Abstract
Novel N(9)-arenethenyl purines, optimized potent dual Src/Abl tyrosine kinase inhibitors, are described. The key structural feature is a trans vinyl linkage at N(9) on the purine core which projects hydrophobic substituents into the selectivity pocket at the rear of the ATP site. Their synthesis was achieved through a Horner-Wadsworth-Emmons reaction of N(9)-phosphorylmethylpurines and substituted benzaldehydes or Heck reactions between 9-vinyl purines and aryl halides. Most compounds are potent inhibitors of both Src and Abl kinase, and several possess good oral bioavailability.
MeSH terms
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Cell Proliferation / drug effects
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Growth Inhibitors / chemistry
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Growth Inhibitors / pharmacology
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Humans
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K562 Cells
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins c-abl / antagonists & inhibitors*
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Proto-Oncogene Proteins c-abl / physiology
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Purines / chemistry*
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Purines / pharmacology*
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Rats
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src-Family Kinases / antagonists & inhibitors*
Substances
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Antineoplastic Agents
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Growth Inhibitors
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Protein Kinase Inhibitors
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Purines
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Proto-Oncogene Proteins c-abl
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src-Family Kinases