Abstract
Human DNA topoisomerase IIα (htIIα) is a validated target for the development of anticancer agents. Starting from the available information about the binding of the purine-based htIIα inhibitors in the ATP binding site we designed a virtual screening campaign combining structure-based and ligand-based pharmacophores with a molecular docking calculation searching for compounds that would contain a monocycle mimetic of the purine moiety. We discovered novel 4-amino-6-(phenylamino)-1,3,5-triazines 6, 7 and 11 as monocyclic htIIα inhibitors targeting the ATP binding site. Compound 6 from the 1,3,5-triazine series also displayed cytotoxicity properties in hepatocellular carcinoma (HepG2) cell lines and selectivity against human umbilical vein endothelial (HUVEC) cell lines.
Keywords:
Anticancer agents; Catalytic inhibitors; Drug design; Human DNA topoisomerase IIα; Virtual screening.
Copyright © 2014 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / chemistry
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Adenosine Triphosphate / metabolism
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Antigens, Neoplasm / metabolism
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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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Binding Sites
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Cell Survival / drug effects
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DNA Topoisomerases, Type II / metabolism
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DNA-Binding Proteins / antagonists & inhibitors*
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DNA-Binding Proteins / metabolism
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Drug Design
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Hep G2 Cells
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Human Umbilical Vein Endothelial Cells
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Humans
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Molecular Docking Simulation
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Protein Binding
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Protein Structure, Tertiary
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Purines / chemistry*
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Structure-Activity Relationship
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Thiocarbamates / chemical synthesis
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Thiocarbamates / chemistry*
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Thiocarbamates / toxicity
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Topoisomerase II Inhibitors / chemical synthesis
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Topoisomerase II Inhibitors / chemistry*
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Topoisomerase II Inhibitors / pharmacology
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Triazines / chemical synthesis
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Triazines / chemistry*
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Triazines / pharmacology
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Triazines / toxicity
Substances
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Antigens, Neoplasm
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Antineoplastic Agents
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DNA-Binding Proteins
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Purines
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Thiocarbamates
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Topoisomerase II Inhibitors
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Triazines
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Adenosine Triphosphate
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DNA Topoisomerases, Type II
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purine