| Sumario: | Background & Objective: Pancreatic cancer is a highly aggressive malignancy that necessitates the development of novel chemotherapeutic agents with improved selectivity and efficacy. This study aimed to synthesize and biologically evaluate a series of Schiff base derivatives as potential anticancer agents against pancreatic cancer by assessing their cytotoxicity, selectivity, and ability to induce apoptosis in vitro. Materials & Methods: A different novel heterocyclic derivative, including dihydroquinazoline, oxazepine, tetrazole, and thiazine, were synthesized via a common Schiff base intermediate (Derivative D). The structural characterization of these compounds was performed using FTIR and 1^11H-NMR spectroscopy. To evaluate their therapeutic potential and selectivity, the synthesized derivatives were tested in vitro against PANC-1 (pancreatic cancer) and HDFn (normal human dermal fibroblast) cell lines. Results: MTT assays demonstrated dose-dependent inhibition of cell proliferation by all synthesized compounds. Among them, derivative D4 exhibited greater selectivity toward pancreatic cancer cells, with IC₅₀ values of 129.5 μg/mL for PANC-1 cells and 237.4 μg/mL for HDFn cells. In contrast, derivative D5 showed greater overall cytotoxicity but lower selectivity, with IC₅₀ values of 68.9 μg/mL for PANC-1 cells and 61.0 μg/mL for HDFn cells. High-content screening revealed that D4 treatment significantly reduced the number of viable cells and decreased mitochondrial membrane potential, accompanied by increased nuclear intensity and cell membrane permeability. Furthermore, D4 significantly activated both caspase-8 and caspase-9 at concentrations of 100 and 200 μg/mL (P = 0.0019 and P < 0.0001, respectively), indicating activation of both the extrinsic and intrinsic apoptotic pathways. Conclusion: These findings suggest that the structural optimization of Schiff base-derived heterocycles is a promising strategy for enhancing tumor selectivity and biological safety, potentially offering new avenues for anticancer therapy.
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