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

• Published in: Journal of inorganic biochemistry 2016-09, Vol.162, p.52-61
• Main Authors: Facchin, Gianella, Veiga, Nicolás, Kramer, M. Gabriela, Batista, Alzir A., Várnagy, Katalin, Farkas, Etelka, Moreno, Virtudes, Torre, María H.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Antitumor agents; Atomic Force Microscopy; Cell Line, Tumor; Cisplatin - pharmacology; Coordination Complexes - chemical synthesis; Coordination Complexes - pharmacology; Copper - chemistry; Copper dipeptide complexes; Dipeptides - chemistry; DNA - chemistry; Docking; Female; Humans; Inhibitory Concentration 50; Isomerism; MCF-7 Cells; Mice; Microscopy, Atomic Force; Molecular Docking Simulation; Plasmids - chemistry; Spectroscopy; Stability; Structure-Activity Relationship; Superoxide Dismutase - antagonists & inhibitors; Superoxide Dismutase - chemistry; Superoxides - chemistry
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2016.06.005

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. Chemical, biochemical and biological studies with isomeric complexes Cu(AlaPhe) and Cu(PheAla) were performed using experimental and theoretical tools. Both complexes presented a good performance against breast cancer cells with low toxicity for fibroblasts. [Display omitted] •Two copper complexes with isomeric dipeptide (AlaPhe and Phe Ala) were developed.•Spectroscopic and voltammetric measurements, and equilibrium studies were performed.•The interaction with DNA and the SOD activity was measured.•Complexes are as effective as Cisplatin against breast cancer cells.•Complexes are considerably less toxic than Cisplatin in non-tumor cells.