Copper complexes as candidate therapeutic agents against infiltrative glioblastoma cells

Copper-based compounds have long been explored for their anti-cancer potential and other biological effects. While positive results have been reported, their use as cytotoxic agents remains limited; additionally, novel ligands and complexes could provide alternative strategies for cancer treatment. In this work, we synthesised three Schiff base ligands and their corresponding copper(ii) complexes; the ligands included a non-substituted, an electron-withdrawing or an electron-donating substituent positioned para to the Cu-coordinating hydroxyl group to evaluate how these modifications might influence cytotoxicity. The complexes were assessed against highly invasive glioblastoma (GBM) cells grown in both 2D monolayers and 3D spheroid models. GBM is a grade 4 brain tumour with an extremely poor prognosis, and patient survival has shown little improvement over the past two decades, underscoring the urgent need for new therapeutic strategies. Our synthesised copper(ii) complexes demonstrated strong cytotoxic activity across four patient-derived GBM cell lines isolated from the tumours' invasive margin. All three compounds exhibited low micromolar potency, with IC₅₀ values below 10 μM in 2D cultures and below 20 μM in 3D spheroids. Treatment with the complexes led to a marked increase in reactive oxygen species, suggesting oxidative stress as a key component of their mechanism. However, caspase-3/7 activation remained minimal, indicating that cell metabolic impairment was not significantly associated with caspase-3/7-mediated apoptosis. This study demonstrates that Schiff base copper(ii) complexes hold meaningful therapeutic potential against a disease for which current outcomes remain devastating.