title: Synthesis, structural characterization and cytotoxic activity of ternary copper(II)-dipeptide-phenanthroline complexes. A step towards the development of new copper compounds for the treatment of cancer.
abstract: In the search for new compounds with antitumor activity, coordination complexes with different metals are being studied by our group. This work presents the synthesis and characterization of six copper complexes with general stoichiometry [Cu(L-dipeptide)(phen)]·nH2O (were phen=1,10-phenanthroline) and their cytotoxic activities against tumor cell lines. To characterize these systems, analytical and spectroscopic studies were performed in solid state (by UV-visible, IR, X-ray diffraction) including the crystal structure of four new complexes (of the six complexes studied): [Cu(Ala-Phe)(phen)]·4H2O, [Cu(Phe-Ala)(phen)]·4H2O, [Cu(Phe-Val)(phen)]·4.5H2O and [Cu(Phe-Phe)(phen)]·3H2O. In all of them, the copper ion is situated in a distorted squared pyramidal environment. The phen ligand is perpendicular to the dipeptide, therefore exposed and potentially available for interaction with biological molecules. In addition, for all the studied complexes, structural information in solution using EPR and UV-visible spectroscopies were obtained, showing that the coordination observed in solid state is maintained. The lipophilicity, DNA binding and albumin interaction were also studied. Biological experiments showed that all the complexes induce cell death in the cell lines: HeLa (human cervical adenocarcinoma), MCF-7 (human metastatic breast adenocarcinoma) and A549 (human lung epithelial carcinoma). Among the six complexes, [Cu(Ala-Phe)(phen)] presents the lowest IC50 values. Taken together all these data we hypothesize that [Cu(Ala-Phe)(phen)] may be a good candidate for further studies in vivo.
authors.affiliation: Facultad de Química, General Flores 2124, UdelaR, Montevideo, Uruguay.
authors.forename: Sebastián
authors.initials: S
authors.lastname: Iglesias
authors.affiliation: Facultad de Química, General Flores 2124, UdelaR, Montevideo, Uruguay.
authors.forename: Natalia
authors.initials: N
authors.lastname: Alvarez
authors.affiliation: Facultad de Química, General Flores 2124, UdelaR, Montevideo, Uruguay.
authors.forename: María H
authors.initials: MH
authors.lastname: Torre
authors.affiliation: Facultad de Química, General Flores 2124, UdelaR, Montevideo, Uruguay.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Kremer
authors.affiliation: Instituto de Física de São Carlos, Universidade de São Paulo, C.P. 369, 13560-970 São Carlos, SP, Brazil.
authors.forename: Javier
authors.initials: J
authors.lastname: Ellena
authors.affiliation: Departamento de Química, Centro Politécnico, Universidade Federal do Paraná, Curitiba, PR, Brazil.
authors.forename: Ronny R
authors.initials: RR
authors.lastname: Ribeiro
authors.affiliation: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes, 14040-901 Ribeirão Preto, SP, Brazil.
authors.forename: Rafael P
authors.initials: RP
authors.lastname: Barroso
authors.affiliation: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes, 14040-901 Ribeirão Preto, SP, Brazil.
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Costa-Filho
authors.affiliation: Instituto de Higiene, Av. Alfredo Navarro 3051, Facultad de Medicina, UdelaR, Montevideo, Uruguay.
authors.forename: M Gabriela
authors.initials: MG
authors.lastname: Kramer
authors.affiliation: Facultad de Química, General Flores 2124, UdelaR, Montevideo, Uruguay. Electronic address: gfacchin@fq.edu.uy.
authors.forename: Gianella
authors.initials: G
authors.lastname: Facchin
mesh_terms: D000418:Albumins / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000494:pharmacology; D003300:Copper / Q000737:chemistry; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D008958:Models, Molecular; D008968:Molecular Conformation; D010618:Phenanthrolines / Q000138:chemical synthesis* / Q000494:pharmacology; D011485:Protein Binding
chemical_list: D000418:Albumins; D000970:Antineoplastic Agents; D056831:Coordination Complexes; D004151:Dipeptides; D010618:Phenanthrolines; D003300:Copper
keywords: Copper complexes; Cytotoxic activity; DNA interaction; Dipeptide; Phen