Abstract
Introduction of an O-alkoxyphenyl substituent at the 8-position of the 2-morpholino-4H-chromen-4-one pharmacophore enabled regions of the ATP-binding site of DNA-dependent protein kinase (DNA-PK) to be probed further. Structure-activity relationships have been elucidated for inhibition of DNA-PK and PI3K (p110α), with N-(2-(cyclopropylmethoxy)-4-(2-morpholino-4-oxo-4H-chromen-8-yl)phenyl)-2-morpholinoacetamide 11a being identified as a potent and selective DNA-PK inhibitor (IC(50)=8 nM).
Copyright © 2010 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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Chromones / chemical synthesis
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Chromones / chemistry*
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Chromones / pharmacology
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DNA-Activated Protein Kinase / antagonists & inhibitors*
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DNA-Activated Protein Kinase / metabolism
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Humans
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Protein Binding
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacology
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Protein Structure, Tertiary
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Structure-Activity Relationship
Substances
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Chromones
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Adenosine Triphosphate
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DNA-Activated Protein Kinase