Oral Presentation 21st International Conference on Biological Inorganic Chemistry 2025

Dimers of N-acylhydrazone-containing copper(II) complexes constitute potent antitumor agents: solution chemistry and mechanistic studies in TNBC cells (122234)

Fagner da Silva Moura 1 , Olivia Espindola-Moreno 2 , Ignacio E. León 2 , Nicolás A. Rey 1
  1. Pontifical Catholic University of Rio de Janeiro, Rio De Janeiro, RJ, Brazil
  2. CEQUINOR, CONICET-Universidad Nacional de La Plata, La Plata, Buenos Aires, Argentina

Breast cancer is one of the prevalent malignancies in women, with a projected 2.3 million cases by 2030.1 Among the most aggressive types is triple-negative breast cancer (TNBC), which accounts for around 15% of cases and is associated with a poor prognosis.2 In recent decades, copper complexes, especially the mononuclear ones, have been studied as potential substitutes for platinum-based chemotherapeutics, aiming to reduce side effects.3 In this context, our research group has been studying dicopper(II) complexes derived from N-acylhydrazonic binucleating ligands with truly promising results.4-6 More recently, we showed that stable dimers of hydrazone-containing copper complexes are also more active than the respective mononuclear derivatives.7,8 Herein, we describe three complexes (a monomer -1- and two dimers -2 and 3) of the tridentate ligand 5-methylsalicylaldehyde-2-furoyl hydrazone (H2L). Besides the crystallographic description, a thorough in-solution characterization was performed, including EPR and UV-Vis spectroscopies, cyclic voltammetry and ESI-MS. Their cytotoxicity was determined in the TNBC cell line MDA-MB-231 and mechanistic studies were executed as well. While the neutral dimer 2 seems to maintain its dinuclear structure in physiological medium, complexes 1 and 3 transform in a single, mononuclear common derivative in solution. All the complexes impaired cell viability from 0.5 to 2.5 μM, with IC50 values around 1.25 μM for complexes 2 and 3 and a slightly higher value of 2.0 μM for the monomer 1. It is important to highlight that the three compounds are more active than cisplatin. Complex 2 increases the ROS production and induces cell programmed death on TNBC cells at 0.5–1.5 μM. Moreover, 2 decreased the amount of breast CSCs on MDA-MB-231 cells reducing the percentage of CD44+/CD24−/low cells at 1 and 1.5 μM. As a conclusion of this work, we can state that this type of dimers constitutes potent antitumor agents.

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