title: New vandetanib analogs: fused tricyclic quinazolines with antiangiogenic potential.
abstract: The antiangiogenic effects of three novel anilinoquinazoline derivatives were studied with the aim to find new multi-kinase inhibitors as anticancer agents. The compounds are characterized by dioxolane, dioxane and dioxepine rings and bear the same aniline substituent in 4 position as vandetanib, known antiangiogenic agent. The in vitro assays were carried out on human umbilical vein endothelial cells (HUVECs), whereas in vivo angiogenesis was evaluated by means of Matrigel plug assay. The results showed that these compounds exert, even though to different extents, antiangiogenic activity affecting the various step of the process that leads to the formation of new blood vessels. At high concentrations they induced antiproliferative effects, whereas at non-cytotoxic concentrations they inhibited cell migration and the formation of tubular structures in Matrigel. In in vitro assays the dioxolane derivative 1 was more effective than vandetanib. Indeed, it inhibited the effects induced by exogenous VEGF and FGF-2 on both cell proliferation and morphogenesis, whereas vandetanib was completely ineffective. Moreover, all the compounds, as vandetanib, counteracted the FGF-2-induced increase in the hemoglobin content in the Matrigel plugs. Our results showed that all the three novel derivatives possess both in vitro and in vivo antiangiogenic activity, with compound 1 more effective than vandetanib to inhibit in vitro angiogenesis induced by exogenous cytokines.
authors.affiliation: Department of Pharmaceutical Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Conconi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Marzaro
authors.forename: Adriano
authors.initials: A
authors.lastname: Guiotto
authors.forename: Luca
authors.initials: L
authors.lastname: Urbani
authors.forename: Ilenia
authors.initials: I
authors.lastname: Zanusso
authors.forename: Francesca
authors.initials: F
authors.lastname: Tonus
authors.forename: Mara
authors.initials: M
authors.lastname: Tommasini
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Parnigotto
authors.forename: Adriana
authors.initials: A
authors.lastname: Chilin
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010766:Phosphorylation; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; C512478:EGFR protein, human; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor; C452423:vandetanib