Abstract
Guided by the principle of nonclassical electronic isosterism and structural optimization, a series of novel HDAC inhibitors bearing a bicyclic heterocycle moiety were designed and synthesized based on the lead compound of MS-275. All the prepared compounds were evaluated for their in vitro antiproliferative activities against HCT-116, MCF-7 and A549 human cancer cell lines, all compounds exerted excellent antitumor activities. Moreover, the compound 4a exhibited an acceptable pharmacokinetic profile with bio-availability in rat of 76% and could be considered as a candidate compound for further development.
Keywords:
Acrylamide; Antiproliferative; Benzamides derivatives; HDAC; Pharmacokinetic; Synthesis.
Copyright © 2015 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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Animals
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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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Benzamides / chemical synthesis
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Benzamides / chemistry
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Benzamides / pharmacology*
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Biological Availability
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Cell Proliferation / drug effects
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Dose-Response Relationship, Drug
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Drug Design*
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Drug Screening Assays, Antitumor
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Female
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HCT116 Cells
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Histone Deacetylase Inhibitors / chemical synthesis
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Histone Deacetylase Inhibitors / chemistry
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Histone Deacetylase Inhibitors / pharmacology*
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Histone Deacetylases / metabolism*
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Humans
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MCF-7 Cells
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Molecular Structure
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents
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Benzamides
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Histone Deacetylase Inhibitors
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Histone Deacetylases