Book of Abstracts - Ruhr-Universität Bochum

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P-19 ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum Organometallic Osmium Arene Complexes with Potent Cancer Cell Cytotoxicity Ying Fu, a Abraha Habtemariam, a Ana M. Pizarro, a Sabine H. van Rijt, a Guy J. Clarkson, a and Peter J. Sadler *a University of Warwick, Department of Chemistry, Gibbet Hill Road, Coventry, CV4 7AL, U.K, E-mail: fuyingpku@gmail.com Arene complexes of the heavier congener osmium(II) display similar structures in the solid state to those of Ru II but are subtly different with regard to their chemical reactivity. For example, Os II arene ethylenediamine chlorido complexes hydrolyze ca. 40x more slowly and the related aqua adducts have pKa values for Os�OH2/OH which are ca. 1.5 pKa units lower (more acidic) than those of the analogous Ru II complexes. 1,2 Faster ligand exchange in Os II complexes can be achieved by incorporating oxygen-containing chelating ligands, e.g. picolinates. 3,4 In general they show a different cytotoxicity profile and have a larger reactivity window compared to Ru arene complexes. The synthesis of a range of osmium complexes of the general structure shown will be discussed including the X-ray crystal structures of five complexes. Surprisingly, several of these Os II Arene X Os N N complexes with iodide as the X ligand are an order of magnitude [Os(Arene)(NN)X] more potent than the clinically-used drug cisplatin towards a range of human cancer cell lines. We thank Dr. Michael Khan (Biological Sciences) for provision of facilities for cell culture, and the MRC, EPSRC (Knowledge Transfer Network), ERC and EU EDRF/AWM (APOC) for funding, and members of COST Action D39 for discussion. + References 1. Peacock, A. F. A.; Habtemariam, A.; Fernandez, R.; Walland, V.; Fabbiani, F. P. A.; Parsons, S.; Aird, R. E.; Jodrell, D. I.; Sadler, P. J. J. Am. Chem. Soc. 2006, 128, 1739-1748. 2. Wang, F.; Habtemariam, A.; van der Geer, E. P.; Fernandez, R.; Melchart, M.; Deeth, R. J.; Aird, R.; Guichard, S.; Fabbiani, F. P.; Lozano-Casal, P.; Oswald, I. D.; Jodrell, D. I.; Parsons, S.; Sadler, P. J. Proc Natl Acad. Sci.U.S.A. 2005, 102, 18269-18274. 3. Peacock, A. F. A.; Sadler, P. J. Chem.--Asian J. 2008, 3, 1890-1899. 4. van Rijt, S. H.; Peacock, A. F. A.; Johnstone, R. D. L.; Parsons, S.; Sadler, P. J. Inorg. Chem. 2009, 48, 1753-1762. 77
P-20 ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum Cytotoxic Apoptosis-Inducing Organometallic Rhodium Complexes with Substituted Polypyridyl Ligands Yvonne Geldmacher, a Riccardo Rubbiani, b Ingo Ott, b and William S. Sheldrick a* a Ruhr-Universität Bochum,Faculty of Chemistry and Biochemistry, Department of Analytical chemistry, Universitätsstr. 150, 44780 Bochum, Germany, b Technical University of Braunschweig, Department of Pharmaceutical Chemistry, Beethovenstr. 55, 38106 Braunschweig, Germany E-mail: yvonne.geldmacher@rub.de The complexes of the type [(η 5 -C5Me5)RhCl(pp)]CF3SO3 (with pp= dpq, dppz, dppn) represent a new class of cytotoxic substances. Cytotoxicity and cellular uptake studies on the HEK-293, MCF-7 and HT-29 cell lines have been employed to establish relationships between the structure and the activity of the complexes. UV/Vis kinetic, thermal denaturation and CD studies have shown, that the prefered binding mode of the complexes to DNA is intercalation. [(η 5 -C5Me5)RhCl(dppz)]CF3SO3 invokes the largest increase in Tm with a value 12 °C being recorded for a 1:10 complex/DNA mixture in the denaturation experiment. In contrast, complexes containing the smaller chelate ligands with pp = en, bpy and phen exhibit negative ΔTm values, which indicates the presence of a covalent binding mode. CD spectra for the complex/DNA mixtures with pp = dpq and dppz contain a negative ICD-signal in the range 280-300 nm, which also indicates intercalation. Viscosity measurements also confirm the conclusions from UV/Vis and CD studies. 1 100 Figure 1: crystal structure of Figure 2: DNA-fragmentation after a 72 h treatment of [(η 5 -C5Me5)RhCl(5,6- Me2phen)]CF3SO3 BJAB cells with [(η 5 -C5Me5)RhCl(5,6- Me2phen)]CF3SO3 at different concentrations The biological activity also correlates with the lipophilicity and thereby with the size of the polypyridyl ligand. The IC50 values decrease in the series en, bpy>> phen,dpq > dppz > dppn. One goal of our ongoing studies is to improve the cell selectivity and identify lead substances by varying the ligands L and pp in complexes [(η 5 -C5Me5)RhL(pp)](CF3SO3)n. It has previously been shown that there are significant differences between the cytotoxicities of Pt(II) complexes with methylated 1,10phenanthroline ligands. 2 We now report studies of the biological activity of [(η 5 - C5Me5)RhCl(pp)]CF3SO3 complexes containing methylated phenanthroline ligands and other substituted polypyridyl ligands. Measurements of the LDH release for lymphoma (BJAB) cells after 1h incubation with phen, 5,6-Me2phen and dppz complexes demonstrated that unspecific necrosis is negligible. Specific cell death apoptosis via DNA fragmentation was detected for BJAB cells after 72 h (Figure 2). References apoptotic cells [%] 75 50 25 0 1. M.A. Scharwitz, I. Ott, Y. Geldmacher, R. Gust, W.S. Sheldrick, J. Organomet. Chem. 2008, 693, 2299-2309. 2. C.R. Brodie, J.G. Jollins, J.R. Aldrich-Wright, Dalton Trans. 2004, 1145. 78 Co DMSO0.1 1 5 10 25 50 75 100 concentration [µM]
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ISBOMC ‘10 5th International Symp
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Foreword ISBOMC `10 5.7 - 9.7. 2010
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General information ISBOMC `10 5.7
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Monday, July 5 th 2010 16:00 to 18:
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Sergey Abramkin Universität Wien,
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Tensim Dallagi ENSCP, France t.dall
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Prof. Dr. Toshikazu Hirao Osaka Uni
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Obiora Augustine Orakwue Hyqid Nige
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