


Publication metadata

Author(s): Watson AF, Liu JF, Bennaceur K, Drummond CJ, Endicott JA, Golding BT, Griffin RJ, Haggerty K, Lu XH, McDonnell JM, Newell DR, Noble MEM, Revill CH, Riedinger C, Xu Q, Zhao Y, Lunec J, Hardcastle IR

Publication type: Article

Publication status: Published

Journal: Bioorganic & Medicinal Chemistry Letters

Year: 2011

Volume: 21

Issue: 19

Pages: 5916-5919

Print publication date: 09/08/2011

ISSN (print): 0960-894X

ISSN (electronic): 1464-3405

Publisher: Pergamon

URL: http://dx.doi.org/10.1016/j.bmcl.2011.07.084

DOI: 10.1016/j.bmcl.2011.07.084


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