Metabolization of [Ru(η6-C6H5CF3)(pta)Cl2]: a cytotoxic RAPTA-type complex with a strongly electron withdrawing arene ligand

Egger, Alexander ; Hartinger, Christian ; Renfrew, Anna ; Dyson, Paul

In: JBIC Journal of Biological Inorganic Chemistry, 2010, vol. 15, no. 6, p. 919-927

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    Summary
    The anticancer ruthenium-arene compound [Ru(η6-C6H5CF3)(pta)Cl2] (where pta is 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane), termed RAPTA-CF3, with the electron-withdrawing α,α,α-trifluorotoluene ligand, is one of the most cytotoxic RAPTA compounds known. To rationalize the high observed cytotoxicity, the hydrolysis of RAPTA-CF3 in water and brine (100mM sodium chloride) and its reactions with the protein ubiquitin and a double-stranded oligonucleotide (5′-GTATTGGCACGTA-3′) were studied using NMR spectroscopy, high-resolution Fourier transform ion cyclotron resonance mass spectrometry, and gel electrophoresis. The aquation of the ruthenium-chlorido complex was accompanied by a loss of the arene ligand, independent of the chloride concentration, which is a special property of the compound not observed for other ruthenium-arene complexes with relatively stable ruthenium-arene bonds. Accordingly, the mass spectra of the biomolecule reaction mixtures contained mostly [Ru(pta)]-biomolecule adducts, whereas [Ru(pta)(arene)] adducts typical of other RAPTA compounds were not observed in the protein or DNA binding studies. Gel electrophoresis experiments revealed a significant degree of decomposition of the oligonucleotide, which was more pronounced in the case of RAPTA-CF3 compared with RAPTA-C. Consequently, facile arene loss appears to be responsible for the increased cytotoxicity of RAPTA-CF3. Graphical abstract: RAPTA-CF3 is a fast-acting cytotoxic compound that degrades DNA and has a mode of action fundamentally different from that of other ruthenium(II)-arene compounds