ABSTRACT
Angiogenesis is vital for solid tumor growth, and its prevention is a proven strategy for the treatment of disease states such as cancer. The vascular endothelial growth factor (VEGF) pathway provides several opportunities by which small molecules can act as inhibitors of endothelial proliferation and migration. Critical to these processes is signaling through VEGFR-2 or the kinase insert domain receptor (KDR) upon stimulation by its ligand VEGF. Herein, we report the discovery of 2,3-dihydro-1,4-benzoxazines as inhibitors of intrinsic KDR activity (IC 50 < 0.1 microM) and human umbilical vein endothelial cell (HUVEC) proliferation with IC 50 < 0.1 microM. More specifically, compound 16 was identified as a potent (KDR: < 1 nM and HUVEC: 4 nM) and selective inhibitor that exhibited efficacy in angiogenic in vivo models. In addition, this series of molecules is typically well-absorbed orally, further demonstrating the 2,3-dihydro-1,4-benzoxazine moiety as a promising platform for generating kinase-based antiangiogenic therapeutic agents.
Subject(s)
Angiogenesis Inhibitors/administration & dosage , Benzoxazines/administration & dosage , Neoplasms/blood supply , Neovascularization, Pathologic/prevention & control , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Administration, Oral , Angiogenesis Inhibitors/chemical synthesis , Angiogenesis Inhibitors/chemistry , Animals , Benzoxazines/chemical synthesis , Benzoxazines/chemistry , Biological Availability , Cell Line , Cell Proliferation/drug effects , Corneal Neovascularization/blood , Crystallography, X-Ray , Dose-Response Relationship, Drug , Endothelial Cells/drug effects , Female , Humans , Injections, Subcutaneous , Ligands , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Models, Animal , Models, Molecular , Molecular Structure , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
Synthesis of the highly biologically valuable cardenolide backbone was achieved via anionic polycyclization. Bromoketone 18, obtained from double-Michael cycloaddition between cyclohexenone 14 and gamma,delta-unsaturated beta-ketoester 16, was efficiently aldolized under reductive conditions. The highly functionalized tetracyclic compound 52 is an important synthetic intermediate that is potentially amenable to natural cardenolide total synthesis.
