A new series of topsentin analogs, in which the central imidazole ring of the natural lead was replaced by a 1,2,4‐oxadiazole moiety, was efficiently synthesized. All derivatives were pre‐screened for antiproliferative activity against the National Cancer Institute (NCI‐60) cell lines panel. The five most potent compounds were further investigated in various pancreatic ductal adenocarcinoma (PDAC) cell lines, including SUIT‐2, Capan‐1, and Panc‐1 cells, eliciting EC50 values in the micromolar and sub‐micromolar range, associated with significant reduction of cell migration. These remarkable results might be explained by the effects of these new topsentin analogues on epithelial‐to‐mesenchymal transition markers, including SNAIL‐1/2 and metalloproteinase‐9. Moreover, flow cytometric analysis after Annexin V‐FITC and propidium iodide staining demonstrated that these derivatives enhanced apoptosis of PDAC cells. Keeping with these data, the PathScan intracellular signaling and ELISA array revealed cleavage of caspase‐3 and PARP and a significant inhibition of GSK3β phosphorylation, suggesting this kinase as a potential downstream target of our novel compounds. This was further supported by a specific assay for the evaluation of GSK3β activity, showing IC50 values for the most active compounds against this enzyme in the micromolar range.
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