Design, synthesis and biological evaluation of benzo[b]thiophene analogues as novel ferroptosis inhibitor that inhibit fibrosarcoma cell proliferation

Abstract

While apoptosis activation has traditionally been considered as an anti-cancer mechanism, current research points to ferroptosis stimulation as a potentially effective cancer therapy. Glutathione peroxidase 4 (GPX4), an essential antioxidant enzyme, serves as a negative regulator of ferroptosis, and its targeted inhibition or degradation can efficiently induce this process. In this study, a potent ferroptosis inducer III-4 that bearing a benzo[b]thiophene moiety was developed by employing a sequential structure optimization process based on RSL-3 to inhibit cancer cells proliferation. At the same time, this cytotoxic activity could be reversed by ferroptosis inducer Fer-1, suggesting that III-4 functions as a ferroptosis inducer. The structure–activity relationship (SAR) of these compounds was also explored. At the cellular level, compound III-4 could block the generation of GSH, cause the accumulation of ROS and MDA, down-regulate GPX4 level, and finally trigger the Fe²⁺-mediated ferroptosis in HT1080 cell lines. Further biological investigation revealed that III-4 arrested the cell cycle at the S phase and inhibited HT1080 cell lines migration. These results indicated that compound III-4 is a candidate for the identification of novel ferroptosis inducer for fibrosarcoma cells.