Structural Modification of Gefitinib with 1,2,3-Triazole Hybrids and Evaluation of Their Anti-Breast Cancer Activity

Objective: Breast cancer is one of the most prevalent malignancies among women worldwide and a leading cause of cancer-related mortality. The emergence of resistance to existing therapies underscores the need for novel agents. Methods: In this study, gefitinib, a well-established tyrosine kinase inhibitor used in non-small cell lung cancer treatment, was structurally modified to generate a series of 1,2,3-triazole hybrids. All synthesized compounds were characterized and evaluated for their antiproliferative activity against the MCF-7 breast cancer cell line and the LO2 normal hepatic cell line. Results and Discussion: The biological assessment revealed that hybrids 2c and 2l exhibited the most potent anti-proliferative effects against MCF-7 cells, with IC50 values of 8.51 and 8.93 μM, respectively, while showing lower cytotoxicity toward LO2 cells. Both compounds significantly reduced MCF-7 cell viability. Apoptosis analysis demonstrated that compound 2l notably induced apoptotic cell death. Gene and protein expression profiling indicated that 2c and 2l modulated the expression of markers associated with oxidative stress, autophagy, DNA damage, and apoptosis. Staining assays for DNA damage and autophagosome formation further corroborated the anti-proliferative effects of 2c and 2l in MCF-7 cells. Conclusions: These findings suggest that the gefitinib-1,2,3-triazole hybrids 2c and 2l are promising candidates for further investigation as potential anti-tumor agents against breast cancer.