title: Antitumor and antiparasitic activity of novel ruthenium compounds with polycyclic aromatic ligands.
abstract: Five novel ruthenium(II)-arene complexes with polycyclic aromatic ligands were synthesized, comprising three compounds of the formula [RuCl(η(6)-p-cym)(L)][PF6], where p-cym = 1-isopropyl-4-methylbenzene and L are the bidentate aromatic ligands 1,10-phenanthroline-5,6-dione, 1, 5-amine-1,10-phenanthroline, 4, or 5,6-epoxy-5,6-dihydro-phenanthroline, 5. In the other two complexes [RuCl2(η(6)-p-cym)(L')], the metal is coordinated to a monodentate ligand L', where L' is phenanthridine, 2, or 9-carbonylanthracene, 3. All compounds were fully characterized by mass spectrometry and elemental analysis, as well as NMR and IR spectroscopic techniques. Obtained ruthenium compounds as well as their respective ligands were tested for their antiparasitic and antitumoral activities. Even though all compounds showed lower Trypanosoma brucei activity than the free ligands, they also resulted less toxic on mammalian cells. Cytotoxicity assays on HL60 cells showed a moderate antitumoral activity for all ruthenium compounds. Compound 1 was the most potent antitumoral (IC50 = 1.26±0.78 μM) and antiparasitic (IC50 = 0.19 ± 0.05 μM) agent, showing high selectivity towards the parasites (selectivity index >100). As complex 1 was the most promising antitumoral compound, its interaction with ubiquitin as potential target was also studied. In addition, obtained ruthenium compounds were found to bind DNA, and they are thought to interact with this macromolecule mainly through intercalation of the aromatic ligand.
authors.affiliation: Departament de Química Inorgànica, Universitat de Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain.
authors.forename: Helena Guiset
authors.initials: HG
authors.lastname: Miserachs
authors.affiliation: Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Gral. Flores 2124, 11800 Montevideo, Uruguay.
authors.forename: Micaella
authors.initials: M
authors.lastname: Cipriani
authors.affiliation: Departament de Química Inorgànica, Universitat de Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Grau
authors.affiliation: Institut de Recerca Biomèdica (IRB-Barcelona), Baldiri Reixac 10, 08020 Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Vilaseca
authors.affiliation: Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.
authors.forename: Julia
authors.initials: J
authors.lastname: Lorenzo
authors.affiliation: Group Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Mataojo 2020, 11400 Montevideo, Uruguay; Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Gral. Flores 2125, 11800 Montevideo, Uruguay.
authors.forename: Andrea
authors.initials: A
authors.lastname: Medeiros
authors.affiliation: Group Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Mataojo 2020, 11400 Montevideo, Uruguay.
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Comini
authors.affiliation: Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Gral. Flores 2124, 11800 Montevideo, Uruguay.
authors.forename: Dinorah
authors.initials: D
authors.lastname: Gambino
authors.affiliation: Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Gral. Flores 2124, 11800 Montevideo, Uruguay. Electronic address: luotero@fq.edu.uy.
authors.forename: Lucía
authors.initials: L
authors.lastname: Otero
authors.affiliation: Departament de Química Inorgànica, Universitat de Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain. Electronic address: mvirtudes.moreno@gmail.com.
authors.forename: Virtudes
authors.initials: V
authors.lastname: Moreno
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002417:Cattle; D002942:Circular Dichroism; D004247:DNA / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000494:pharmacology; D008024:Ligands; D013058:Mass Spectrometry; D051379:Mice; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D010618:Phenanthrolines / Q000138:chemical synthesis / Q000494:pharmacology*; D010957:Plasmids; D011084:Polycyclic Aromatic Hydrocarbons / Q000138:chemical synthesis / Q000494:pharmacology*; D012428:Ruthenium / Q000737:chemistry*; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007364:Intercalating Agents; D008024:Ligands; D009942:Organometallic Compounds; D010618:Phenanthrolines; D011084:Polycyclic Aromatic Hydrocarbons; D014344:Trypanocidal Agents; D025801:Ubiquitin; C037153:1,10-phenanthroline-5,6-dione; D012428:Ruthenium; D004247:DNA; C427203:calf thymus DNA
keywords: Antiparasitic; Antitumor; DNA interaction; Protein interaction; Ruthenium(II)–arene complexes