Abstract
Previously, we reported a click-chemistry based approach to the synthesis of a novel class of histone deacetylase (HDAC) inhibitors [1]. The lead compound NSC746457 was found to be as potent as SAHA (Vorinostat). Further optimization of NSC746457 by using the HDAC2-TSA crystal structure is described herein. Docking of NSC746457 into HDAC2 binding domain suggested that the hydrophobic residue Phe210 flanking the cap-group binding-motif could be exploited for structural optimization. Substitution on the methylene group of cinnamic cap region led to identification of more potent HDAC inhibitors: isopropyl derivative 5 and tert-butyl derivative 6, with an IC(50) value of 22 nM and 18 nM, respectively.
Copyright © 2011 Elsevier Masson SAS. 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 / pharmacology
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Binding Sites
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Cell Line, Tumor
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Cell Proliferation / drug effects*
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Click Chemistry
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Crystallography, X-Ray
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Drug Design
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Drug Screening Assays, Antitumor
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Histone Deacetylase 1 / chemistry*
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Histone Deacetylase 1 / metabolism
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Histone Deacetylase 2* / chemistry
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Histone Deacetylase 2* / metabolism
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Histone Deacetylase Inhibitors / chemical synthesis*
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Histone Deacetylase Inhibitors / pharmacology
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Humans
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Hydrophobic and Hydrophilic Interactions
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Hydroxamic Acids / chemical synthesis*
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Hydroxamic Acids / pharmacology
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Models, Molecular
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Neoplasms / drug therapy
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Neoplasms / enzymology*
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Neoplasms / pathology
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Phenylalanine / chemistry
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Phenylalanine / metabolism
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Protein Binding
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Protein Structure, Secondary
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Structure-Activity Relationship
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Triazoles / chemical synthesis*
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Triazoles / pharmacology
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Vorinostat
Substances
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3-(1-cinnamyl-1H-1,2,3-triazol-4-yl)-N-hydroxyacrylamide
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Antineoplastic Agents
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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Triazoles
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Phenylalanine
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Vorinostat
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HDAC1 protein, human
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HDAC2 protein, human
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Histone Deacetylase 1
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Histone Deacetylase 2