Abstract
4-Amino-2-phenylquinazolines 7 were designed as bioisosteres of 3-arylisoquinolinamines 6 that were energy minimized to provide stable conformers. Interestingly, the 2-phenyl ring of 4-amino-2-phenylquinazolines was parallel to the quinazoline ring and improved their DNA intercalation ability in the DNA-topo I complex. Among the synthesized 4-amino group-substituted analogs, 4-cyclohexylamino-2-phenylquinazoline 7h exhibited potent topo I inhibitory activity and strong cytotoxicity. Interestingly, consistency was observed between the cytotoxicities and topo I activities in these quinazoline analogs, suggesting that the target of 4-amino-2-phenylquinazolines is limited to topo I. Molecular docking studies were performed with the Surflex-Dock program to afford the ideal interaction mode of the compound into the binding site of the DNA-topo I complex in order to clarify the topo I activity of 7h.
Copyright © 2011 Elsevier Ltd. 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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Cattle
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Crystallography, X-Ray
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Cyclohexylamines / chemical synthesis
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Cyclohexylamines / chemistry
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Cyclohexylamines / pharmacology*
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DNA Topoisomerases, Type I / metabolism*
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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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Humans
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Models, Molecular
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Molecular Structure
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Quinazolines / chemical synthesis
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Quinazolines / chemistry
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Quinazolines / pharmacology*
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Stereoisomerism
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Structure-Activity Relationship
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Thymus Gland / enzymology
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Topoisomerase I Inhibitors / chemical synthesis
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Topoisomerase I Inhibitors / chemistry
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Topoisomerase I Inhibitors / pharmacology*
Substances
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Antineoplastic Agents
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Cyclohexylamines
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Quinazolines
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Topoisomerase I Inhibitors
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cyclohexyl(2-phenylquinazolin-4-yl)amine
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DNA Topoisomerases, Type I