Novel 1,4-benzoxazine and 1,4-benzodioxine inhibitors of angiogenesis

Esters of 1,4-benzoxazine and 1,4-benzodioxine compounds 1 and 10, which combine thrombin inhibitory and GPIIb/IIIa antagonistic activity in one molecule are shown to inhibit endothelial cell migration and tube formation in vitro and angiogenesis in the chicken chorioallantoic membrane (CAM) assay. The corresponding carboxylic acids 1 (R2 = H) and 11 were devoid of anti-angiogenic activity, most probably due to their insufficient entry into the cell. Although thrombin inhibition remains the most probable explanation for their inhibition of angiogenesis, VEGFR2 kinase assay suggest that other targets such as VEGFR2 might be involved.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Potential dual antithrombotic compounds 1 and 10 are potent angiogenesis inhibitors. ► 1 and 10 inhibit proliferation of 4 cell lines, MAEC migration and tube formation. ► Compounds 1 and 10 are potent inhibitors of angiogenesis in CAM assay. ► Inhibition of thrombin and VEGFR2 kinase activity are most probable mechanisms.