Anti‐Cancer Effect of a New 5‐FU Derivative Containing Triazole‐Bearing Mannose (5‐FUD‐MAN) Against Human Breast Cancer Cells Through LC3B‐Mediated Cell Death

ABSTRACT Breast cancer remains one of the most common malignancies affecting women worldwide. Despite the effectiveness of traditional chemotherapeutic agents such as 5‐fluorouracil (5‐FU), their lack of selectivity often results in damage to healthy tissues, leading to undesirable adverse effects. The aim of this study was to modify 5‐FU with mannose containing 1,2,3‐triazole compound to reduce its toxic effect, and to investigate the anticancer properties of the resulting 5‐FU derivative (5‐FUD‐Man) in ER‐positive MCF‐7 breast cancer cells. Our results demonstrated that while 5‐FU caused significant cytotoxicity in both cancerous and healthy cells, 5‐FUD‐Man showed selective cytotoxicity, with minimal effects on MCF‐10A cells. Furthermore, immunofluorescence staining results indicated that 5‐FUD‐Man was more strongly activated apoptosis (Caspase‐3, AIF), autophagy‐mediated (LC3B), and stress‐associated signaling pathways (ERK1/2) in MCF‐7 cells compared to 5‐FU. These findings suggest that the combined use of carbohydrate‐based targeting via mannose and a bioactive triazole compound may enhance the selectivity and therapeutic efficacy of 5‐FU‐based treatments in breast cancer. Overall, 5‐FUD‐Man appears to be a promising candidate for further development as a more targeted and potentially safer therapeutic strategy.