title: The contrasting chemistry and cancer cell cytotoxicity of bipyridine and bipyridinediol ruthenium(II) arene complexes.
abstract: The synthesis and characterization of ruthenium(II) arene complexes [(eta(6)-arene)Ru(N,N)Cl](0/+), where N,N = 2,2'-bipyridine (bipy), 2,2'-bipyridine-3,3'-diol (bipy(OH)(2)) or deprotonated 2,2'-bipyridine-3,3'-diol (bipy(OH)O) as N,N-chelating ligand, arene = benzene (bz), indan (ind), biphenyl (bip), p-terphenyl (p-terp), tetrahydronaphthalene (thn), tetrahydroanthracene (tha) or dihydroanthracene (dha), are reported, including the X-ray crystal structures of [(eta(6)-tha)Ru(bipy)Cl][PF(6)] (1), [(eta(6)-tha)Ru(bipy(OH)O)Cl] (2) and [(eta(6)-ind)Ru(bipy(OH)(2))Cl][PF(6)] (8). Complexes 1 and 2 exibit CH (arene)/pi (bipy or bipy(OH)O) interactions. In the X-ray structure of protonated complex 8, the pyridine rings are twisted (by 17.31 degrees). In aqueous solution (pH = 2-10), only deprotonated (bipy(OH)O) forms are present. Hydrolysis of the complexes was relatively fast in aqueous solution (t(1/2) = 4-15 min, 310 K). When the arene is biphenyl, initial aquation of the complexes is followed by partial arene loss. Complexes with arene = tha, thn, dha, ind and p-terp, and deprotonated bipyridinediol (bipy(OH)O) as chelating ligands, exhibited significant cytotoxicity toward A2780 human ovarian and A549 human lung cancer cells. Complexes [(eta(6)-bip)Ru(bipy(OH)O)Cl] (7) and [(eta(6)-bz)Ru(bipy(OH)O)Cl] (5) exhibited moderate cytotoxicity toward A2780 cells, but were inactive toward A549 cells. These activity data can be contrasted with those of the parent bipyridine complex [(eta(6)-tha)Ru(bipy)Cl][PF(6)] (1) which is inactive toward both A2780 ovarian and A549 lung cell lines. DFT calculations suggested that hydroxylation and methylation of the bipy ligand have little effect on the charge on Ru. The active complex [(eta(6)-tha)Ru(bipy(OH)O)Cl] (2) binds strongly to 9-ethyl-guanine (9-EtG). The X-ray crystal structure of the adduct [(eta(6)-tha)Ru(bipy(OH)O)(9-EtG-N7)][PF(6)] shows intramolecular CH (arene)/pi (bipy(OH)O) interactions and DFT calculations suggested that these are more stable than arene/9-EtG pi-pi interactions. However [(eta(6)-ind)Ru(bipy(OH)(2))Cl][PF(6)] (8) and [(eta(6)-ind)Ru(bipy)Cl][PF(6)] (16) bind only weakly to DNA. DNA may therefore not be the major target for complexes studied here.
authors.affiliation: School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, UK.
authors.forename: Tijana
authors.initials: T
authors.lastname: Bugarcic
authors.forename: Abraha
authors.initials: A
authors.lastname: Habtemariam
authors.forename: Jana
authors.initials: J
authors.lastname: Stepankova
authors.forename: Pavla
authors.initials: P
authors.lastname: Heringova
authors.forename: Jana
authors.initials: J
authors.lastname: Kasparkova
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Deeth
authors.forename: Russell D L
authors.initials: RD
authors.lastname: Johnstone
authors.forename: Alessandro
authors.initials: A
authors.lastname: Prescimone
authors.forename: Andrew
authors.initials: A
authors.lastname: Parkin
authors.forename: Simon
authors.initials: S
authors.lastname: Parsons
authors.forename: Viktor
authors.initials: V
authors.lastname: Brabec
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sadler
mesh_terms: D015082:2,2'-Dipyridyl / Q000633:toxicity; D002412:Cations / Q000737:chemistry; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D018360:Crystallography, X-Ray / Q000379:methods; D005260:Female; D006801:Humans; D006860:Hydrogen Bonding; D006868:Hydrolysis; D008175:Lung Neoplasms / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008958:Models, Molecular; D010051:Ovarian Neoplasms / Q000473:pathology; D012428:Ruthenium / Q000633:toxicity*; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology*
chemical_list: D002412:Cations; D015082:2,2'-Dipyridyl; D012428:Ruthenium