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. 2023 Apr 18;28(8):3558.
doi: 10.3390/molecules28083558.

Systematic Studies on Anti-Cancer Evaluation of Stilbene and Dibenzo[ b,f]oxepine Derivatives

Filip Borys  1   2 , Piotr Tobiasz  1 , Marcin Poterała  1 , Hanna Fabczak  2 , Hanna Krawczyk  1 , Ewa Joachimiak  2
Affiliations

Systematic Studies on Anti-Cancer Evaluation of Stilbene and Dibenzo[ b,f]oxepine Derivatives

Filip Borys et al. Molecules. .

Abstract

Cancer is one of the most common causes of human death worldwide; thus, numerous therapies, including chemotherapy, have been and are being continuously developed. In cancer cells, an aberrant mitotic spindle-a microtubule-based structure necessary for the equal splitting of genetic material between daughter cells-leads to genetic instability, one of the hallmarks of cancer. Thus, the building block of microtubules, tubulin, which is a heterodimer formed from α- and β-tubulin proteins, is a useful target in anti-cancer research. The surface of tubulin forms several pockets, i.e., sites that can bind factors that affect microtubules' stability. Colchicine pockets accommodate agents that induce microtubule depolymerization and, in contrast to factors that bind to other tubulin pockets, overcome multi-drug resistance. Therefore, colchicine-pocket-binding agents are of interest as anti-cancer drugs. Among the various colchicine-site-binding compounds, stilbenoids and their derivatives have been extensively studied. Herein, we report systematic studies on the antiproliferative activity of selected stilbenes and oxepine derivatives against two cancer cell lines-HCT116 and MCF-7-and two normal cell lines-HEK293 and HDF-A. The results of molecular modeling, antiproliferative activity, and immunofluorescence analyses revealed that compounds 1a, 1c, 1d, 1i, 2i, 2j, and 3h were the most cytotoxic and acted by interacting with tubulin heterodimers, leading to the disruption of the microtubular cytoskeleton.

Keywords: biological activity; cancer cell; colchicine-binding site; dibenzo[b,f]oxepine; microtubule; tubulin.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 6
Figure 6
The structure of: (E)-2-hydroxy-2′,4′-dinitrostilbene (1a), (E)-2-hydroxy-3-methoxy-2′,4′-dinitrostilbene (1b), (E)-2-hydroxy-4-methoxy-2′,4′-dinitrostilbene (1c), (E)-2-hydroxy-5-methoxy-2′,4′-dinitrostilbene (1d), (E)-2-hydroxy-6-methoxy-2′,4′-dinitrostilbene (1e), (E)-2-hydroxy-4,5-dimethoxy-2′,4′-dinitrostilbene (1f), (E)-2-hydroxy-5,2′,4′-trinitrostilbene (1g), (E)-1-(2,4-dinitrostyryl)naphthalen-2-ol (1h) and (E)-2,4-dihydroxy-2′,4′-dinitrostilbene (1i).
Figure 7
Figure 7
The structure of: 3-nitrodibenzo[b,f]oxepine (2a), 6-methoxy-3-nitrodibenzo[b,f]oxepine (2b), 3-methoxy-7-nitrodibenzo[b,f]oxepine (2c), 2-methoxy-7-nitrodibenzo[b,f]oxepine (2d), 1-methoxy-7-nitrodibenzo[b,f]oxepine (2e), 2,3-dimethoxy-7-nitrodibenzo[b,f]oxepine (2f), 2,7-dinitrodibenzo[b,f]oxepine (2g), 9-nitrobenzo[b]naphtho[1,2-f]oxepine (2h), 7-nitrodibenzo[b,f]oxepin-3-ol (2i) and 7-nitrodibenzo[b,f]oxepin-3-yl acetate (2j).
Figure 8
Figure 8
The structure of: dibenzo[b,f]oxepin-3-amine (3a), 6-methoxydibenzo[b,f]oxepin-3-amine (3b), 7-methoxydibenzo[b,f]oxepin-3-amine (3c), 8-methoxydibenzo[b,f]oxepin-3-amine (3d), 9-methoxydibenzo[b,f]oxepin-3-amine (3e), 7,8-dimethoxydibenzo[b,f]oxepin-3-amine (3f), 8-nitrodibenzo[b,f]oxepin-3-amine (3g), benzo[b]naphtho[1,2-f]oxepin-9-amine (3h) and 7-aminodibenzo[b,f]oxepin-3-yl acetate (3j).
Figure 1
Figure 1
Structure of natural stilbenoids with anti-cancer activity: combretastatin CA1 and CA4 phosphate (CA1P and CA4P, respectively), as well as their disodium salts (OXi4503 and fosbretabulin, respectively).
Scheme 1
Scheme 1
Synthesis of stilbene 1a–i and dibenzo[b,f]oxepine 2a–j, 3a–h, 3j derivatives.
Figure 2
Figure 2
The cytotoxicity effect of tested compounds 1a–g, 1i, 2a–2j, 3a–3h, 3j at 100 μM on cancer HCT116 cells based on MTT assay after 48h of treatment.
Figure 3
Figure 3
Activity of compounds 1a, 1c, 1d, 1i, 2i, 2j, and 3h, in cancer cell lines (HCT116 and MCF-7) and normal cell lines (HEK293 and HDF-A) as determined with an MTT assay after 48 h of treatment. Experiments were performed in triplicate (N = 3). Data are presented as the mean ± SD.
Figure 4
Figure 4
Microtubular networks in the control and 1d-treated HTC116 cells visualized by staining with anti-α-tubulin 12g10 Ab. (a) Control cells—arrow: MTs arranged along the long cell axis; arrowhead: MTs lining the cell border. (b) Cells treated with compound 1d—arrow: amorphous material; arrowhead: center of microtubule organization with the arising microtubules.
Figure 5
Figure 5
Stick representation of the top-ranked docking poses (orange) and predicted interactions of compounds (a) 1d, (b) 1i, (c) 2i, and (d) 3h with αβ-tubulin (PDB code: 1SA0). For clarity, only amino acids interacting with ligands are shown. Blue lines represent hydrogen bond interactions; dashed gray lines represent hydrophobic interactions.
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