Abstract
A series of coumarin derivatives and isosteres were synthesized from the reaction of triflic intermediates with phenylboronic acids, terminal alkynes, and organozinc compounds through palladium-catalyzed cross-coupling reactions. The in vitro cytotoxic effect of the compounds was evaluated against two non-small cell lung carcinoma (NSCLC) cell lines (A-549 and H2170) and a normal cell line (NIH-3T3) using cisplatin as a reference drug. Additionally, the effects of the most promising coumarin derivative (9f) in reversing the epithelial-to-mesenchymal transition (EMT) in IL-1β-stimulated A549 cells and in inhibiting the EMT-associated migratory ability in A549 cells were also evaluated. 9f had the greatest cytotoxic effect (CC50 = 7.1 ± 0.8 and 3.3 ± 0.5 μM, respectively against A549 and H2170 cells) and CC50 value of 25.8 µM for NIH-3T3 cells. 9f inhibited the IL-1β-induced EMT in epithelial cells by inhibiting the F-actin reorganization, attenuating changes in the actin cytoskeleton reorganization, and downregulating vimentin in A549 cells stimulated by IL-1β. Treatment of A549 cells with 9f at 7 µM for 24 h significantly reduced the migration of IL-1β-stimulated cells, which is a phenomenon confirmed by qualitative assessment of the wound closure. Taken together, our findings suggest that coumarin derivatives, especially compound 9f, may become a promising candidate for lung cancer therapy, especially in lung cancer promoted by NSCLC cell lines.
Highlights
Cancer is characterized by cells with uncontrolled division, genome heterogeneity, and invasiveness to other tissues via blood or lymph nodes
The synthesis of the coumarin core can be performed by different synthetic methodologies, among which the most common are Pechmann, Wittig, Knoevenagel, and Perkin reactions [11]
We found that the treatment of cells with 9f (7 μM) significantly diminished the expression of mesenchymal marker vimentin in IL-1β-stimulated A549 cells (Figure 3A,B), which is a phenomenon confirmed by the quantitative assessment by flow cytometry (Figure 3B–C)
Summary
Cancer is characterized by cells with uncontrolled division, genome heterogeneity, and invasiveness to other tissues via blood or lymph nodes. Lung cancer is one of the most common types, with a mortality rate of around 18.4% according to the GLOBOCAN report [2]. Mesenchymal transition (EMT)—a known cellular program allowing polarized cells to shift to a mesenchymal phenotype with increased cellular motility [5]—has a central role in cancer progression and metastatic dissemination [6,7,8]. For this reason, the EMT has become as a target of interest for anticancer therapy [9,10]
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