Copper complexes bearing heteroscorpionate ligands conjugated with bioactive compounds as potential anticancer agents

Copper complexes are coming out as promising antitumor agents due to the elevated need for copper in cancer tissues compared to that in normal cells and its role as a limiting factor for multiple aspects of tumor progression, including angiogenesis, growth, and metastasis. Copper complexes were synthesized employing bis(pyrazolyl)acetic acids as ligands, due to their stability, flexibility and ease to be functionalized. They were bioconjugated with biologically active compounds, such as metronidazole, an antibiotic agent investigated for hypoxia-selective cytotoxicity, an antagonist for the NMDA receptor, endowed with micromolar cytotoxic activity on a panel of solid tumor cell lines and lonidamine, an antineoplastic drug, to obtain Cu(I) and Cu(II) complexes potentially able to exert an anticancer activity through synergistic mechanisms of action. To stabilize copper in the +1 oxidation state and to modulate the solubility profile of the related Cu(I) complexes, hydrophilic or lipophilic phosphanes, such as PTA and PPh3 respectively, were used as coligands. The new copper complexes and the corresponding uncoordinated ligands were evaluated for their ability to promote cell death against a panel of human cancer cell lines, cisplatin resistant tumor cell lines and spheroids, evaluating also cellular uptake, mechanism of action and morphological modifications induced inside the tumor cells. All the complexes were in general more active that cisplatin, both in 2D and 3D cell cultures, showing their effect in the low micromolar concentration, while the related free ligands did not show relevant cytotoxic activity. The mechanism of action for the tested complexes was the paraptotic one, a type of programmed cell death different from the classical apoptosis induced by drugs such as cisplatin, potentially leading to the overcoming of the inherited or acquired cisplatin or multi-drug resistance.