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Biological evaluation of 4,5-diarylimidazoles with hydroxamic acid appendages as novel dual mode anticancer agents

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Abstract

Purpose

New (4-aryl-1-methylimidazol-5-yl)cinnamoylhydroxamic acids were prepared as potential dual mode anticancer agents combining the antivascular effect of the 4,5-diarylimidazole moiety and the histone deacetylases (HDAC) inhibition by the cinnamoyl hydroxamate.

Methods

Their antiproliferative activity against a panel of primary cells and cancer cell lines was determined by MTT assays and their apoptosis induction by caspase-3 activation. Their ability to reduce the activity of HDAC was measured by enzymatic assays and Western blot analyses of cellular HDAC substrates. Additional effects on cancer cell migration were ascertained via immunofluorescence staining of cytoskeleton components and three-dimensional migration assays. The chorioallantoic membrane assay was used as an in vivo model to assess their antiangiogenic properties.

Results

The 4-phenyl- and 4-(p-methoxyphenyl)-imidazole derivatives had a greater antiproliferative and apoptosis inducing effect in a variety of cancer cell lines when compared with the approved HDAC inhibitor SAHA, and most distinctly so in non-malignant human umbilical vein endothelial cells. Like SAHA, both compounds acted as pan-HDAC inhibitors. In 518A2 melanoma cells, they led to hyperacetylation of histones and of the cytoplasmic HDAC6 substrate alpha-tubulin. As a consequence, they inhibited the migration and invasion of these cells in transwell invasion assays. In keeping with its pronounced impact on endothelial cells, the 4-phenyl-imidazole derivative also inhibited the growth and sprouting of blood vessels in the chorioallantoic membrane of fertilized hen eggs.

Conclusions

The 4-phenyl- and 4-(p-methoxyphenyl)-imidazole compounds combine the antivascular effects of 4,5-diarylimidazoles with HDAC inhibition by cinnamoyl hydroxamates and show additional antimetastatic activity. They are promising candidates for pleiotropic HDAC inhibitors.

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Authors and Affiliations

  1. Organic Chemistry Laboratory, University Bayreuth, 95440, Bayreuth, Germany

    Katharina Mahal, Sebastian Schruefer, Rainer Schobert & Bernhard Biersack

  2. Institute of Physiology, Charité-Universitätsmedizin Berlin, Virchowweg 6, 10117, Berlin, Germany

    Gustav Steinemann, Franziska Rausch & Michael Höpfner

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  1. Katharina Mahal
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  2. Sebastian Schruefer
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Correspondence to Bernhard Biersack or Michael Höpfner.

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280_2015_2685_MOESM1_ESM.doc

The online version of this article contains supplementary material (synthesis and compound characterization; additional method descriptions and data; original Western blot images), which is available to authorized users 1 (DOC 3705 kb)

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Mahal, K., Schruefer, S., Steinemann, G. et al. Biological evaluation of 4,5-diarylimidazoles with hydroxamic acid appendages as novel dual mode anticancer agents. Cancer Chemother Pharmacol 75, 691–700 (2015). https://doi.org/10.1007/s00280-015-2685-z

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  • DOI: https://doi.org/10.1007/s00280-015-2685-z

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