title: MDM2-p53 protein-protein interaction inhibitors: a-ring substituted isoindolinones.
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.
authors.affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research and School of Chemistry, Bedson Building, Newcastle University, Newcastle, NE1 7RU, UK.
authors.forename: Anna F
authors.initials: AF
authors.lastname: Watson
authors.forename: Junfeng
authors.initials: J
authors.lastname: Liu
authors.forename: Karim
authors.initials: K
authors.lastname: Bennaceur
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Drummond
authors.forename: Jane A
authors.initials: JA
authors.lastname: Endicott
authors.forename: Bernard T
authors.initials: BT
authors.lastname: Golding
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Griffin
authors.forename: Karen
authors.initials: K
authors.lastname: Haggerty
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Lu
authors.forename: James M
authors.initials: JM
authors.lastname: McDonnell
authors.forename: David R
authors.initials: DR
authors.lastname: Newell
authors.forename: Martin E M
authors.initials: ME
authors.lastname: Noble
authors.forename: Charlotte H
authors.initials: CH
authors.lastname: Revill
authors.forename: Christiane
authors.initials: C
authors.lastname: Riedinger
authors.forename: Qing
authors.initials: Q
authors.lastname: Xu
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.forename: John
authors.initials: J
authors.lastname: Lunec
authors.forename: Ian R
authors.initials: IR
authors.lastname: Hardcastle
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D054833:Isoindoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D054833:Isoindoles; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2