Design and synthesis of Sorafenib analogues and evaluation of their ferroptosis-inducing effects in tumor cells

Ferroptosis, a newly discovered form of cell death, has garnered significant attention in recent years, particularly in the development of anticancer drugs. This study was based on the marketed anticancer drug sorafenib and involved the design and synthesis of 12 novel derivatives of pyrrolo[2,1-f][1,2,4]triazine and quinazoline with various linkers to explore their potential to induce ferroptosis in cancer cells. Activity evaluations in three different cancer cell lines (HepG2, MDA-MB-231, and HT-1080) revealed that compounds using squaramide as a linker, particularly N-2-c1, exhibited significant anti-proliferative effects against ferroptosis-sensitive HT1080 cells, outperforming Sorafenib. Further mechanistic studies demonstrated that N-2-c1 effectively induced ferroptosis in HT1080 cells, leading to increased intracellular reactive oxygen species (ROS), lipid peroxidation accumulation, membrane potential damage, and elevated LDH release. Atomic force microscopy was employed to observe morphological changes in the cells, confirming ferroptosis-like alterations in HT1080 cells treated with N-2-c1. Additionally, computational docking analyses indicated that N-2-c1 exhibited superior binding affinity to GPX4 compared to Sorafenib and the control compound 7j-a1, further supporting its potential as a ferroptosis inducer. In conclusion, the compound N-2-c1 demonstrated selective induction of ferroptosis in tumor cells, providing a novel approach for the development of new anticancer therapies. Further investigations were recommended to elucidate the mechanisms and assess the clinical applicability.