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From a set of weakly potent lead compounds, using in silico screening and small library synthesis, a series of 2-alkyl-3-aryl-3-alkoxyisoindolinones has been identified as inhibitors of the MDM2-p53 interaction. Two of the most potent compounds, 2-benzyl-3-(4-chlorophenyl)-3-(3-hydroxypropoxy)-2,3-dihydroisoindol-1-one (76; IC(50) = 15.9 +/- 0.8 microM) and 3-(4-chlorophenyl)-3-(4-hydroxy-3,5-dimethoxybenzyloxy)-2-propyl-2,3-dihydroisoindol-1-one (79; IC(50) = 5.3 +/- 0.9 microM), induced p53-dependent gene transcription, in a dose-dependent manner, in the MDM2 amplified, SJSA human sarcoma cell line.

Original publication

DOI

10.1021/jm0601194

Type

Journal article

Journal

Journal of medicinal chemistry

Publication Date

10/2006

Volume

49

Pages

6209 - 6221

Addresses

Northern Institute for Cancer Research, School of Natural Sciences--Chemistry, Bedson Building, University of Newcastle upon Tyne, Newcastle, NE1 7RU, United Kingdom. i.r.hardcastle@ncl.ac.uk

Keywords

Cell Line, Tumor, Humans, Indoles, Antineoplastic Agents, Drug Screening Assays, Antitumor, Combinatorial Chemistry Techniques, Transcription, Genetic, Protein Binding, Structure-Activity Relationship, Stereoisomerism, Models, Molecular, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-mdm2