title: Copper(II) Complexes of Phenanthroline and Histidine Containing Ligands: Synthesis, Characterization and Evaluation of their DNA Cleavage and Cytotoxic Activity.
abstract: Copper(II) complexes have been intensely investigated in a variety of diseases and pathological conditions due to their therapeutic potential. The development of these complexes requires a good knowledge of metal coordination chemistry and ligand design to control species distribution in solution and tailor the copper(II) centers in the right environment for the desired biological activity. Herein we present the synthesis and characterization of two ligands HL1 and H2L2 containing a phenanthroline unit (phen) attached to the amino group of histidine (His). Their copper(II) coordination properties were studied using potentiometry, spectroscopy techniques (UV-vis and EPR), mass spectrometry (ESI-MS) and DFT calculations. The data showed the formation of single copper complexes, [CuL1]+and [CuL2], with high stability within a large pH range (from 3.0 to 9.0 for [CuL1]+and from 4.5 to 10.0 for [CuL2]). In both complexes the Cu2+ion is bound to the phen unit, the imidazole ring and the deprotonated amide group, and displays a distorted square pyramidal geometry as confirmed by single crystal X-ray crystallography. Interestingly, despite having similar structures, these copper complexes show different redox potentials, DNA cleavage properties and cytotoxic activity against different cancer cell lines (human ovarian (A2780), its cisplatin-resistant variant (A2780cisR) and human breast (MCF7) cancer cell lines). The [CuL2] complex has lower reduction potential (Epc= -0.722 V vs -0.452 V for [CuL1]+) but higher biological activity. These results highlight the effect of different pendant functional groups (carboxylate vs amide), placed out of the coordination sphere, in the properties of these copper complexes.
authors.affiliation: Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa , Avenida da República, 2780-157 Oeiras, Portugal.
authors.forename: Sílvia M G
authors.initials: SM
authors.lastname: Leite
authors.affiliation: Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa , Avenida da República, 2780-157 Oeiras, Portugal.
authors.forename: Luís M P
authors.initials: LM
authors.lastname: Lima
authors.affiliation: Centro de Ciências e Tecnologias Nucleares, IST, Universidade de Lisboa , Estrada Nacional 10, 2695-066 Bobadela LRS, Portugal.
authors.forename: Sofia
authors.initials: S
authors.lastname: Gama
authors.affiliation: Centro de Ciências e Tecnologias Nucleares, IST, Universidade de Lisboa , Estrada Nacional 10, 2695-066 Bobadela LRS, Portugal.
authors.forename: Filipa
authors.initials: F
authors.lastname: Mendes
authors.affiliation: Aix Marseille Univ, CNRS, Centrale Marseille , iSm2, Marseille, France.
authors.forename: Maylis
authors.initials: M
authors.lastname: Orio
authors.affiliation: Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa , Avenida da República, 2780-157 Oeiras, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Bento
authors.affiliation: Centro de Ciências e Tecnologias Nucleares, IST, Universidade de Lisboa , Estrada Nacional 10, 2695-066 Bobadela LRS, Portugal.
authors.forename: António
authors.initials: A
authors.lastname: Paulo
authors.affiliation: Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa , Avenida da República, 2780-157 Oeiras, Portugal.
authors.forename: Rita
authors.initials: R
authors.lastname: Delgado
authors.affiliation: Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa , Avenida da República, 2780-157 Oeiras, Portugal.|Aix Marseille Univ, CNRS, Centrale Marseille , iSm2, Marseille, France.
authors.forename: Olga
authors.initials: O
authors.lastname: Iranzo
mesh_terms: D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000737:chemistry* / Q000494:pharmacology; D003300:Copper / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004247:DNA / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004578:Electron Spin Resonance Spectroscopy; D006639:Histidine / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D010618:Phenanthrolines / Q000737:chemistry*
chemical_list: D056831:Coordination Complexes; D008024:Ligands; D010618:Phenanthrolines; D006639:Histidine; D003300:Copper; D004247:DNA