期刊
JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY
卷 15, 期 6, 页码 919-927出版社
SPRINGER
DOI: 10.1007/s00775-010-0654-x
关键词
Anticancer drugs; Bioorganometallic chemistry; DNA interactions; Mass spectrometry; Protein binding
资金
- EPFL
- Swiss National Science Foundation
- University of Vienna
- Austrian Council for Research and Technology Development
- COST [D39, CM0902]
The anticancer ruthenium-arene compound [Ru(eta(6)-C6H5CF3)(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.
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