title: Antiangiogenic and Toxic Effects of Genistein, Usnic Acid, and Their Copper Complexes in Zebrafish Embryos at Different Developmental Stages.
abstract: Angiogenesis plays a major role in the normal embryonic development and in diseases such as cancer. Drugs that control angiogenesis are an alternative way to tackle this disease. The polyphenols usnic acid (3), genistein (5), and daidzein (6) were tested for antiangiogenic and unwanted effects in zebrafish embryos whose blood vessel system resembles that of mammals. The established tyrosine kinase inhibitors axitinib (1) and tyrphostin AG490 (2) were included for comparison. All compounds except 6 caused distinct antiangiogenic effects such as a concentration-dependent reduction of intersegmental vessels, dorsal longitudinal anastomotic vessels, subintestinal veins and secondary sprouts. As side effects, pericardial oedema and the impairment of blood flow were observed. Usnic acid (3), genistein (5) and Cu(II)-genisteinate (7) gave rise to a curvature of the spine. Compounds 5 and 7 also induced cell death in the head of the embryos at higher doses. All effects were more pronounced when the compounds had been applied at an early stage (24 hpf) rather than at 48 hpf. The copper complexes 4 and 7 showed a stronger antiangiogenic effect than the free ligands 3 and 5. The genistein complex 7 was antiangiogenic at doses so low that side effects were tolerable, and thus it may be a potential anticancer drug candidate.
authors.affiliation: Organic Chemistry, University Bayreuth, Universitätsstrasse 30, NW 1, 95447, Bayreuth, Germany.|Developmental Biology, University Bayreuth, Universitätsstrasse 30, 95440, Bayreuth, Germany.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Draut
authors.affiliation: Organic Chemistry, University Bayreuth, Universitätsstrasse 30, NW 1, 95447, Bayreuth, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Rehm
authors.affiliation: Developmental Biology, University Bayreuth, Universitätsstrasse 30, 95440, Bayreuth, Germany.
authors.forename: Gerrit
authors.initials: G
authors.lastname: Begemann
authors.affiliation: Organic Chemistry, University Bayreuth, Universitätsstrasse 30, NW 1, 95447, Bayreuth, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Schobert
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D000077784:Axitinib; D001572:Benzofurans / Q000737:chemistry*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity*; D003300:Copper / Q000737:chemistry*; D004625:Embryo, Nonmammalian / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D047108:Embryonic Development / Q000187:drug effects; D019833:Genistein / Q000737:chemistry*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000633:toxicity; D007191:Indazoles / Q000494:pharmacology / Q000633:toxicity; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008856:Microscopy, Fluorescence; D018919:Neovascularization, Physiologic / Q000187:drug effects; D015027:Zebrafish / Q000254:growth & development* / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D001572:Benzofurans; D056831:Coordination Complexes; D007093:Imidazoles; D007191:Indazoles; C073339:usnic acid; D003300:Copper; D000077784:Axitinib; D019833:Genistein; D020782:Matrix Metalloproteinases
keywords: Antiangiogenic compounds; Flavonoids; Usnic acid; Zebrafish