Curcumin derivatives as ferroptosis inducers: design, synthesis and anti breast cancer activity evaluation

Curcumin (CUR) is a natural product isolated from Curcuma longa L., which has become a research hotspot due to its significant anti-tumor activity by inducing tumor cell apoptosis and inhibiting proliferation. This study designed and synthesized 20 CUR derivatives containing 1,2,3-triazoles and heterocycles by modifying the methylene group between two carboxyl groups of CUR and hybridizing with aldehyde containing fragments. Among them, compound A4 showed significant in vitro anti proliferative activity against 4T1 and MDA-MB-231, and could dose dependently induce early and late apoptosis in 4T1 cells. Further research has found that A4 induces ferroptosis in 4T1 cells by regulating the levels of reactive oxygen species (ROS), ferrous ions (Fe²⁺), lipid peroxidation (LPO), and glutathione (GSH), as well as disrupting the integrity and homeostasis of mitochondrial membranes. In addition, A4 significantly inhibits the expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), while promoting the expression of p53 protein. Gene knockout test confirmed that A4 may induce cell ferroptosis through p53/SLC7A11/GPX4 signaling pathway and play an anti breast cancer role. These findings indicate that CUR derivative A4 is a new type of ferroptosis inducer. It can induce apoptosis of cells by regulating multiple targets in cells to achieve the purpose of anti breast cancer, which is helpful for cancer treatment and overcoming the further development of drug resistance.