New copper(ii) and oxidovanadium(iv) complexes with a vitamin B6 Schiff base: mechanism of action and synergy studies on 2D and 3D human osteosarcoma cell models

Abstract

We report the synthesis, characterization and anticancer activity of a new Schiff base (H₂L) derived from the condensation of pyridoxamine with pyridoxal and its novel copper(II) and oxidovanadium(IV) complexes: [Cu(HL)Cl] (1), [Cu(LH₂)(phen)]Cl₂ (2), [Cu(LH₂)(amphen)]Cl₂ (3), [V^IVO(HL)Cl] (4), and [V^IVO(LH₂)(phen)]Cl₂ (5), where phen is 1,10-phenanthroline and amphen is its 5-amino derivative. All compounds were characterized by analytical and spectroscopic techniques, namely FTIR, UV-vis and EPR spectroscopy. Their stability in aqueous media was evaluated, revealing that the presence of the phen co-ligand significantly increases the stability. The ternary Cu(II) complexes (2 and 3) impaired cell viability of osteosarcoma cells (MG-63) (IC₅₀ values of 3.6 ± 0.6 and 7 ± 1.9 μM for 2 and 3), while 1 and the V^IVO complexes did not show relevant anticancer activity. Complexes 2 and 3 are also more active than cisplatin (CDDP). Synergistic studies between 2 and sorafenib showed significant synergism on MG-63 cells for the following combinations: 2 (2.0 μM) + sorafenib (10.0 μM) and 2 (2.5 μM) + sorafenib (12.5 μM), whilst the combination of 2 and CDDP did not show synergy. Complex 2 interacts with DNA, inducing significant genotoxic effects on MG-63 cells from 1.0 to 2.5 μM and it increases the ROS levels 880% over basal. Moreover, 2 induces apoptosis at 1.0 and 2.0 μM, while its combination with sorafenib induces apoptosis and necrosis. Finally, compound 2 reduces the cell viability of MG-63 spheroids showing an IC₅₀ value 7-fold lower than that of CDDP (8.5 ± 0.4 μM vs. 65 ± 6 μM). The combination of 2 and sorafenib also showed synergism on spheroids, suggesting that the combination of these drugs improves the anticancer effect against bone cancer cells.