Oral Presentation 21st International Conference on Biological Inorganic Chemistry 2025

Antitumoral vs. antiparasitic activity of Cu(II) and Zn(II) mixed ligands complexes (122254)

Lucia Otero 1 , José Ortega-Campos 2 , Mercedes Fernández 1 , Santiago Rostán Talasimov 1 , Juan Diego Maya 3 , Claudio Olea-Azar 2
  1. Química Inorgánica, Facultad de Química, Universidad de la República, Montevideo, MONTEVIDEO, Uruguay
  2. Laboratorio de Radicales Libres y Antioxidantes, Departamento de Química Inorgánica y Analítica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile
  3. Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile

Both cancer and parasitic illnesses are major global public health concerns. These diseases have many features in common which have prompted research into metal-based drugs with the potential to treat both conditions1. Based on that, we developed two families of zinc and copper heteroleptic complexes including hybrid 3-acetyl-4-hydroxycoumarin-thiosemicarbazones2 as ligands (H2L) and 1,10-phenanthroline (phen) as co-ligand. On one hand, the selected hybrid ligands combine in the same molecule two structures capable of inhibiting the growth of Trypanosoma cruzi (T. cruzi) parasite. On the other hand, introducing phenanthroline is intended to include DNA as a potential target for these complexes. Finally, complexation with bioactive essential metal ions, such as Cu(II) and Zn(II), aims to obtain species with an improved pharmacological profile.

Eight new [M(L)(phen)] M=Cu(II) and Zn(II) compounds were synthesized and fully characterized in solid state and in solution. Their biological activity was evaluated on MCF7, HCT-15, NCI-H1299, HL-60 cancer cell lines as well as on Dm28c T. cruzi trypomastigotes. HFF-1 and EA.hy926 cells were also included to evaluate compounds´ selectivity. Both copper and zinc compounds were likewise potent on selected cancer cell lines being two orders of magnitude more active than cisplatin. The most active and selective compound, [Zn(L4)(phen)], showed an IC50 of 150 nM on MCF7 cells. However, only [Cu(L)(phen)] complexes showed significant anti T. cruzi activities (IC50 = 0.5-1.5 mM).

The potential modes of antineoplastic and antiparasitic activity were studied. ESR spin trapping experiments and those using 2′,7′-dichlorodihydrofluorescein diacetate as redox probe showed that [Cu(L)(phen)] were able to selectively induce ROS generation inside the parasite. On the other hand, [Zn(L)(phen)] compounds induced over 90 % apoptotic cell death in MCF7 cells, causing mitochondrial dysfunction and a significant increase in mitochondrial superoxide. Finally, [M(L)(phen)] compounds interact weakly with DNA in an intercalative like manner.

67e6efa88d89b-Imagen1.png

  1. Machado J. F. et al. ChemMedChem 2023, 18, e202300074
  2. Rostán S. et al. Journal of Molecular Structure 2022, 1251, 131980.