title: Evaluation of cellular uptake, cytotoxicity and cellular ultrastructural effects of heteroleptic oxidovanadium(IV) complexes of salicylaldimines and polypyridyl ligands.
abstract: Searching for prospective vanadium-based drugs for cancer treatment, a new series of structurally related [VIVO(L-2H)(NN)] compounds (1-8) was developed. They include a double deprotonated salicylaldimine Schiff base ligand (L-2H) and different NN-polypyridyl co-ligands having DNA intercalating capacity. Compounds were characterized in solid state and in solution. EPR spectroscopy suggests that the NN ligands act as bidentate and bind through both nitrogen donor atoms in an axial-equatorial mode. The cytotoxicity was evaluated in human tumoral cells (ovarian A2780, breast MCF7, prostate PC3). The cytotoxic activity was dependent on type of cell and incubation time. At 24h PC3 cells presented low sensitivity, but at 72h all complexes showed high cytotoxic activity in all cells. Human kidney HEK293 and ovarian cisplatin resistant A2780cisR cells were also included to evaluate selectivity towards cancer cells and potency to overcome cisplatin resistance, respectively. Most complexes showed no detectable interaction with plasmid DNA, except 2 and 7 which depicted low ability to induce single strand breaks in supercoiled DNA. Based on the overall cytotoxic profile, complexes with 2,2´-bipyridine and 1,10-phenanthroline ligands (1 and 2) were selected for further studies, which consisted on cellular distribution and ultrastructural analyses. In the A2780 cells both depicted different distribution profiles; the former accumulates mostly at the membrane and the latter in the cytoskeleton. Morphology of treated cells showed nuclear atypia and membrane alterations, more severe for 1. Complexes induce different cell death pathways, predominantly necrosis for 1 and apoptosis for 2. Complexes alternative mode of cell death motivates the possibility for further developments.
authors.affiliation: Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Gral. Flores 2124, 11800, Montevideo, Uruguay.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Scalese
authors.affiliation: Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av Rovisco Pais, 1049-001, Lisboa, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Correia
authors.affiliation: Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Gral. Flores 2124, 11800, Montevideo, Uruguay.
authors.forename: Julio
authors.initials: J
authors.lastname: Benítez
authors.affiliation: Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Gral. Flores 2124, 11800, Montevideo, Uruguay.
authors.forename: Santiago
authors.initials: S
authors.lastname: Rostán
authors.affiliation: Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10, 2695-066, Bobadela LRS, Portugal.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Marques
authors.affiliation: Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10, 2695-066, Bobadela LRS, Portugal.
authors.forename: Filipa
authors.initials: F
authors.lastname: Mendes
authors.affiliation: Centro de Investigação Interdisciplinar Egas Moniz, Campus Universitário, Quinta da Granja, Monte de Caparica, Portugal.
authors.forename: António Pedro
authors.initials: AP
authors.lastname: Matos
authors.affiliation: Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av Rovisco Pais, 1049-001, Lisboa, Portugal. Electronic address: joao.pessoa@ist.utl.pt.
authors.forename: João
authors.initials: J
authors.lastname: Costa Pessoa
authors.affiliation: Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Gral. Flores 2124, 11800, Montevideo, Uruguay. Electronic address: dgambino@fq.edu.uy.
authors.forename: Dinorah
authors.initials: D
authors.lastname: Gambino
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D002945:Cisplatin / Q000494:pharmacology; D003603:Cytotoxins / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000648:ultrastructure; D012459:Salicylates / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D012545:Schiff Bases / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D014638:Vanadates / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D003603:Cytotoxins; D012459:Salicylates; D012545:Schiff Bases; D014638:Vanadates; D002945:Cisplatin
keywords: Anticancer drugs; Cellular ultrastructural effects; Cellular uptake; Oxidovanadium(IV) complexes; Polypyridyl ligands; Salicylaldimines