title: Experimental and theoretical studies of copper complexes with isomeric dipeptides as novel candidates against breast cancer.
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 IC50for 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.
authors.affiliation: Química Inorgánica (DEC), Facultad de Química, UdelaR, Gral. Flores 2124, Montevideo, Uruguay.
authors.forename: Gianella
authors.initials: G
authors.lastname: Facchin
authors.affiliation: Química Inorgánica (DEC), Facultad de Química, UdelaR, Gral. Flores 2124, Montevideo, Uruguay.
authors.forename: Nicolás
authors.initials: N
authors.lastname: Veiga
authors.affiliation: Departamento de Desarrollo Biotecnológico, Instituto de Higiene, Facultad de Medicina, UdelaR, A. Navarro 3051, Montevideo, Uruguay.
authors.forename: M Gabriela
authors.initials: MG
authors.lastname: Kramer
authors.affiliation: Departamento de Química, Universidade Federal de São Carlos, 13565-905 São Carlos, SP, Brazil.
authors.forename: Alzir A
authors.initials: AA
authors.lastname: Batista
authors.affiliation: Department of Inorganic and Analytical Chemistry, University of Debrecen, H-4010 Debrecen, PO Box 21, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Várnagy
authors.affiliation: Department of Inorganic and Analytical Chemistry, University of Debrecen, H-4010 Debrecen, PO Box 21, Hungary.
authors.forename: Etelka
authors.initials: E
authors.lastname: Farkas
authors.affiliation: Departamento de Química Inorgánica, Universitat de Barcelona, Martíi Franquès 1-11, 08028 Barcelona, Spain.
authors.forename: Virtudes
authors.initials: V
authors.lastname: Moreno
authors.affiliation: Química Inorgánica (DEC), Facultad de Química, UdelaR, Gral. Flores 2124, Montevideo, Uruguay. Electronic address: mtorre@fq.edu.uy.
authors.forename: María H
authors.initials: MH
authors.lastname: Torre
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000494:pharmacology; D003300:Copper / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D004151:Dipeptides / Q000737:chemistry*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007536:Isomerism; D061986:MCF-7 Cells; D051379:Mice; D018625:Microscopy, Atomic Force; D062105:Molecular Docking Simulation; D010957:Plasmids / Q000737:chemistry; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000737:chemistry; D013481:Superoxides / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D004151:Dipeptides; D013481:Superoxides; C014309:alanylphenylalanine; C039552:phenylalanylalanine; D003300:Copper; D004247:DNA; D013482:Superoxide Dismutase; D002945:Cisplatin
keywords: Antitumor agents; Atomic Force Microscopy; Copper dipeptide complexes; Docking; Spectroscopy; Stability