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

• Published in: Bioorganic & medicinal chemistry letters 2008-09, Vol.18 (17), p.4907-4912
• Main Authors: Wang, Yihan, Shakespeare, William C., Huang, Wei-Sheng, Sundaramoorthi, Raji, Lentini, Scott, Das, Sasmita, Liu, Shuangying, Banda, Geeta, Wen, David, Zhu, Xiaotian, Xu, Qihong, Keats, Jeffrey, Wang, Frank, Wardwell, Scott, Ning, Yaoyu, Snodgrass, Joseph T., Broudy, Mark I., Russian, Karin, Dalgarno, David, Clackson, Tim, Sawyer, Tomi K.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Proliferation - drug effects; General aspects; Growth Inhibitors - chemistry; Growth Inhibitors - pharmacology; Humans; K562 Cells; Medical sciences; N9-arenethenyl purines; Pharmacology. Drug treatments; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-abl - antagonists & inhibitors; Proto-Oncogene Proteins c-abl - physiology; Purines - chemistry; Purines - pharmacology; Rats; src-Family Kinases - antagonists & inhibitors; Src/Abl tyrosine kinase inhibitors
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2008.06.042

Novel N9-arenethenyl purines, optimized potent dual Src/Abl tyrosine kinase inhibitors, are described. 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.