title: Structural and functional effects of benzimidazole/thioether-copper complexes with antitumor activity on cell membranes and molecular models.
abstract: Two cytotoxic copper(II) complexes with N-H and N-methylated benzimidazole-derived ligands (Cu-L(2) and Cu-L(2Me)) were synthesized and made to interact with human erythrocytes and molecular models of their plasmatic membranes. The latter consisted in lipid bilayers of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE), lipids of the types present in the outer and inner monolayers of the human erythrocyte membrane, respectively. Initial assessment of the interaction of the complexes with DMPC and DMPE consisted of X-ray diffraction studies, which showed preferential interactions with the former. Scanning electron microscopy (SEM) of erythrocytes incubated with solutions of the Cu(II) complexes evidenced deformation of the cells to stomatocytes and knizocytes by Cu-L(2) and Cu-L(2Me) due to interactions with the inner and outer leaflets of the cell membranes, respectively. This was further confirmed by real-time observation of the dose-dependent effects of the complexes on live erythrocytes by defocusing microscopy (DM). The combined observations, including the increased antiproliferative activity of the N-methylated complex Cu-L(2Me) over that of Cu-L(2) is rationalized based on the higher lipophilicity of the former. This property would facilitate passive diffusion of Cu-L(2Me) through the cell membrane, particularly in the initial stages when the DMPC-rich outer leaflet is involved. In contrast, the benzimidazole N-H groups of Cu-L(2) may participate in hydrogen bonding with DMPE polar groups; this result is consistent with the formation of stomatocyte induced by the latter complex.
authors.affiliation: Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, México, D. F. 04510, Mexico. Electronic address: joseivan@unam.mx.
authors.forename: Ivan
authors.initials: I
authors.lastname: Castillo
authors.affiliation: Faculty of Chemical Sciences, University of Concepción, Chile.
authors.forename: Mario
authors.initials: M
authors.lastname: Suwalsky
authors.affiliation: Center for Optics and Photonics, University of Concepción, Chile.
authors.forename: María José
authors.initials: MJ
authors.lastname: Gallardo
authors.affiliation: Center of Biotechnology, University of Concepción, Chile.
authors.forename: Valentina
authors.initials: V
authors.lastname: Troncoso
authors.affiliation: Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, México, D. F. 04510, Mexico.
authors.forename: Brenda N
authors.initials: BN
authors.lastname: Sánchez-Eguía
authors.affiliation: Facultad de Estudios Superiores-Zaragoza, Universidad Nacional Autónoma de México, Batalla del 5 de Mayo y Fuerte de Loreto, México, D. F. 09230, Mexico.
authors.forename: Edelmiro
authors.initials: E
authors.lastname: Santiago-Osorio
authors.affiliation: Facultad de Estudios Superiores-Zaragoza, Universidad Nacional Autónoma de México, Batalla del 5 de Mayo y Fuerte de Loreto, México, D. F. 09230, Mexico.
authors.forename: Itzen
authors.initials: I
authors.lastname: Aguiñiga
authors.affiliation: Facultad de Estudios Superiores-Zaragoza, Universidad Nacional Autónoma de México, Batalla del 5 de Mayo y Fuerte de Loreto, México, D. F. 09230, Mexico.
authors.forename: Ana K
authors.initials: AK
authors.lastname: González-Ugarte
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D001562:Benzimidazoles / Q000737:chemistry*; D003300:Copper / Q000737:chemistry*; D004912:Erythrocytes / Q000648:ultrastructure; D006801:Humans; D008051:Lipid Bilayers; D008855:Microscopy, Electron, Scanning; D013440:Sulfides / Q000737:chemistry*; D014961:X-Ray Diffraction
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D008051:Lipid Bilayers; D013440:Sulfides; D003300:Copper; C031000:benzimidazole
keywords: Benzimidazoles; Cell membrane; Cu complexes; Cytotoxicity; Human erythrocyte