Ferroptosis of Cancer Cells via Tubulin Degradation and Mitochondrial Dysfunction: A Novel Mechanism of Anticancer Effect for Small-Molecule Anion Transporters

Synthetic anion transporters disrupt the homeostasis of cellular anions and may therefore be developed as a promising cancer therapy. Herein, we demonstrated that trifluoromethylation of a benzimidazole-based anion transporter led to up to 4.84 × 103-fold increase in the anionophoric activity and promising cytotoxicity toward the selected solid tumor cells. The most active compound 6 was able to efficiently elevate intracellular chloride anions, induce the degradation of tubulin, perturb microtubule stability, increase lipid peroxidation, and impair mitochondrial function. This compound predominantly triggered ferroptosis, along with apoptosis as a complementary mechanism, unveiling a new pathway for the anticancer effects of synthetic anion transporters. Furthermore, compound 6 demonstrated potent antitumor activity against HeLa xenografts with minimal side effects and might find high potentials in the field of cancer chemotherapy.