DNA interactions of dinuclear Ru-II arene antitumor complexes in cell-free media

Publikace: BIOCHEMICAL PHARMACOLOGY 77, 364-374 Autoři: Novakova, O., Nazarov, AA., Hartinger, CG., Keppler, BK., Brabec, V. Rok: 2009

Abstrakt

We recently synthesized and characterized water-soluble dinuclear Ru-II arene complexes, in which two {(eta(6)-p-isopropyltoluene)RuCl[3-(oxo-kappa O)-2-methyl-4-pyridinonato-kappa O4]} units were linked by flexible chains of different length [(CH2)(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. (C) 2008 Elsevier Inc. All rights reserved.