Anti-Cancer Stem Cell Properties of Square Planar Copper(II) Complexes with Vanillin Schiff Base Ligands

Current breast cancer therapies are unable to positively impact the lives of a significant proportion of diagnosed patients (24% based on 10-year survival rate). Breast cancer relapse and metastasis, the leading cause of breast cancer-associated deaths, is linked to the existence of breast cancer stem cells (CSCs). Redox-modulating metal complexes have been used to perturb the redox balance in breast CSCs and effect cell death. Here, we sought to expand this promising class of anti-breast CSC agents. Specifically, we report the synthesis, and anti-breast CSC properties of a series of copper(II) complexes bearing regioisomeric vanillin Schiff base ligands (<b>1</b>-<b>4</b>). X-ray crystallography studies show that the copper(II) complexes <b>1</b>-<b>4</b> adopt square planar geometries with the copper(II) centre coordinated to two vanillin Schiff base ligands. The most effective copper(II) complex within the series <b>4</b> displays low micromolar potency towards breast CSCs, up to 4.6-fold higher than salinomycin and cisplatin. Mechanistic studies indicate that copper(II) complex <b>4</b> elevates reactive oxygen species levels in breast CSCs, leading to activation of the JNK/p38 pathway and caspase-dependent apoptosis. Overall, this work expands the library of anti-breast CSC copper(II) complexes and provides insight into their mode of action.