Novel N9-arenethenyl purines as potent dual Src/Abl tyrosine kinase inhibitors

Novel N9-arenethenyl purines, optimized potent dual Src/Abl tyrosine kinase inhibitors, are described. The key structural feature is a trans vinyl linkage at N9 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 N9-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.

Graphical abstractNovel N9-arenethenyl purines, optimized potent dual Src/Abl tyrosine kinase inhibitors, are described.Figure optionsDownload full-size imageDownload as PowerPoint slide