Journal Article

Synthesis, Structural Studies, and Biological Evaluation of Copper(I) and Copper(II) Complexes Supported by Bis(pyrazol-1-yl)acetate Ligand Functionalized with Amantadine for the Treatment of Glioblastoma

Aguzzi, Cristina, Colone, Marisa, Santini, Carlo, Stringaro, Annarita, Dupuis, Maria Luisa, Iucci, Giovanna, Calcabrini, Annarica, Caviglia, Miriam, Venditti, Iole, Quaglia, Wilma, Battocchio, Chiara, Migani, Sofia, Pellei, Maura, Meneghini, Carlo, Bozzuto, Giuseppina, Del Bello, Fabio, Amatori, Simone, Morelli, Maria Beatrice

2026

Overview

This paper reports the synthesis, structural characterization, and biological evaluation of a novel series of CuI and CuII complexes supported by an amantadine-functionalized bis(pyrazol-1-yl)acetate ligand (LAd) as potential anticancer agents for the treatment of glioblastoma (GBM). Comprehensive spectroscopic and structural investigations, including SR-XPS, XANES/EXAFS, and DFT modeling, confirmed the successful coordination of LAd to copper centers in both oxidation states, affording well-defined molecular architectures with distinct coordination geometries. Among the synthesized compounds, the CuI complexes bearing triphenylphosphine co-ligands (compounds 4 and 5) exhibited the strongest cytotoxicity against U87 MG and LN18 GBM cell lines, showing IC50 values lower than those of cisplatin. These complexes induced a pronounced redox imbalance through reactive oxygen species (ROS) overproduction and glutathione (GSH) depletion, leading to G2/M cell cycle arrest and cell death. Flow cytometry and Western blot analyses demonstrated that cell death occurs via caspase-dependent apoptosis in LN18 cells, as evidenced by PARP cleavage, downregulation of Bcl-xL, release of cytochrome c, and mitochondrial translocation of Bax. Altogether, these findings highlight the potential of lipophilic amantadine-functionalized CuI complexes as promising anticancer candidates targeting glioma cells through mitochondrial dysfunction and redox-mediated pathways.

• Publisher: MDPI AG,Multidisciplinary Digital Publishing Institute (MDPI)
• Subject: Amantadine - chemistry / Amantadine - pharmacology / Antineoplastic Agents - chemical synthesis / Antineoplastic Agents - chemistry / Antineoplastic Agents - pharmacology / Apoptosis - drug effects / Brain cancer / Cancer therapies / Cell growth / Cell Line, Tumor / Coordination Complexes - chemical synthesis / Coordination Complexes - chemistry / Coordination Complexes - pharmacology / Copper / Copper - chemistry / Copper - pharmacology / Cytotoxicity / Glioblastoma - drug therapy / Glioblastoma - metabolism / Glioblastoma - pathology / Glioma / Glutathione - metabolism / Humans / Ligands / Oxidation / Pyrazoles - chemistry / Reactive Oxygen Species - metabolism