Antiproliferative activity of a series of copper(ii) complexes derived from a furan-containing N-acylhydrazone: monomers, dimers, charge status, and cell mechanistic studies on triple negative breast cancer cells

Abstract

In this work, we evaluated the anticancer activity of compounds 1 (mononuclear) and 2 (dinuclear) copper(II) coordination compounds derived from the ligand 5-methylsalicylaldehyde 2-furoyl hydrazone (H₂L) over MDA-MB-231 Triple-negative breast cancer (TNBC) cells, and compared their activities with that of a newly synthesized, protonated, dinuclear analogue of 2 (complex 3). Here, we report the synthesis of compound 3 and it has been characterized in the solid state (X-ray diffraction, FTIR) and in solution (EPR, UV-Vis, ESI) as well as its electrochemical profile. Complexes 1–3 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 (CDDP), by a factor of 100 in the case of 2 and 3. Our results indicate that the protonation status of the amide group in H₂L plays an important role in the stability of the dimer, being compound 2 (amide-deprotonated) fairly stable in solution so we decided to continue the study of mechanism of action using this compound. Complex 2 increases the ROS production and induces cell programmed death on TNBC cells at very low micromolar concentrations (0.5–1.5 μM). Moreover, the compound 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.