Design and biological evaluation of novel biphenyl-dihydropyrimidinone derivatives with selective anticancer and...

This study reports the p-toluenesulfonic acid-catalyzed synthesis of three novel 3,4-dihydropyrimidin-2(1H)-one derivatives (4a = PMe, 4b = PPh, 4c = PNO₂) based on a 1,1'-biphenyl, and the evaluation of their cytotoxic, genotoxic, antioxidant, and apoptosis-related effects in vitro and in vivo. Structural characterization was performed using FT-IR, ¹H NMR, APT-¹³C NMR, and LC/MS-MS. Cytotoxicity was assessed on A549 human lung cancer and MRC-5 normal lung fibroblast cells using the WST-8 assay, while genotoxicity was evaluated using the Drosophila wing SMART assay. qRT-PCR was conducted to analyze gene expression related to cellular stress responses, antioxidant defense, and apoptosis in both cell lines and Drosophila melanogaster. All compounds exhibited dose-dependent cytotoxicity toward A549 cells with low toxicity in MRC-5 cells, indicating selective anticancer activity. Compound 4b showed the strongest cytotoxic effect (highest potency), whereas compound 4c exhibited the highest selectivity index (SI = 1.22), indicating a more favorable therapeutic window. Compound 4a induced a pro-apoptotic shift in the BAX/BCL-2 ratio, and all compounds enhanced antioxidant gene expression, particularly 4a. No significant genotoxic effects were detected. These findings suggest that the synthesized dihydropyrimidinone derivatives possess selective anticancer potential and favorable genotoxic safety profile, with mechanistic diversity supporting their relevance for targeted cancer therapy.