Selenium‐Containing 1,4‐Naphthoquinone Derivatives Trigger Reactive Oxygen Species and Apoptosis in Triple‐Negative Breast Cancer Cells

Cancer ranks as a leading cause of death worldwide, demanding new affordable therapies. Nature offers a diverse array of bioactive scaffolds, including 1,4-naphthoquinone, which serves as a precursor for numerous natural and synthetic compounds with potent antitumor properties. Selenium, an essential trace element, has shown significant potential in medicinal chemistry when incorporated into organic molecules. In this study, we synthesized 24 novel selenium-containing derivatives based on menadione (series A) and 1,4-naphthoquinone (series B), incorporating selenium as selenoester and selenocyanate functionalities. Initial cytotoxic screening at 25 and 10 µM against four cancer cell lines (MDA-MB-231, PC-3, HTB-54 and HCT-116) identified five active compounds, with B2 and B8 exhibiting the highest potency and selectivity against breast cancer cells. Further biological evaluation via the NCI Developmental Therapeutics Program confirmed their apoptosis induction and antiproliferative activity through reactive oxygen species (ROS) production. Molecular dynamics simulations additionally suggest that B2 and B8 may act as topoisomerase II alpha inhibitors. These results position compounds B2 and B8 as promising candidates for breast cancer therapy, paving the way for further investigation into their potential as chemotherapeutic agents.