title: A novel vanadyl complex with a polypyridyl DNA intercalator as ligand: a potential anti-protozoa and anti-tumor agent.
abstract: In the search for new metal-based drugs for the treatment of tumoral and parasitic diseases a vanadyl complex, [V(IV)O(SO(4))(H2O)(2)(dppz)].2H(2)O, that includes the bidentate polypyridyl DNA intercalator dipyrido[3,2-a:2',3'-c]phenazine (dppz), was synthesized, characterized by a combination of techniques, and in vitro evaluated on the human acute promyelocytic leukemia cell line HL-60 and against Dm28c strain epimastigotes of the parasite Trypanosoma cruzi, causative agent of Chagas' disease. EPR spectroscopy suggests a distorted octahedral geometry for the complex with the dppz ligand acting as bidentate, binding through both nitrogen donor atoms in an axial-equatorial mode. An oxo group, two water molecules and a sulphate donor occupy the remainder coordination positions. The complex, as well as the anti-trypanosomal reference drug Nifurtimox, showed IC(50) values in the muM range against T. cruzi Dm28c strain. In addition the complex exhibited excellent in vitro anti-tumor activity against leukemia (HL-60 cell line) comparable to that of cisplatin, inducing cell death by apoptosis with IC(50) values in the micromolar range. Data from gel electrophoresis and atomic force microscopy indicate that the complex interacts with DNA, suggesting that its mechanism of action may include DNA as a target. EPR and (51)V NMR experiments were also carried out with aged aerated solutions of the complex to get insight into the stability of the complex in solution and the species responsible for the in vitro activities observed.
authors.affiliation: Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Gral. Flores 2124, C. C. 1157, 11800 Montevideo, Uruguay.
authors.forename: Julio
authors.initials: J
authors.lastname: Benítez
authors.forename: Lucía
authors.initials: L
authors.lastname: Guggeri
authors.forename: Isabel
authors.initials: I
authors.lastname: Tomaz
authors.forename: João Costa
authors.initials: JC
authors.lastname: Pessoa
authors.forename: Virtudes
authors.initials: V
authors.lastname: Moreno
authors.forename: Julia
authors.initials: J
authors.lastname: Lorenzo
authors.forename: Francesc X
authors.initials: FX
authors.lastname: Avilés
authors.forename: Beatriz
authors.initials: B
authors.lastname: Garat
authors.forename: Dinorah
authors.initials: D
authors.lastname: Gambino
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D014355:Chagas Disease / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy*; D010619:Phenazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000254:growth & development*; D014638:Vanadates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D000981:Antiprotozoal Agents; D007364:Intercalating Agents; D010619:Phenazines; C443808:dipyrido(3,2-a-2',3'-c)phenazine; D014638:Vanadates