Synthesis and Antiangiogenic Activity of N-Alkylated Levamisole Derivatives

Anders N. Hansen, Christine D. Bendiksen, Lene Sylvest, Tina Friis, Dan Staerk, Flemming Steen Jorgensen, Christian A. Olsen, Gunnar Houen

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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.
Original languageEnglish
JournalP L o S One
Volume7
Issue number9
Pages (from-to)Article No.: e45405
ISSN1932-6203
DOIs
Publication statusPublished - 2012

Keywords

  • cell morphology
  • structure-activity relationship
  • tumor Neoplasms (MeSH) neoplastic disease drug therapy
  • Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] HUVEC cell line cell_line human umbilical vein endothelial cells NHDF cell line cell_line normal human dermal fibroblast cells
  • (S)-levamisole hydrochloride antineoplastic-drug synthesis efficacy
  • N-methyllevamisole antineoplastic-drug synthesis efficacy
  • para-bromolevamisole antineoplastic-drug synthesis efficacy
  • suramin 145-63-1 antineoplastic-drug efficacy
  • 02508, Cytology - Human
  • 10060, Biochemistry studies - General
  • 12512, Pathology - Therapy
  • 22002, Pharmacology - General
  • 22005, Pharmacology - Clinical pharmacology
  • 24004, Neoplasms - Pathology, clinical aspects and systemic effects
  • 24008, Neoplasms - Therapeutic agents and therapy
  • 32500, Tissue culture, apparatus, methods and media
  • cell culture laboratory techniques, culturing techniques
  • in vitro angiogenesis assay laboratory techniques
  • Pharmacology
  • Tumor Biology

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