Synthesis and cellular impact of diene-ruthenium(II) complexes: a new class of organoruthenium anticancer agents |
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Authors: | Kasper Christine Alborzinia Hamed Can Suzan Kitanovic Igor Meyer Andreas Geldmacher Yvonne Oleszak Melanie Ott Ingo Wölfl Stefan Sheldrick William S |
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Affiliation: | a Fakultät für Chemie und Biochemie, Ruhr-Universität Bochum, Universitätsstrasse 150, 44780 Bochum, Germanyb Institut für Pharmazie und Molekulare Biotechnologie, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimerfeld 364, 69120 Heidelberg, Germanyc Institute of Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstrasse 55, 38106 Braunschweig, Germany |
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Abstract: | The cytostatic properties and cellular effects of novel diene-ruthenium(II) complexes of the types OC-6-13-[RuCl2(pp)(cod)] 1-5 (pp = 2,2′-bipyridyl (bpy), phen = 1,10-phenanthroline (phen), 5,6-dimethylphenanthroline (5,6-Me2phen), dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq), ethylenediamine (en)) and OC-6-24-[RuCl{(Me2N)2CS}(pp)(cod)](CF3SO3) 6-8 (pp = phen, 5,6-Me2phen, dpq) have been studied for the human cancer cell lines MCF-7 and HT-29 and for Jurkat leukemia cells. CD spectra indicate that 7 causes a massive distortion of the CT DNA B double helix toward the A form. Whereas the neutral complexes 1, 2 and 5 exhibit only modest antiproliferative activity toward MCF-7 and HT-29 cells, the monocationic complexes are significantly more active, in particular the DNA-distorting complex 7 with its IC50 values of 0.73 and 0.42 μM, respectively. As established by online monitoring with a cell-based sensor chip, this potent 5,6-Me2phen complex invokes dose-dependent decreases in MCF-7 cellular respiration and extracellular acidification rates and causes a time-delayed decrease in the impedance of the cell layers, that can be ascribed to cell death. Treatment of Jurkat cells with 7 leads to high concentrations of reactive oxygen species and the induction of apoptosis. The pronounced dose-dependent inhibition of oxygen consumption by isolated mice mitochondria indicates the involvement of an intrinsic mitochondrial pathway in the programmed cell death process. |
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Keywords: | Ruthenium Bioorganometallic Chemistry DNA binding Anticancer agents Apoptosis Cell metabolism |
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