Molekulární biofyzika a farmakologie
Bifunctional amine-tethered Ruthenium(II) arene complexes form monofunctional adducts on DNA
Publikace: INORGANIC CHEMISTRY 46, 8950-8962 Autoři: Melchart, M., Habtemariam, A., Novakova, O., Moggach, SA., Fabbiani, FPA., Parsons, S., Brabec, V., Sadler, PJ. Rok: 2007
The tethered Ru-II half-sandwich complexes [eta(6):eta(1)-C6H5(CH2)(n)NH2)RuCl2] 1 (n = 3) and 2 (n = 2) have been synthesized as potential bifunctional anticancer complexes, and their X-ray crystal structures have been determined. They hydrolyze rapidly in aqueous solution to give predominantly mono-aqua mono-chlorido species. Mono-9EtG adducts, where 9EtG = 9-ethylguanine, form rapidly, but the second 9EtG binds more slowly and more weakly. In the X-ray crystal structure of the di-9EtG adduct [(eta(6):eta(1)-C6H5(CH2)(3)NH2)Ru(9EtG)(2)](CF3SO3)(2)center dot H2O (8 center dot H2O), one of the Ru-N7 bonds is significantly longer than the other (2.1588(18) vs 2.101(2) angstrom). The bound guanine bases adopt a head-to-head configuration, stabilized by tether NH2 hydrogen bonding to C60 of 9EtG. The X-ray crystal structure of the dinitrato complex [(eta(6):eta(1) -C6H5(CH2)(3)NH2)Ru(NO3)(2)] (3) showed both nitrates to be bound to ruthenium. This complex readily rutheniated calf thymus DNA but failed to produce stop sites on pSP73KB plasmid DNA during DNA transcription by an RNA polymerase. This suggested that only monofunctional DNA adducts formed, as did interstrand cross-linking assays. Also, the unwinding angle induced in negatively supercoiled DNA (9 +/- 1 degrees) was less than that induced by cisplatin (13 degrees). These findings may explain why complexes such as 1 and 2 exhibited low cytotoxicities (IC50 values >100 mu M) toward A2780 human ovarian cancer cells.