Abstract
A series of thio-benzodiazepine p53-MDM2 inhibitors were designed and synthesized based on the principle of bioisosterism. Most of the thio-benzodiazepines had nanomolar to micromolar affinity toward MDM2. Particularly, compounds 8a (K(i) = 0.52μM) and 8f (K(i) = 0.32 μM) showed binding activity comparable to the positive drug nutlin-3a (K(i) = 0.23 μM). Meanwhile, compound 8j exhibited excellent antitumor activity against the U-2 OS human osteosarcoma cell line with an IC(50) value of 1.06 μM, which was about 23 times higher than that of nutlin-3a. The docking model also successfully predicted that this class of compounds mimicked three p53 critical residues binding to MDM2. The thio-benzodiazepines represent a promising class of non-peptide inhibitors of the p53-MDM2 interaction.
Copyright © 2011. Published by Elsevier Masson SAS.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Benzodiazepines / chemical synthesis*
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Benzodiazepines / chemistry
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Benzodiazepines / pharmacology*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Chemistry Techniques, Synthetic*
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Humans
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Models, Molecular
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Molecular Conformation
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Protein Binding / drug effects
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Proto-Oncogene Proteins c-mdm2 / metabolism*
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Small Molecule Libraries / chemical synthesis
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology
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Structure-Activity Relationship
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Sulfur / chemistry*
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Tumor Suppressor Protein p53 / metabolism*
Substances
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Antineoplastic Agents
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Small Molecule Libraries
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Tumor Suppressor Protein p53
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Benzodiazepines
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Sulfur
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Proto-Oncogene Proteins c-mdm2