Microtubule targeting agents (MTAs) are used as clinically effective chemotherapies for cancer treatment but might be limited by the acquired or intrinsic resistance of cancer cells to apoptosis. The vulnerability of therapy-resistant cancers to ferroptosis provides an alternative way to overcome drug resistance. In this study, on the basis of the MTAs obtained in our previous studies, a series of MTAs were synthesized, and detailed structure-activity relationships were obtained through extensive molecular dynamics studies. Among them, a diphenylethene derivative, compound 33, displayed the most potent activity in vitro and in vivo, with IC50 values of 10-50 nM toward six cancer cell lines and a 78.6% tumor growth inhibition in vivo. Interestingly, although it acted as the MTA, compound 33 triggered cell death mainly through cell ferroptosis rather than apoptosis, which might provide an alternative way to eradicate apoptosis-related drug resistance.