Abstract
A series of 3,4,5-trisubstituted aminothiophenes were designed, synthesized, and evaluated for their p53-MDM2 binding inhibitory potency and anti-proliferation activities against A549 and PC3 tumor cell lines. Fourteen compounds had appreciably improved MDM2 binding affinities than lead compound MCL0527 (3) and a few compounds showed comparable activities to that of Nutlin-3. Meanwhile, most of the 3,4,5-trisubstituted aminothiophenes displayed better or equivalent anti-proliferation activities against wild-type p53 cell line A549 compared to that of Nutlin-3. Over ten compounds exhibited desirable selective profiles of p53 status. Particularly, compounds 9, 16 and 18 displayed 22-, 6- and 22-fold selectivity of p53 status, respectively, much better than that of Nutlin-3 (fourfold).
Copyright © 2013 Elsevier Ltd. All rights reserved.
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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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Design
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Drug Screening Assays, Antitumor
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Humans
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Inhibitory Concentration 50
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Kinetics
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Molecular Docking Simulation
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Protein Binding / drug effects
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Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-mdm2 / chemistry
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Proto-Oncogene Proteins c-mdm2 / metabolism
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Sensitivity and Specificity
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Structure-Activity Relationship
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Thiophenes / chemical synthesis*
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Thiophenes / chemistry
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Thiophenes / pharmacology
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Tumor Suppressor Protein p53 / antagonists & inhibitors*
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Tumor Suppressor Protein p53 / chemistry
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Tumor Suppressor Protein p53 / metabolism
Substances
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Antineoplastic Agents
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Thiophenes
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Tumor Suppressor Protein p53
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2