Abstract
Efficient methods were developed to synthesize a novel series of macrocyclic bisindolylmaleimides containing linkers with multiple heteroatoms. Potent inhibitors (single digit nanomolar IC(50)) for PKC-beta and GSK-3beta were identified, and compounds showed good selectivity over PKC-alpha, -gamma, -delta, -epsilon, and -zeta. Representative compound 5a also had high selectivity in a screening panel of 10 other protein kinases. In cell-based functional assays, several compounds effectively blocked interleukin-8 release induced by PKC-betaII and increased glycogen synthase activity by inhibiting GSK-3beta.
MeSH terms
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacology
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Cell Line
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Cyclization
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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 beta
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Humans
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Indoles / chemical synthesis*
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Indoles / pharmacology
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Inhibitory Concentration 50
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Isoenzymes / chemical synthesis
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Isoenzymes / pharmacology
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Maleimides / chemical synthesis*
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Maleimides / pharmacology
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Protein Kinase C / antagonists & inhibitors*
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Protein Kinase C beta
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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Indoles
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Isoenzymes
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Maleimides
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Protein Kinase C
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Protein Kinase C beta
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Glycogen Synthase Kinase 3
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bisindolylmaleimide