1. Novel tricyclic azepine derivatives: Biological evaluation of pyrimido[4,5-b]-1,4-benzoxazepines, thiazepines, and diazepines as inhibitors of the epidermal growth factor receptor tyrosine kinase
- Author
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Evgueni L. Piatnitski, Andrey Konovalov, Leon M. Smith, Daniel L. Milligan, Matthew A. J. Duncton, Sabina Burdzovic-Wizemann, Ki H. Kim, Yaron R. Hadari, Chris Balagtas, Alexander S. Kiselyov, John Columbus, Wai C. Wong, Yong-Jiang Xu, Jacqueline Doody, Sui Ping Lee, Ying Wang, Robin L. Rosler, and Yunyu Mao
- Subjects
Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Antineoplastic Agents ,Biochemistry ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,chemistry.chemical_compound ,Cell Line, Tumor ,Drug Discovery ,Humans ,Thiazepine ,Epidermal growth factor receptor ,Phosphorylation ,Azepine ,Molecular Biology ,chemistry.chemical_classification ,biology ,Organic Chemistry ,Autophosphorylation ,Kinase insert domain receptor ,Azepines ,Vascular Endothelial Growth Factor Receptor-2 ,Neoplasm Proteins ,ErbB Receptors ,Diazepine ,chemistry ,biology.protein ,Molecular Medicine ,Oxazepine ,Heterocyclic Compounds, 3-Ring ,Tricyclic - Abstract
Novel tricyclic derivatives containing an oxazepine, thiazepine, or diazepine ring were studied for their EGFR tyrosine kinase inhibitory activity. While the oxazepines were in general more potent than thiazepines, the diazepines displayed somewhat different structure–activity relationships. Moreover, the diazepines, in contrast to the oxazepines, showed appreciable inhibitory activity against the KDR tyrosine kinase. Furthermore, both oxazepines and diazepines demonstrated significant ability to inhibit autophosphorylation of EGFR in DiFi cells (generally, IC50 values in the single-digit micromolar to submicromolar range).
- Published
- 2006
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