Cytotoxicity, cellular uptake, and DNA interactions of new monodentate ruthenium(II) complexes containing terphenyl arenes.
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.
Bugarcic
Tijana
T
School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, United Kingdom.
Nováková
Olga
O
Halámiková
Anna
A
Zerzánková
Lenka
L
Vrána
Oldrich
O
Kaspárková
Jana
J
Habtemariam
Abraha
A
Parsons
Simon
S
Sadler
Peter J
PJ
Brabec
Viktor
V
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*
D000970:Antineoplastic Agents; D004278:DNA, Superhelical; D009942:Organometallic Compounds; D013730:Terphenyl Compounds; D006147:Guanine; D012428:Ruthenium; D004247:DNA; C427203:calf thymus DNA