RESUMO
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.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Benzoxazinas/administração & dosagem , Neoplasias/irrigação sanguínea , Neovascularização Patológica/prevenção & controle , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Administração Oral , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Animais , Benzoxazinas/síntese química , Benzoxazinas/química , Disponibilidade Biológica , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Neovascularização da Córnea/sangue , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos dos fármacos , Feminino , Humanos , Injeções Subcutâneas , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Animais , Modelos Moleculares , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
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.