title: Reactivity of dinuclear copper(II) complexes towards melanoma cells: Correlation with its stability, tyrosinase mimicking and nuclease activity.
abstract: In this work, the influence of two new dinuclear copper(II) complexes in the viability of melanoma cells (B16F10 and TM1MNG3) was investigated, with the aim of verifying possible correlations between their cytotoxicity and their structure. One of the complexes had a polydentate dinucleating amine-imine ligand (complex 2), and the other a tridentate imine and a diamine-bridging ligand (complex 4). The analogous mononuclear copper(II) species (complexes 1 and 3, respectively) were also prepared for comparative studies. Crystal structure determination of complex 2 indicated a square-based pyramidal geometry around each copper, coordinated to three N atoms from the ligand and the remaining sites being occupied by either solvent molecules or counter-ions. Complex 4 has a tetragonal geometry. Interactions of these complexes with human albumin protein (HSA) allowed an estimation of their relative stabilities. Complementary studies of their reactivity towards DNA indicated that all of them are able of causing significant oxidative damage, with single and double strand cleavages, in the presence of hydrogen peroxide. However, nuclease activity of the dinuclear species was very similar and much higher than that of the corresponding mononuclear compounds. Although complex 2, with a more flexible structure, exhibits a much higher tyrosinase activity than complex 4, having a more rigid environment around the metal ion, both complexes showed comparable cytotoxicity towards melanoma cells. Corresponding mononuclear complexes showed to be remarkably less reactive as tyrosinase mimics as well as cytotoxic agents. Moreover, the dinuclear complexes showed higher cytotoxicity towards more melanogenic cells. The obtained results indicated that the structure of these species is decisive for its activity towards the malignant tumor cells tested.
authors.affiliation: Departamento de Química, Instituto de Química, Universidade de São Paulo, 05508-000 São Paulo, SP, Brazil.
authors.forename: Cléia Justino
authors.initials: CJ
authors.lastname: Nunes
authors.affiliation: Departamento de Patologia Básica, Universidade Federal do Paraná, 81531-990 Curitiba, PR, Brazil.
authors.forename: Beatriz Essenfelder
authors.initials: BE
authors.lastname: Borges
authors.affiliation: Departamento de Patologia Básica, Universidade Federal do Paraná, 81531-990 Curitiba, PR, Brazil.
authors.forename: Lia Sumie
authors.initials: LS
authors.lastname: Nakao
authors.affiliation: Aix Marseille Université, Centrale Marseille, CNRS, ISM2 UMR 7313, 13397 Marseille, France.
authors.forename: Eugénie
authors.initials: E
authors.lastname: Peyroux
authors.affiliation: Aix Marseille Université, Centrale Marseille, CNRS, ISM2 UMR 7313, 13397 Marseille, France.
authors.forename: Renaud
authors.initials: R
authors.lastname: Hardré
authors.affiliation: Aix Marseille Université, Centrale Marseille, CNRS, ISM2 UMR 7313, 13397 Marseille, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Faure
authors.affiliation: Aix Marseille Université, Centrale Marseille, CNRS, ISM2 UMR 7313, 13397 Marseille, France.
authors.forename: Marius
authors.initials: M
authors.lastname: Réglier
authors.affiliation: Aix Marseille Université, CNRS, Spectropole FR1739, 13397 Marseille, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Giorgi
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, 05508-000 São Paulo, SP, Brazil.
authors.forename: Marcela Bach
authors.initials: MB
authors.lastname: Prieto
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, 05508-000 São Paulo, SP, Brazil.
authors.forename: Carla Columbano
authors.initials: CC
authors.lastname: Oliveira
authors.affiliation: Departamento de Química, Instituto de Química, Universidade de São Paulo, 05508-000 São Paulo, SP, Brazil. Electronic address: amdcferr@iq.usp.br.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Da Costa Ferreira
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003300:Copper / Q000737:chemistry*; D004249:DNA Damage; D003851:Deoxyribonucleases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000378:metabolism; D014442:Monophenol Monooxygenase / Q000737:chemistry* / Q000378:metabolism; D018384:Oxidative Stress
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D003300:Copper; D014442:Monophenol Monooxygenase; D003851:Deoxyribonucleases
keywords: Cell viability; Dinuclear copper complexes; EPR and CD spectroscopies; Melanomas; Tyrosinase mimics