DNA interactions of dinuclear RuII arene antitumor complexes in cell-free media.

We recently synthesized and characterized water-soluble dinuclear Ru(II) arene complexes, in which two {(eta(6)-p-isopropyltoluene)RuCl[3-(oxo-kappaO)-2-methyl-4-pyridinonato-kappaO(4)]} units were linked by flexible chains of different length [(CH(2))(n) (n=4, 6, 8, 12)]. These new dinuclear ruthenium drugs were found to exert promising cytotoxic effects in human cancer cells. In the present work DNA modifications by these new dinuclear Ru(II) arene compounds, which differed in the length of the linker between the two Ru(II) centers, were examined by biochemical and biophysical methods. The complexes bind DNA forming intrastrand and interstrand cross-links in one DNA molecule in the absence of proteins. An intriguing aspect of the DNA-binding mode of these dinuclear Ru(II) compounds is that they can cross-link two DNA duplexes and also proteins to DNA--a feature not observed for other antitumor ruthenium complexes. Thus, the concept for the design of interhelical and DNA-protein cross-linking agents based on dinuclear Ru(II) arene complexes with sufficiently long linkers between two Ru centers may result in new compounds which exhibit a variety of biological effects and can be also useful in nucleic acids research.