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

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• 作者：Olga Nová ; ková ; Alexey A. Nazarov ; Christian G. Hartinger ; Bernhard K. Keppler ; Viktor Brabec
• 关键词：Dinuclear ruthenium complex ; Arene ; Antitumor ; DNA ; Cross-links ; Cytotoxicity
• 刊名：Biochemical Pharmacology
• 出版年：2009
• 出版时间：1 February 2009
• 年：2009
• 卷：77
• 期：3
• 页码：364-374
• 全文大小：698 K

文摘

We recently synthesized and characterized water-soluble dinuclear Ru^II 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 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.