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.

Imidazoles as potential anticancer agents

“…3) for the in vitro inhibition of angiogenesis. 81 The authors summarized the morphological effect of the three groups of This journal is © The Royal Society of Chemistry 2017 levamisole. In the first group, the authors found p-bromolevamisole 2 was an equivalent angiogenic agent to levamisole, and N-methyllevamisoles 4a and 4b were more potent than the parent inhibitor, levamisole.…”

Cocaine Induced Pleural and Pericardial Effusion Syndrome

“…It inhibits the proliferation, the differentiation, and capillary network formation of endothelial cells in vitro [ 5 ]. Levamisole derivatives disrupt endothelial network formation less efficiently than levamisole itself [ 6 ]. Levamisole has been reported to induce apoptosis in cultured endothelial cells [ 7 ].…”

In Vitro Angiogenesis Inhibition and Endothelial Cell Growth and Morphology

“…Levamisole has previously shown inhibition of angiogenesis in vitro, when HUVECs were propagated on NHDFs, and inhibition of tumor growth in vivo [30,31]. Levamisole and various derivatives were tested at 1 mM and 100 µM, respectively, which were the highest concentrations with an inhibitory effect without being lethal (Figure 3).…”