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, IC(50) values in the single-digit micromolar to submicromolar range).
Subject(s)
Antineoplastic Agents/chemical synthesis , Azepines/chemical synthesis , Azepines/pharmacology , ErbB Receptors/antagonists & inhibitors , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/pharmacology , Antineoplastic Agents/pharmacology , Azepines/chemistry , Cell Line, Tumor , Heterocyclic Compounds, 3-Ring/chemistry , Humans , Inhibitory Concentration 50 , Neoplasm Proteins/antagonists & inhibitors , Phosphorylation/drug effects , Structure-Activity Relationship , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitorsABSTRACT
A novel class of pyrimido[4,5-b]-1,4-benzoxazepines is described as inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase. Two compounds display potent EGFR inhibitory activity of less than 1 microM in cellular phosphorylation assays (IC(50) 0.47-0.69 microM) and are highly selective against a small kinase panel. Such compounds demonstrate anti-EGFR activity within a class that is different from any known EGFR inhibitor scaffolds. They also provide a basis for the design of kinase inhibitors with the desired selectivity profile.
Subject(s)
Azepines/chemical synthesis , Azepines/pharmacology , ErbB Receptors/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Adenosine Triphosphate/metabolism , Azepines/chemistry , Binding Sites , Cell Proliferation/drug effects , Cells, Cultured , Humans , Molecular Structure , Phosphorylation/drug effects , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Receptor, ErbB-2/antagonists & inhibitors , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Oxadiazole derivatives were synthesized and evaluated for their ability to inhibit tubulin polymerization and to cause mitotic arrest in tumor cells. The most potent compounds inhibited tubulin polymerization at concentrations below 1 microM. Lead analogs caused mitotic arrest of A431 human epidermoid cells and cells derived from multi-drug resistant tumors (10, EC(50)=7.8 nM). Competition for the colchicine binding site and pharmacokinetic properties of selected potent compounds were also investigated and are reported herein, along with structure-activity relationships for this novel series of antimitotic agents.
