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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Antineoplastic Agents / chemical synthesis*
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / pharmacology
-
Cell Line, Tumor
-
Combinatorial Chemistry Techniques
-
Drug Screening Assays, Antitumor
-
Humans
-
Indoles / chemical synthesis*
-
Indoles / chemistry
-
Indoles / pharmacology
-
Models, Molecular
-
Protein Binding
-
Proto-Oncogene Proteins c-mdm2 / metabolism*
-
Stereoisomerism
-
Structure-Activity Relationship
-
Transcription, Genetic
-
Tumor Suppressor Protein p53 / genetics
-
Tumor Suppressor Protein p53 / metabolism*
Substances
-
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