Biospeciation, Interaction with Biomolecules and Mechanism of Action of Potential Cu and V Drugs

This doctoral project focused on copper(II) and vanadium(IV) complexes as prospective metallodrugs, investigating their coordination chemistry, speciation, and reactivity in biologically relevant media. A wide set of ligands, including phenanthroline derivatives, pyridinones, thiosemicarbazones, hydrazones, and 8-hydroxyquinoline, was employed to explore the structural diversity of these systems. The interactions of these metal complexes with proteins such as myoglobin, ubiquitin, lysozyme, cytochrome c, ribonuclease A, and serum albumin were analyzed by electrospray ionization mass spectrometry (ESI-MS), electron paramagnetic resonance (EPR) spectroscopy, quantum-mechanical (QM) calculations, and molecular docking. These studies identified specific binding sites, competition between ancillary ligands and protein residues, and stabilization of coordination motifs within the protein environment. Complementary investigations addressed their binding to DNA using molecular docking. The results clarified different binding modes, from groove binding to intercalation, and linked them to biological outcomes, particularly for newly synthesized copper hydrazone complexes tested against triple-negative breast cancer and melanoma cell lines. Overall, the findings demonstrate that the biological environment profoundly reshapes the chemistry of Cu(II) and V(IV) complexes. Proteins can stabilize transient species that are unstable in solution, while in the case of V(IV)O(acac)2, protein binding can even promote the assembly of polyoxidovanadates. These results highlight both the opportunities and the challenges in translating copper and vanadium coordination chemistry into therapeutic applications, and provide molecular-level insights for the rational design of new metallodrugs with improved selectivity and safety.