title: Synthesis and antiangiogenic activity of N-alkylated levamisole derivatives.
abstract: Inhibition of angiogenesis is a promising addition to current cancer treatment strategies. Neutralization of vascular endothelial growth factor by monoclonal antibodies is clinically effective but may cause side effects due to thrombosis. Low molecular weight angiogenesis inhibitors are currently less effective than antibody treatment and are also associated with serious side effects. The discovery of new chemotypes with efficient antiangiogenic activity is therefore of pertinent interest. (S)-levamisole hydrochloride, an anthelminthic drug approved for human use and with a known clinical profile, was recently shown to be an inhibitor of angiogenesis in vitro and exhibited tumor growth inhibition in mice. Here we describe the synthesis and in vitro evaluation of a series of N-alkylated analogues of levamisole with the aim of characterizing structure-activity relationships with regard to inhibition of angiogenesis. N-methyllevamisole and p-bromolevamisole proved more effective than the parent compound, (S)-levamisole hydrochloride, with respect to inhibition of angiogenesis and induction of undifferentiated cluster morphology in human umbilical vein endothelial cells grown in co-culture with normal human dermal fibroblasts. Interestingly, the cluster morphology caused by N-methyllevamisole was different than the clusters observed for levamisole, and a third "cord-like" morphology resembling that of the known drug suramin was observed for an aniline-containing derivative. New chemotypes exhibiting antiangiogenic effects in vitro are thus described, and further investigation of their underlying mechanism of action is warranted.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anders N
authors.initials: AN
authors.lastname: Hansen
authors.forename: Christine D
authors.initials: CD
authors.lastname: Bendiksen
authors.forename: Lene
authors.initials: L
authors.lastname: Sylvest
authors.forename: Tina
authors.initials: T
authors.lastname: Friis
authors.forename: Dan
authors.initials: D
authors.lastname: Staerk
authors.forename: Flemming Steen
authors.initials: FS
authors.lastname: Jørgensen
authors.forename: Christian A
authors.initials: CA
authors.lastname: Olsen
authors.forename: Gunnar
authors.initials: G
authors.lastname: Houen
mesh_terms: D000469:Alkaline Phosphatase / Q000037:antagonists & inhibitors; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D007978:Levamisole / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D008968:Molecular Conformation; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors
chemical_list: D020533:Angiogenesis Inhibitors; D007978:Levamisole; D000469:Alkaline Phosphatase; D056564:Sirtuin 1