title: Redox-active and DNA-binding coordination complexes of clotrimazole.
abstract: DNA interactions of anticancer mononuclear Cu(2+), Co(2+), Zn(2+), and Ni(2+) complexes with the biologically active ligand clotrimazole (clotri) are reported. To fully characterize DNA binding modes for these complexes of the formulae [M(clotri)2Cl2]·nH2O (1-4), [M(clotri)2Br2]·nH2O (5,6), [M(clotri)3NO3]NO3·nH2O (9), and [M(clotri)3(NO3)2] (10), circular dichroism (CD) and linear dichroism (LD) spectroscopy, UV melting experiments, atomic force microscopy (AFM) and ethidium bromide (EtBr) displacement methods were used. Results indicate mixed electrostatic interactions, possibly through groove binding, that result in accretion and coiling of DNA. Electrochemical studies indicate that the Cu(2+) complex 9 readily reduces to the reactive-oxygen-species-generating Cu(+), which oxidatively damages DNA. There is a subtle correlation between log P values, calculated electrostatic potentials, and cytotoxicity of the complexes. The extent of cell-nucleus DNA-metal adduct formation in the HeLa cervix-uterine carcinoma cell line does not necessarily correlate with cytotoxicity, indicating that the nature of DNA lesions may be crucial to activity.
authors.affiliation: Departamento de Química Inorgánica, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán, México, D.F. 04510, Mexico. norah@unam.mx.
authors.forename: Soledad
authors.initials: S
authors.lastname: Betanzos-Lara
authors.forename: Nikola P
authors.initials: NP
authors.lastname: Chmel
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Zimmerman
authors.forename: Lidia R
authors.initials: LR
authors.lastname: Barrón-Sosa
authors.forename: Claudio
authors.initials: C
authors.lastname: Garino
authors.forename: Luca
authors.initials: L
authors.lastname: Salassa
authors.forename: Alison
authors.initials: A
authors.lastname: Rodger
authors.forename: Julia L
authors.initials: JL
authors.lastname: Brumaghim
authors.forename: Isabel
authors.initials: I
authors.lastname: Gracia-Mora
authors.forename: Norah
authors.initials: N
authors.lastname: Barba-Behrens
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002942:Circular Dichroism; D003022:Clotrimazole / Q000737:chemistry*; D003035:Cobalt / Q000737:chemistry; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D003300:Copper / Q000737:chemistry; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008670:Metals / Q000737:chemistry*; D018625:Microscopy, Atomic Force; D008968:Molecular Conformation; D009532:Nickel / Q000737:chemistry; D009691:Nucleic Acid Denaturation; D010084:Oxidation-Reduction; D014466:Ultraviolet Rays; D015032:Zinc / Q000737:chemistry
chemical_list: D056831:Coordination Complexes; D008670:Metals; D003035:Cobalt; D003300:Copper; D009532:Nickel; D004247:DNA; D003022:Clotrimazole; D015032:Zinc