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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Authors | Ian R Hardcastle, Shafiq U Ahmed, Helen Atkins, Gillian Farnie, Bernard T Golding, Roger J Griffin, Sabrina Guyenne, Claire Hutton, Per Källblad, Stuart J Kemp, Martin S Kitching, David R Newell, Stefano Norbedo, Julian S Northen, Rebecca J Reid, K Saravanan, Henriëtte M G Willems, John Lunec |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 49
Issue 21
Pg. 6209-21
(Oct 19 2006)
ISSN: 0022-2623 [Print] United States |
PMID | 17034127
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 2-benzyl-3-(4-chlorophenyl)-3-(3-hydroxypropoxy)-2,3-dihydroisoindol-1-one
- 3-(4-chlorophenyl)-3-(4-hydroxy-3,5-dimethoxybenzyloxy)-2-propyl-2,3-dihydroisoindol-1-one
- Antineoplastic Agents
- Indoles
- Tumor Suppressor Protein p53
- MDM2 protein, human
- Proto-Oncogene Proteins c-mdm2
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Topics |
- Antineoplastic Agents
(chemical synthesis, chemistry, pharmacology)
- Cell Line, Tumor
- Combinatorial Chemistry Techniques
- Drug Screening Assays, Antitumor
- Humans
- Indoles
(chemical synthesis, chemistry, pharmacology)
- Models, Molecular
- Protein Binding
- Proto-Oncogene Proteins c-mdm2
(metabolism)
- Stereoisomerism
- Structure-Activity Relationship
- Transcription, Genetic
- Tumor Suppressor Protein p53
(genetics, metabolism)
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