Synthesis and antiangiogenic activity of N-alkylated levamisole derivatives.

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 le...

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Autores principales:	Anders N Hansen, Christine D Bendiksen, Lene Sylvest, Tina Friis, Dan Staerk, Flemming Steen Jørgensen, Christian A Olsen, Gunnar Houen
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9d81b70e42684a82a4be34cf4f293ded
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spelling	oai:doaj.org-article:9d81b70e42684a82a4be34cf4f293ded2021-11-18T07:05:26ZSynthesis and antiangiogenic activity of N-alkylated levamisole derivatives.1932-620310.1371/journal.pone.0045405https://doaj.org/article/9d81b70e42684a82a4be34cf4f293ded2012-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0045405https://doaj.org/toc/1932-6203Inhibition 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.Anders N HansenChristine D BendiksenLene SylvestTina FriisDan StaerkFlemming Steen JørgensenChristian A OlsenGunnar HouenPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 9, p e45405 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Anders N Hansen Christine D Bendiksen Lene Sylvest Tina Friis Dan Staerk Flemming Steen Jørgensen Christian A Olsen Gunnar Houen Synthesis and antiangiogenic activity of N-alkylated levamisole derivatives.
description	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.
format	article
author	Anders N Hansen Christine D Bendiksen Lene Sylvest Tina Friis Dan Staerk Flemming Steen Jørgensen Christian A Olsen Gunnar Houen
author_facet	Anders N Hansen Christine D Bendiksen Lene Sylvest Tina Friis Dan Staerk Flemming Steen Jørgensen Christian A Olsen Gunnar Houen
author_sort	Anders N Hansen
title	Synthesis and antiangiogenic activity of N-alkylated levamisole derivatives.
title_short	Synthesis and antiangiogenic activity of N-alkylated levamisole derivatives.
title_full	Synthesis and antiangiogenic activity of N-alkylated levamisole derivatives.
title_fullStr	Synthesis and antiangiogenic activity of N-alkylated levamisole derivatives.
title_full_unstemmed	Synthesis and antiangiogenic activity of N-alkylated levamisole derivatives.
title_sort	synthesis and antiangiogenic activity of n-alkylated levamisole derivatives.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/9d81b70e42684a82a4be34cf4f293ded
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Synthesis and antiangiogenic activity of N-alkylated levamisole derivatives.

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