Organoselenocyanate-Conjugated NBDHEX Derivatives as Potent Anticancer Agents for the Treatment of Breast Cancer via ROS-Regulated Signaling Pathways

Estrogen receptor-positive (ER+) breast cancer is the predominant subtype of breast cancer, having significant therapeutic drawbacks, largely driven by undesired toxicity and drug resistance associated with conventional treatment regimens. Conjugating organoselenium moieties to various drugs or enzyme inhibitors can be a promising approach for the treatment of breast cancer with multimodal benefits in overcoming the limitations of conventional therapies. Herein, we report the synthesis and evaluation of a series of organoselenium-NBDHEX hybrids as potent anticancer agents. Based on the selective antiproliferative activities of these derivatives against ER+ breast cancer cells (MCF-7) over the nonmalignant cells (L132), the hybrid <b>NHSe-2</b>, having a 2-selenocyanatoacetyl linker, was chosen as the lead analogue for further studies. The compound <b>NHSe-2</b> exhibited notable antiproliferative activity with S-phase arrest of cells and late-phase apoptosis in MCF-7 cells. Most importantly, <b>NHSe-2</b> induced ROS-mediated degradation of HDAC4, NF-κB, and c-Myc, resulting in potent antiproliferation and eventually leading to apoptosis of MCF-7 cells. Moreover, it suppressed β-catenin expression, unlike NBDHEX; however, it retained GSTP1 inhibitory potency, indicating its add-on therapeutic potential. Therefore, <b>NHSe-2</b> could be a potential anticancer agent and can be considered for further analysis for its multimodal activity in the realm of cancer research in the future.