Abstract
Novel bis(indolyl)maleimide pyridinophanes 3, 9a, 9b, 10a, 10b, and 11 were prepared by cobalt-mediated [2+2+2] cycloaddition of an appropriate alpha,omega-diyne with an N,N-dialkylcyanamide. These macrocyclic heterophanes were found to be potent, selective inhibitors of glycogen synthase kinase-3beta. An X-ray structure of a co-crystal of GSK-3beta and 3 (IC(50)=3nM) depicts the hydrogen bonding and hydrophobic interactions in the ATP-binding pocket of this serine/threonine protein kinase.
MeSH terms
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Adenosine Triphosphate / metabolism
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Binding Sites
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Drug Design
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / pharmacology*
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Glycogen Synthase Kinase 3 / antagonists & inhibitors*
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Glycogen Synthase Kinase 3 / chemistry
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Glycogen Synthase Kinase 3 beta
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Hydrophobic and Hydrophilic Interactions
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Maleimides / chemistry
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Models, Molecular
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Molecular Structure
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Protein Conformation
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Pyridines / chemistry
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Pyridines / pharmacology*
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Structure-Activity Relationship
Substances
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Enzyme Inhibitors
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Maleimides
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Pyridines
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maleimide
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Adenosine Triphosphate
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Glycogen Synthase Kinase 3 beta
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Glycogen Synthase Kinase 3