COPPER COMPLEXES WITH MEMANTINE-CONJUGATED LIGANDS: SYNTHESIS AND CYTOTOXICITY AGAINST GLIOBLASTOMA

Over the years, copper complexes have gained significant interest for their diverse and promising applications in medicinal inorganic chemistry.[1] We have designed and synthesized novel copper(I) and copper(II) complexes bearing heteroscorpionate ligands conjugated with the bioactive molecule memantine, an antagonist of the N-methyl-D-aspartate (NMDA) receptor, widely used for treating different neurodegenerative diseases like Alzheimer. Bis(pyrazolyl)- and bis(3,5-dimethylpyrazolyl)-acetic acids were chosen as ligands thanks to their κ3N,N’,O coordination mode and conjugated with the drug memantine to yield the new chelating ligands LMem and L2Mem, respectively. The synthesis of the Cu(I) complexes involved the use of phosphane co-ligands, such as PPh3 and PTA, which served both to stabilize the +1 oxidation state of copper and to modulate the solubility of the resulting complexes. The MTT cell viability assay was employed as a primary method to evaluate the cytotoxicity of the newly synthesized complexes and uncoordinated ligands toward U87, T98, and U251 glioblastoma cell lines. Selected copper(I) complexes show a significant ability to reduce cell viability with IC50 values in the low micromolar range. Notably, unlike cisplatin, they exhibited significantly lower toxicity in non-tumor microglial BV2 cells, highlighting selective cytotoxicity. Their anticancer activity was shown to be Cu-dependent and it is mediated by increased ROS production, mitochondrial depolarization, and intracellular redistribution.