Abstract
Two novel series of compounds based on the 4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 4,5,6,7-tetrahydrobenzo[b]thiophene molecular skeleton, characterized by the presence of a 3′,4′,5′-trimethoxyanilino moiety and a cyano or an alkoxycarbonyl group at its 2- or 3-position, respectively, were designed, synthesized, and evaluated for antiproliferative activity on a panel of cancer cell lines and for selected highly active compounds, inhibition of tubulin polymerization, and cell cycle effects. We have identified the 2-(3′,4′,5′-trimethoxyanilino)-3-cyano-6-methoxycarbonyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine derivative 3a and its 6-ethoxycarbonyl homologue 3b as new antiproliferative agents that inhibit cancer cell growth with IC50 values ranging from 1.1 to 4.7 μM against a panel of three cancer cell lines. Their interaction with tubulin at micromolar levels leads to the accumulation of cells in the G2/M phase of the cell cycle and to an apoptotic cell death. The cell apoptosis study found that compounds 3a and 3b were very effective in the induction of apoptosis in a dose-dependent manner. These two derivatives did not induce cell death in normal human peripheral blood mononuclear cells, suggesting that they may be selective against cancer cells. Molecular docking studies confirmed that the inhibitory activity of these molecules on tubulin polymerization derived from binding to the colchicine site.
Highlights
Cancer, which is the result of deviation of cell growth control mechanisms, has become a major worldwide disease and the second leading cause of mortality in developed countries, with almost 20Molecules 2020, 25, 1690; doi:10.3390/molecules25071690 www.mdpi.com/journal/moleculesMolecules 2020, 25, 1690 million deaths annually [1,2]
A large number of small molecules displaying wide structural diversity and derived from natural sources or obtained by chemical synthesis have been identified within the last several decades [11,12,13] and have been shown to interfere with microtubules, polymeric structures composed of α- and β-tubulin heterodimers [14,15,16]
We have described the synthesis and biological evaluation of two classes of compounds based on the 4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 4,5,6,7-tetrahydrobenzo[b]thiop hene skeletons, both characterized by the presence of a common 30,40,50 -trimethoxyanilino moiety at the 2-position and a cyano or different alkoxycarbonyl groups at the 3-position
Summary
Cancer, which is the result of deviation of cell growth control mechanisms, has become a major worldwide disease and the second leading cause of mortality in developed countries, with almost 20Molecules 2020, 25, 1690; doi:10.3390/molecules25071690 www.mdpi.com/journal/moleculesMolecules 2020, 25, 1690 million deaths annually [1,2]. Prominent examples of tubulin-binding compounds used clinically for cancer treatment include microtubule-stabilizers that inhibit microtubule function by promoting abnormally high levels of tubulin polymerization. Examples of such drugs include paclitaxel (Taxol) and its semisynthetic analogue docetaxel (Taxotere) [17,18]. The vinca alkaloids vincristine, vinorelbine, and vinblastine destabilize microtubules and act as microtubule depolymerizers by inhibiting tubulin polymerization [19]. Both taxoids and vinca alkaloids interact with β-tubulin, but at different sites, named the taxol and vinca sites, respectively [20]. The colchicine-site binders that inhibit tubulin assembly [21] are another class of compounds in discovery and development, including combretastatin
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