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

Miloš Ilić; Janez Ilaš; Petra Dunkel; Péter Mátyus; Andrej Boháč; Sandra Liekens; Danijel Kikelj

doi:10.1016/j.ejmech.2012.10.001

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

Eur J Med Chem. 2012 Dec:58:160-70. doi: 10.1016/j.ejmech.2012.10.001. Epub 2012 Oct 8.

Authors

Miloš Ilić¹, Janez Ilaš, Petra Dunkel, Péter Mátyus, Andrej Boháč, Sandra Liekens, Danijel Kikelj

Affiliation

¹ University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI - 1000 Ljubljana, Slovenia.

PMID: 23124213
DOI: 10.1016/j.ejmech.2012.10.001

Abstract

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 (R(2) = 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiogenesis Inhibitors / chemical synthesis
Angiogenesis Inhibitors / chemistry
Angiogenesis Inhibitors / pharmacology*
Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Benzoxazines / chemical synthesis
Benzoxazines / chemistry
Benzoxazines / pharmacology*
Cattle
Cell Line
Cell Movement / drug effects
Cell Proliferation / drug effects
Chickens
Chorioallantoic Membrane / drug effects
Dioxanes / chemical synthesis
Dioxanes / chemistry
Dioxanes / pharmacology*
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Endothelial Cells / drug effects
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
MCF-7 Cells
Mice
Molecular Structure
Platelet Aggregation Inhibitors / chemical synthesis
Platelet Aggregation Inhibitors / chemistry
Platelet Aggregation Inhibitors / pharmacology*
Platelet Glycoprotein GPIIb-IIIa Complex / antagonists & inhibitors*
Platelet Glycoprotein GPIIb-IIIa Complex / metabolism
Structure-Activity Relationship
Thrombin / antagonists & inhibitors*
Thrombin / metabolism

Substances

Angiogenesis Inhibitors
Antineoplastic Agents
Benzoxazines
Dioxanes
Enzyme Inhibitors
Platelet Aggregation Inhibitors
Platelet Glycoprotein GPIIb-IIIa Complex
Thrombin