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  2. Experimental and theoretical studies of copper complexes with isomeric dipeptides as novel candidates against breast cancer

Experimental and theoretical studies of copper complexes with isomeric dipeptides as novel candidates against breast cancer

  • J Inorg Biochem. 2016 Sep;162:52-61. doi: 10.1016/j.jinorgbio.2016.06.005.
Gianella Facchin 1 Nicolás Veiga 1 M Gabriela Kramer 2 Alzir A Batista 3 Katalin Várnagy 4 Etelka Farkas 4 Virtudes Moreno 5 María H Torre 6
Affiliations

Affiliations

  • 1 Química Inorgánica (DEC), Facultad de Química, UdelaR, Gral. Flores 2124, Montevideo, Uruguay.
  • 2 Departamento de Desarrollo Biotecnológico, Instituto de Higiene, Facultad de Medicina, UdelaR, A. Navarro 3051, Montevideo, Uruguay.
  • 3 Departamento de Química, Universidade Federal de São Carlos, 13565-905 São Carlos, SP, Brazil.
  • 4 Department of Inorganic and Analytical Chemistry, University of Debrecen, H-4010 Debrecen, PO Box 21, Hungary.
  • 5 Departamento de Química Inorgánica, Universitat de Barcelona, Martíi Franquès 1-11, 08028 Barcelona, Spain.
  • 6 Química Inorgánica (DEC), Facultad de Química, UdelaR, Gral. Flores 2124, Montevideo, Uruguay. Electronic address: mtorre@fq.edu.uy.
Abstract

In the search for new cytotoxic drugs, two copper complexes with isomeric dipeptides (Ala-Phe and Phe-Ala) were developed in order to determine the influence of their different structures in the modulation of the chemical, biochemical and biological properties. Spectroscopic, voltammetric and equilibrium studies were performed providing information about the chemical properties. The superoxide dismutase (SOD) activity was studied and showed differences of IC50 for both Cu-Ala-Phe (IC50=4.5) and Cu-Phe-Ala (IC50=45). The computational results permitted to explain this behavior proposing that it is feasible that the O2- anion is attracted straight to the positive zone in Cu-Ala-Phe whereas for Cu-Phe-Ala this phenomenon would happen to a smaller extent. Confirming our previous studies, both complexes interacted with DNA. Molecular docking studies showed that the position of the phenyl ring modulates the complex-DNA affinity and in Cu-Ala-Phe the docked conformation allows the copper ion to face the DNA basis, giving rise to a more stable complex-DNA adduct than for Cu-Phe-Ala. In spite of the fact that Atomic Force Microscopy showed plasmid compactation and aggregation for both complexes, the image showed softer changes in the case of Cu-Ala-Phe in comparison with those produced by Cu-Phe-Ala. In order to evaluate the effect of Cu-Ala-Phe and Cu-Phe-Ala complexes against tumor cells, we have employed three aggressive metastatic breast adenocarcinoma cellular models, derived from human (MDA-MB-231 and MCF-7) and mouse (4T1) spontaneous tumors. These experiments showed that both Cu-dipeptide complexes have a similar cytotoxic effect against breast Cancer cells, and lower toxicity against BJ non-tumor cells in comparison to Cisplatin.

Keywords

Antitumor agents; Atomic Force Microscopy; Copper dipeptide complexes; Docking; Spectroscopy; Stability.

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