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

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.

Synthesis and Study of Building Blocks with Dibenzo[b,f]oxepine: Potential Microtubule Inhibitors

“…We decided to introduce fluoride into the molecule because, as described by Hecht et al [ 32 , 33 ], it is well-tolerated by the body [ 34 ], and its presence may shift the bands in the UV-vis spectra towards higher (not harmful for humans) frequencies. We obtained five amines using the optimized conditions for azo bond synthesis [ 31 ] ( 5a , 5b , and 5d – f ). In the reactions of aminedibenzo[ b,f ]oxepine derivatives ( 5a , 5b , and 5d – f ) with 1-fluoro-4-nitrosobenzene obtained in situ from the oxidation of 4-fluoroaniline were a set of five products ( 7a – e ).…”

“…The nitro group and the double bond were reacted in all cases (4a-4j). To reduce only the amino group (part (b) in Scheme 2), we used Zn in acetic acid acting on nitrodibenzo[b,f]oxepines (3a-c) to convert them to amino derivatives (5a-c) [31]. These results suggested that connecting a new biphenyl substituent with an expanded linker to dibenzo[b,f ]oxepine is relatively easy.…”

“…The nitro group and the double bond were reacted in all cases (4a-4j). To reduce only the amino group (part (b) in Scheme 2), we used Zn in acetic acid acting on nitrodibenzo[b,f ]oxepines (3a-c) to convert them to amino derivatives (5a-c) [31]. Next, according to the procedure described in reference [7], we obtained an azo dimer (6).…”

Medicinal chemistry perspective on the structure–activity relationship of stilbene derivatives

“…One of the traditional and commonly used methods for cancer treatment is chemotherapy, which targets specific proteins and cellular structures or processes. 50 …”