Synthesis, encapsulation, and cytotoxic effects of new Schiff-base copper complexes

Gliomas remain one of the most lethal malignancies, with limited therapeutic options and poor prognosis under current standard-of-care regimens. Copper-based metallodrugs represent an emerging therapeutic strategy, but their clinical translation is hampered by rapid speciation in biological media and poor tumor selectivity. In this work, eight novel copper(II) Schiff-base complexes were synthesized from four diamine backbones (1,3-diaminopropane, 2,2-dimethyl-1,3-propanediamine, 2,2'-(ethylenedioxy)bis(ethylamine) and 1,3-diaminopropan-2-ol) and four aldehydes (3,4-dimethoxybenzaldehyde, vanillin, ethyl vanillin, and ortho-vanillin), and characterized by IR, UV-Vis, EPR, elemental analysis, and mass spectrometry. EPR spectroscopy revealed distinct coordination geometries across the series, ranging from distorted tetrahedral to a unique square-planar N₂O₂ geometry in [Cu(OVDP)](ClO₄)₂ (compound OVDPCu, where OV = ortho-vanillin and DP = 1,3-diaminopropane). All complexes were encapsulated in liposomal nanocarriers by solvent nanoprecipitation, yielding monodisperse vesicles with incorporation efficiencies of 20-60%. Cytotoxicity was assessed by MTT assay against the glioblastoma cell line LN-18 and the non-tumorigenic hippocampal line mHippoE-2. Free ligands were low in activity, confirming that cytotoxicity is copper-dependent. OVDPCu was the most potent free complex against LN-18 cells, consistent with its square-planar geometry enhanced DNA-targeting capacity. Liposomal encapsulation of OVDPCu enhanced potency 3.8-fold over the free complex (EC₅₀ = 3.4 μM against LN-18), while maintaining a selectivity index of 5.1 over non-tumorigenic cells, attributed differential endocytic uptake by tumor cells and protection of the intact complex from premature serum protein interaction. These findings establish a clear structure-geometry-activity relationship in copper(II) Schiff-base chemistry and support encapsulated OVDPCu as a compelling candidate for further preclinical validation in glioblastoma models.