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Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Small-molecule inhibitors of the MDM2-p53 protein-protein interaction based on an isoindolinone scaffold
Ian R Hardcastle1, Shafiq U Ahmed, Helen Atkins
1Northern 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
Abstract:
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.
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