Cytotoxicity, cellular uptake, and DNA interactions of new monodentate ruthenium(II) complexes containing terphenyl arenes

Publikace: JOURNAL OF MEDICINAL CHEMISTRY 51, 5310-5319 Autoři: Bugarcic, T., Novakova, O., Halamikova, A., Zerzankova, L., Vrana, O., Kasparkova, J., Habtemariam, A., Parsons, S., Sadler, PJ., Brabec, V. Rok: 2008

Abstrakt

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 I 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.