Ferrocenyl Aminocresols Display Multimodal Activity Against Triple‐Negative Breast Cancer Cells In Vitro

Abstract Triple‐negative breast cancer (TNBC) lacks expression of the oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu), has an aggressive tumor phenotype, shows only a partial response to chemotherapy, and lacks clinically established targeted therapies. Therefore, there is a need to develop more effective drugs for the treatment of TNBC. The ferrocenyl benzoxazine and α‐aminocresols class of compounds gave a potential source of multimodal inhibitors of cancer based on previous studies. In this study, a set of ferrocenyl benzoxazines and α‐aminocresols were screened and characterized as potential inhibitors of TNBC in vitro. A panel of 11 compounds was screened for selective cytotoxicity to cancer cells over normal cell equivalents. Focusing on the previously proposed modes of action of their building blocks, α‐aminocresols 3a and 3b exhibited significant DNA binding capabilities and caused robust DNA damage in TNBC cells. In addition, both compounds exhibited significant ROS generation capability; however, introducing a ROS quencher in a cell viability assay only partially rescued the cells from the cytotoxicity effects of the α‐aminocresols. This, together with the observation that compounds 3a and 3b triggered significant protein aggregation in HCC1806 cells, supports a mixed mode of action for these compounds.