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

The anticancer ruthenium-arene compd. [Ru(η6-C6H5CF3)(pta)Cl2] (pta = 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 compds. known. To rationalize the high obsd. cytotoxicity, the hydrolysis of RAPTA-CF3 in water and brine (100 mM sodium chloride) and its reactions with the protein ubiquitin and a double-stranded oligonucleotide (5'-GTATTGGCACGTA-3') were studied using NMR spectroscopy, high-resoln. 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 concn., which is a special property of the compd. not obsd. for other ruthenium-arene complexes with relatively stable ruthenium-arene bonds. Accordingly, the mass spectra of the biomol. reaction mixts. contained mostly [Ru(pta)]-biomol. adducts, whereas [Ru(pta)(arene)] adducts typical of other RAPTA compds. were not obsd. in the protein or DNA binding studies. Gel electrophoresis expts. revealed a significant degree of decompn. 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 abstr.: RAPTA-CF3 is a fast-acting cytotoxic compd. that degrades DNA and has a mode of action fundamentally different from that of other ruthenium(II)-arene compds.