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.