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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

J Med Chem

Publication Date

19/10/2006

Volume

49

Pages

6209 - 6221

Keywords

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