Propriedades citotóxicas de complexos de Cu(I)-Trifenilfosfina com ligantes aciltioureias ou naftoquinonas

Abstract

In this work, the synthesis, characterization, and evaluation of the cytotoxic activity of sixteen Cu(I)/Triphenylphosphine complexes containing the acylthiourea or naphthoquinones ligands are presented. The complexes were divided into two series based on the classes of the ligands used. The first series is composed of the neutral complexes of general formula [Cu(Ln)(PPh3)2] (1-6) and monocationic complexes of general formula [Cu(Ln)(PPh3)2]NO3 (1a 6a), where Ln= acylthiourea and PPh3= triphenylphosphine. The second series is composed of the neutral complexes of general formula [Cu(NQn)(PPh3)2] (1b 4b), where NQn= naphthoquinone and PPh3= triphenylphosphine. All complexes were characterized by different techniques such as elemental analysis, molar conductivity, infrared absorption spectroscopy, 1D and 2D nuclear magnetic resonance (31P{1H}, 1H and 13C{1H}), mass spectrometry, and X-ray diffraction. In the 13C{1H} NMR spectra, the complexes (1-6) stood out by showing the unusual chemical shift pattern, for the C=O and C=S carbon atoms of the acylthiourea ligand after bidentate (S, O) and anionic coordination. The experimental results were supported by DFT studies that suggested that relativistic effects strongly influenced the NMR protection constants of the light atoms due to coordination to the heavy atom Cu. The stability of the complexes in the cell culture medium was investigated and all the complexes were shown to be unstable, directly influencing the biological results obtained. The in vitro cytotoxicity of the complexes was determined in the breast (MCF7 and MDA MB-231) and lung (A549) tumor cell lines and in the corresponding non-tumor breast (MCF-10A) and lung (MRC-5) cell lines, and all complexes were actives exhibiting IC50 values in the same range in different cell lines. The compounds were more active than the free ligands and the precursor salt of the complexes in different cell lines, showing that even unstable complexes are relevant for the cytotoxic action. In general, the acylthiourea series complexes, 1 and 1a, were able to change the morphology of MDA-MB-231 cells, inhibit colony formation, showing cytotoxic and cytostatic effects on this cell line, significantly altering the cytoskeleton of cells, reducing the density, and promoting the condensation of the F-actin filaments. They promoted the increase of cells in the fragmented DNA region (sub-G0) and induced cell death by apoptosis. The complexes of the naphthoquinone series, 1b, and 4b, altered the morphology of MDA-MB-231 cells, inhibited colony formation at concentrations higher than the IC50, and were able to inhibit cell migration. Finally, the compounds synthesized and characterized in this work are relevant reports of copper (I) complexes with cytotoxic properties in different tumor cell lines with potential for future studies in vivo models.