title: Nuclease and anti-proliferative activities of copper(II) complexes of N3O tripodal ligands involving a sterically hindered phenolate.
abstract: Copper(II) complexes 1(2+)-6 of a series of tripodal ligands involving a N3O donor set, namely 2-[(bis-pyridin-2-ylmethyl-amino)-methyl]-4-methoxy-phenol (1L), 2-tert-butyl-4-methoxy-6-[bis-pyridin-2-ylmethyl-amino)-methyl]-phenol (2L), 2-tert-butyl-4-methoxy-6-{[(2-pyridin-2-yl-ethyl)-pyridin-2-ylmethyl-amino]-methyl}-phenol (3L), 2-tert-butyl-4-methoxy-6-{[(6-methyl-pyridin-2-ylmethyl)-pyridin-2-ylmethyl-amino]-methyl}-phenol (4L), 2-tert-butyl-4-fluoro-6-{[(6-methyl-pyridin-2-ylmethyl)-pyridin-2-ylmethyl-amino]-methyl}-phenol (5L) and 2-tert-butyl-4-methoxy-6-{bis[(6-methyl-pyridin-2-ylmethyl)-amino]-methyl}-phenol (6L), respectively, were synthesized. Complexes 1(2+), 3(+) and 4(+) were structurally characterized by X-ray diffraction. The structure of 1(2+) is dimeric, with an essentially trigonal bipyramidal geometry around the copper(II) ions and two bridging deprotonated phenolate moieties. The mononuclear complexes 3(+) and 4(+) contain a square pyramidal copper ion, coordinated in axial position by the phenol moiety. In the water-DMF (90 : 10) mixture at pH 7.3 all the copper(II) complexes are mononuclear, mainly under their phenolate neutral form (except 3(+)), with a coordinated solvent molecule. The DNA cleavage activity of the complexes was tested towards the ϕX174 DNA plasmid. In the absence of an exogenous agent 1(2+) does not show any cleavage activity, 2(+) and 3(+) are moderately active, while 4(+), 5(+) and 6(+) exhibit a high nuclease activity. Experiments in the presence of various scavengers reveal that reactive oxygen species (ROS) are not involved in the strand scission mechanism. The cytotoxicity of the complexes was evaluated on bladder cancer cell lines sensitive or resistant to cisplatin. The IC50 values of the complexes 2(+), 4(+), 5(+) and 6(+) are lower than that of cisplatin (range from 6.3 to 3.1 μM against 9.1 μM for cisplatin). Furthermore, complexes 2(+), 4(+), 5(+) and 6(+) are able to circumvent cisplatin cellular resistance.
authors.affiliation: Département de Chimie Moléculaire, Chimie Inorganique Redox Biomimétique (CIRE), UMR CNRS 5250, Université J. Fourier, B.P. 53, 38041 Grenoble cedex 9, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Berthet
authors.forename: Véronique
authors.initials: V
authors.lastname: Martel-Frachet
authors.forename: Fabien
authors.initials: F
authors.lastname: Michel
authors.forename: Christian
authors.initials: C
authors.lastname: Philouze
authors.forename: Sylvain
authors.initials: S
authors.lastname: Hamman
authors.forename: Xavier
authors.initials: X
authors.lastname: Ronot
authors.forename: Fabrice
authors.initials: F
authors.lastname: Thomas
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003300:Copper / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D003851:Deoxyribonucleases / Q000737:chemistry* / Q000494:pharmacology; D006131:Growth Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D062385:Hydroxybenzoates / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D013237:Stereoisomerism; D014961:X-Ray Diffraction
chemical_list: D006131:Growth Inhibitors; D062385:Hydroxybenzoates; D008024:Ligands; D003300:Copper; D003851:Deoxyribonucleases; C017616:phenolic acid