Novel Promising Estrogenic Receptor Modulators: Cytotoxic and Estrogenic Activity of Benzanilides and Dithiobenzanilides

Abstract

The cytotoxicity of 27 benzanilides and dithiobenzanilides built on a stilbene scaffold and possessing various functional groups in aromatic rings previously described for their spasmolytic properties was assayed on three human cancer cell lines (A549 –lung adenocarcinoma, MCF-7 estrogen dependent breast adenocarcinoma and MDA-MB-231 estrogen independent breast adenocarcinoma) and 2 non-tumorigenic cell lines (CCD39Lu–lung fibroblasts, MCF-12A - breast epithelial). Three compounds (6, 15 and 18) showed selective antiproliferative activity against estrogen dependent MCF-7 cancer cells and their estrogenic activity was further confirmed in MCF-7 transfected with an estrogen receptor reporter plasmid and in HEK239 cells over-expressing the estrogen receptor alpha (ERα). Compound 18 is especially interesting as a potential candidate for therapy since it is highly toxic and selective towards estrogen dependent MCF7 cell lines (IC50 = 5.07 μM versus more than 100 μM for MDA-MB-231) and almost innocuous for normal breast cells (IC50 = 91.46 μM for MCF-12A). Docking studies have shown that compound 18 interacts with the receptor in the same cavity as estradiol although the extra aromatic ring is involved in additional binding interactions with residue W383. The role of W383 and the extended binding mode were confirmed by site-directed mutagenesis.

Application of Various Molecular Modelling Methods in the Study of Estrogens and Xenoestrogens

“…Docking serves either to investigate the binding of estradiol to the ER or to dock other molecules, potentially new drugs, such as potent and highly selective estriol analogues [ 69 ]. In the second case, information from previous studies on estradiol behavior in an active site serves as reference data [ 70 , 71 , 72 , 73 ]. This is a starting point for the commonly applied research sequence: investigation of E2 binding mode, comparison with the calculation results for potential drugs, and confirmation of the hypothesis by analytical techniques.…”

“…This is a starting point for the commonly applied research sequence: investigation of E2 binding mode, comparison with the calculation results for potential drugs, and confirmation of the hypothesis by analytical techniques. Such a three-step process has been performed, for example, for estrogen-dependent MCF-7 cancer cells [ 70 ]. Eighteen compounds with antiproliferative activity have been docked into the cavity where E2 normally binds.…”

More Than Resveratrol: New Insights into Stilbene-Based Compounds

“…For example, 2-hydroxy-N-(4-hydroxyphenyl) benzamide, also known as osalmid (Figure 9) is a medicine used for treating acute and chronic cholecystitis and gallstone disease [178]. Previously, the literature data reported that osalmid is a potential ribonucleotide reductase small subunit M2-targeting compound with potent activity against a lamivudine (3TC)-resistant hepatitis B virus strain in vitro and in vivo [191].…”

“…The anticancer effect was confirmed in the OCI-LY8 xenograft model. Administration of DCZ0858 significantly prevented tumour growth by decreasing cell proliferation and inducing apoptosis without causing any damage to important organs [178]. Currently, osalmid is under clinical trial in the treatment of MM (ClinicalTrials.gov).…”

“…and NU-DUL-1 cell lines, respectively [178]. Treatment with DCZ0858 was associated with cell cycle block at phase G0/G1, the activation of internal and external apoptotic pathways, and the inhibition of the JAK2/STAT3 pathway [178].…”