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DNA interactions of dinuclear Ru arene antitumor complexes in cell-free media |
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| Authors: | Olga Nová ková ,Christian G. Hartinger,Viktor Brabec |
| Affiliation: | a Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., CZ-61265 Brno, Czech Republic b Institute of Inorganic Chemistry, University of Vienna, A-1090 Vienna, Austria |
| Abstract: | We recently synthesized and characterized water-soluble dinuclear RuII arene complexes, in which two {(η6-p-isopropyltoluene)RuCl[3-(oxo-κO)-2-methyl-4-pyridinonato-κO4]} 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 RuII arene compounds, which differed in the length of the linker between the two RuII 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 RuII 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 RuII 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. |
| Keywords: | bp, base pair CD, circular dichroism cisplatin, cis-diamminedichloridoplatinum(II) CL, cross-link CT, calf thymus DMS, dimethyl sulphate EtBr, ethidium bromide FAAS, flameless atomic absorption spectrometry IC50, the concentration of the compound that afforded 50% cell killing ICD, induced circular dichroism KF&minus , Klenow fragment from DNA polymerase I, exonuclease minus mutated to remove the 3&prime &rarr 5&prime proofreading activity [PtCl(dien)]Cl, chloridodiethylenetriamineplatinum(II) chloride rb, the number of molecules of the metal-based compound bound per nucleotide residue ri, the molar ratio of free metal complex to nucleotides at the onset of incubation with DNA Ru(4), 1,4-bis{chlorido[3-(oxo-κO)-2-methyl-4-pyridinonato-κO4](η6-p-isopropyltoluene)ruthenium}butane Ru(6), 1,6-bis{chlorido[3-(oxo-κO)-2-methyl-4-pyridinonato-κO4](η6-p-isopropyltoluene)ruthenium}hexane Ru(8), 1,8-bis{chlorido[3-(oxo-κO)-2-methyl-4-pyridinonato-κO4](η6-p-isopropyltoluene)ruthenium}octane Ru(12), 1,12-bis{chlorido[3-(oxo-κO)-2-methyl-4-pyridinonato-κO4](η6-p-isopropyltoluene)ruthenium}dodecane SDS, sodium dodecyl sulphate |
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