title: Synthesis, characterization and biological evaluation of novel Ru(II)-arene complexes containing intercalating ligands.
abstract: Three new ruthenium(II)-arene complexes, namely [(η(6)-p-cymene)Ru(Me2dppz)Cl]PF6 (1), [(η(6)-benzene)Ru(Me2dppz)Cl]PF6 (2) and [(η(6)-p-cymene)Ru(aip)Cl]PF6 (3) (Me2dppz=11,12-dimethyldipyrido[3,2-a:2',3'-c]phenazine; aip=2-(9-anthryl)-1H-imidazo[4,5-f] [1,10] phenanthroline) have been synthesized and characterized using different spectroscopic techniques including elemental analysis. The complexes were found to be well soluble and stable in DMSO. The biological activity of the three complexes was tested in three different human cancer cell lines (A549, MDA-MB-231 and HeLa) and in one human non-cancerous cell line (MRC-5). Complexes 1 and 3, carrying η(6)-p-cymene as the arene ligand, were shown to be toxic in all cell lines in the low micromolar/subnanomolar range, with complex 1 being the most cytotoxic complex of the series. Flow cytometry analysis revealed that complex 1 caused concentration- and time-dependent arrest of the cell cycle in G2-M and S phases in HeLa cells. This event is followed by the accumulation of the sub-G1 DNA content after 48h, in levels higher than cisplatin and in the absence of phosphatidylserine externalization. Fluorescent microscopy and acridine orange/ethidium bromide staining revealed that complex 1 induced both apoptotic and necrotic cell morphology characteristics. Drug-accumulation and DNA-binding studies performed by inductively coupled plasma mass spectrometry in HeLa cells showed that the total ruthenium uptake increased in a time- and concentration-dependent manner, and that complex 1 accumulated more efficiently than cisplatin at equimolar concentrations. The introduction of a Me2dppz ligand into the ruthenium(II)-p-cymene scaffold was found to allow the discovery of a strongly cytotoxic complex with significantly higher cellular uptake and DNA-binding properties than cisplatin.
authors.affiliation: Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Serbia.
authors.forename: Stefan
authors.initials: S
authors.lastname: Nikolić
authors.affiliation: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors.forename: Loganathan
authors.initials: L
authors.lastname: Rangasamy
authors.affiliation: Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia.
authors.forename: Nevenka
authors.initials: N
authors.lastname: Gligorijević
authors.affiliation: Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Aranđelović
authors.affiliation: Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia.
authors.forename: Siniša
authors.initials: S
authors.lastname: Radulović
authors.affiliation: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. Electronic address: gilles.gasser@chem.uzh.ch.
authors.forename: Gilles
authors.initials: G
authors.lastname: Gasser
authors.affiliation: Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Serbia. Electronic address: sanjag@chem.bg.ac.rs.
authors.forename: Sanja
authors.initials: S
authors.lastname: Grgurić-Šipka
mesh_terms: D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002413:Cations, Divalent; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000494:pharmacology*; D000081007:Cymenes; D004305:Dose-Response Relationship, Drug; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D039821:Monoterpenes / Q000737:chemistry; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D010618:Phenanthrolines / Q000737:chemistry*; D010619:Phenazines / Q000737:chemistry; D012428:Ruthenium / Q000737:chemistry*; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D012995:Solubility
chemical_list: D000970:Antineoplastic Agents; D002413:Cations, Divalent; D056831:Coordination Complexes; D000081007:Cymenes; D007364:Intercalating Agents; D039821:Monoterpenes; D009942:Organometallic Compounds; D010618:Phenanthrolines; D010619:Phenazines; C007210:4-cymene; D012428:Ruthenium; D002945:Cisplatin
keywords: Anticancer agents; Bioorganometallic chemistry; DNA intercalating ligand; Medicinal inorganic chemistry; Ruthenium(II)–arene complex