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Cancer Chemother Pharmacol (2015) 75:691700
DOI 10.1007/s00280-015-2685-z
ORIGINAL ARTICLE
Biological evaluation of 4,5diarylimidazoles with hydroxamic acid appendages as novel dual mode anticancer agents
Katharina Mahal Sebastian Schruefer Gustav Steinemann Franziska Rausch Rainer Schobert Bernhard Biersack Michael Hpfner
Received: 16 December 2014 / Accepted: 16 January 2015 / Published online: 25 January 2015 Springer-Verlag Berlin Heidelberg 2015
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.
Keywords Imidazole Hydroxamate HDAC inhibitor
Antiangiogenic agent Antitumor agent Antimetastatic activity
Introduction
Histone deacetylases (HDACs) are among the most promising targets for anticancer drug development [1, 2]. The classical role of HDACs is to catalyze the N-deacetylation of lysine residues of histone proteins as part of the nucleosomes and thus to regulate gene expression. However, certain members of different HDAC classes are also responsible for the post-translational modication of non-histone substrates or proteins implicated in cell growth, cell migration or differentiation [38]. As a consequence, their inhibition interferes with a great number of cellular processes besides altering gene expression, by affecting proteinprotein interactions, signaling transduction or protein degradation [3, 4, 6, 9].
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 immunouorescence staining of cytoskeleton components and three-dimensional migration assays. The chorioallantoic membrane assay was used as an in...