title: Cytotoxicity, cellular uptake, and DNA interactions of new monodentate ruthenium(II) complexes containing terphenyl arenes.
abstract: We have compared the cancer cell cytotoxicity, cell uptake, and DNA binding properties of the isomeric terphenyl complexes [(eta(6)-arene)Ru(en)Cl](+), where the arene is ortho- (2), meta- (3), or para-terphenyl (1) (o-, m-, or p-terp). Complex 1, the X-ray crystal structure of which confirms that it has the classical "piano-stool" geometry, has a similar potency to cisplatin but is not cross-resistant and has a much higher activity than 2 or 3. The extent of Ru uptake into A2780 or A2780cis cells does not correlate with potency. Complex 1 binds to DNA rapidly and quantitatively, preferentially to guanine residues, and causes significant DNA unwinding. Circular and linear dichroism, competitive binding experiments with ethidium bromide, DNA melting, and surface-enhanced Raman spectroscopic data are consistent with combined intercalative and monofunctional (coordination) binding mode of complex 1. This unusual DNA binding mode may therefore make a major contribution to the high potency of complex 1.
authors.affiliation: School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, United Kingdom.
authors.forename: Tijana
authors.initials: T
authors.lastname: Bugarcic
authors.forename: Olga
authors.initials: O
authors.lastname: Nováková
authors.forename: Anna
authors.initials: A
authors.lastname: Halámiková
authors.forename: Lenka
authors.initials: L
authors.lastname: Zerzánková
authors.forename: Oldrich
authors.initials: O
authors.lastname: Vrána
authors.forename: Jana
authors.initials: J
authors.lastname: Kaspárková
authors.forename: Abraha
authors.initials: A
authors.lastname: Habtemariam
authors.forename: Simon
authors.initials: S
authors.lastname: Parsons
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sadler
authors.forename: Viktor
authors.initials: V
authors.lastname: Brabec
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D004278:DNA, Superhelical; D006147:Guanine / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D009691:Nucleic Acid Denaturation; D009942:Organometallic Compounds / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D012428:Ruthenium; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship; D013730:Terphenyl Compounds / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004278:DNA, Superhelical; D009942:Organometallic Compounds; D013730:Terphenyl Compounds; D006147:Guanine; D012428:Ruthenium; D004247:DNA; C427203:calf thymus DNA