Metabolization of [Ru(eta(6)-C (6)H (5)CF (3))(pta)Cl (2)]: a cytotoxic RAPTA-type complex with a strongly electron withdrawing arene ligand.
The anticancer ruthenium-arene compound [Ru(eta(6)-C(6)H(5)CF(3))(pta)Cl(2)] (where pta is 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane), termed RAPTA-CF3, with the electron-withdrawing alpha,alpha,alpha-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 (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-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.
Egger
Alexander E
AE
Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland.
Hartinger
Christian G
CG
Renfrew
Anna K
AK
Dyson
Paul J
PJ
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D001483:Base Sequence; D004583:Electrons; D006841:Hydrocarbons, Aromatic / Q000737:chemistry*; D006868:Hydrolysis; D008024:Ligands; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000378:metabolism; D009942:Organometallic Compounds / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D014050:Toluene / Q000031:analogs & derivatives / Q000737:chemistry
D000970:Antineoplastic Agents; D006841:Hydrocarbons, Aromatic; D008024:Ligands; D009838:Oligodeoxyribonucleotides; D009942:Organometallic Compounds; C513519:alpha,alpha,alpha-trifluorotoluene; D014050:Toluene