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

Abstract

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.

4-(1-Ethyl-4-anisyl-imidazol-5-yl)-N-hydroxycinnamide – A new pleiotropic HDAC inhibitor targeting cancer cell signalling and cytoskeletal organisation

“…Table 1 summarises the respective IC 50 values including those for vorinostat which serves as a reference pan-HDACi. As previously shown, bimacroxam 1 displayed a high toxicity against endothelial cells (Ea.hy926, HUVEC) [37] while the new etacrox 3 turned out to be most active with lowest IC 50 (72 h) values against most of the tested cancer cell lines including the multidrug-resistant HT-29 colon, MCF-7/Topo mammary, and KB-V1/Vbl cervix carcinoma cells. Non-malignant primary fibroblasts (CHF) were hardly affected by vorinostat or the imidazoles 1-3 which is typical of HDACi in general.…”

“…For bimacroxam 1 and animacroxam 2, a correlation between growth inhibition and an induction of apoptosis via caspase-3 activation was already detected [37]. For etacrox 3, we now examined the involvement of caspase-9 in its effect on 518A2 cells ( Fig.…”

“…Band intensity was recorded by visualisation of chemiluminescence (secondary antibody-HRP conjugates; ECL detection system, SER-VA) using a LAS-3000 imager (Fujifilm). If not stated otherwise, alpha-tubulin was used as a suitable loading control as previously shown [37]. The additional visualisation of acetylated alpha-tubulin was performed on a separate membrane from an identically loaded gel.…”

“…As a potential workaround we recently developed a new HDACi motif that links the common 2nd-generation para-cinnamylhydroxamate pharmacophore to 4,5-diphenylimidazoles, derived from the natural vascular-disrupting cis-stilbene combretastatin A-4 [35]. Such conjugates showed pronounced pan-HDAC inhibition exceeding that of vorinostat, but they lacked the tubulin affinity typical of the original imidazoles and of combretastatin A-4 [35][36][37]. Moreover, the 4,5-diaryl imidazole moiety confered an improved water-solubility and chemical stability.…”

HTP Nutraceutical Screening for Histone Deacetylase Inhibitors and Effects of HDACis on Tumor-suppressing miRNAs by Trichostatin A and Grapeseed (Vitis vinifera) in HeLa cells

“…Elevated expression of HDACs are evident in advanced malignancy, where inhibitors (HDACis) antagonize tumor growth (2,3) antagonize tumor growth (2,3), augment chemotherapy (4-7), reverse chemoresistance (3,8,9), attenuate metastasis, halt epithelial-mesenchymal transition (10)(11)(12) and block tumor immune evasion (13,14). With the overwhelming surge of HDACis being sought worldwide for nearly every type of cancer (e.g.…”