Book of Abstracts - Ruhr-Universität Bochum

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OP-21 ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum Organometallic Pyrone and Pyridone Complexes as Anticancer Agents Christian G. Hartinger, *a Wolfgang Kandioller, a Muhammad Hanif, a Andrea Kurzwernhart, a Helena Henke, a Robert Trondl, a Caroline Bartel, a Gerhard Mühlgassner, a Michael A. Jakupec, a Maria G. Mendoza-Ferri, a Alexey A. Nazarov, a,b Bernhard K. Keppler a a University of Vienna, Institute of Inorganic Chemistry, Waehringer Str. 42, A-1090, Vienna, Austria. b Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland. E-mail: christian.hartinger@univie.ac.at Organometallic compounds have received growing interest as potential chemotherapeutics for the treatment of cancer. Ru(II) compounds bearing ligands such as 1,3,5-triaza-7-phosphaadamantane, ethylene-1,2-diamine or maltol-derived ligands have shown promising anticancer properties with in vitro or in vivo anticancer activity comparable to or in some cases superior to cisplatin. 1 Some of the compounds are even active in cisplatin-resistant cell lines, probably due to different modes of action, and potentially provide a means to overcome drug resistance. 2 Organometallic Ru–arene compounds bearing a maltol ligand were shown to be nearly inactive in vitro. 3 In order to study their biological properties, compounds with different substitution pattern [e.g. 3-hydroxy-2-pyr(id)one vs. 3-hydroxy-4-pyr(id)one] of the pyrone-derived ligands were prepared, or an oxygen donor of the chelating moiety was replaced by sulphur. Furthermore, polynuclear compounds were obtained by linking pyridone moieties via aliphatic chains. The chemical properties of the obtained compounds are very different from that of the parent maltolato complex with regard to stability in aqueous solution, lipophilicity and, depending on the metal centre, reactivity with biomolecules. For example, reactions with amino acids demonstrate higher stability of thiopyrone than of pyrone complexes, which may explain their activity against human tumour cells. In general, the compounds show affinity to nucleobases, but the polynuclear compounds form extremely rare types of DNA and protein adducts and are efficient cross-linkers. 4 Anticancer potencies of the arene complexes are as divergent as their chemical behaviour, from compounds active in the low μM range to inactive compounds. Based on the chemical and biological data, structure-activity relationships have been elucidated, and further directions of development will be discussed. References 1. G. Süss-Fink, Dalton Transactions 2010, 1673-1688. 2. (a) W. H Ang, P. J. Dyson, Eur. J. Inorg. Chem. 2006, 4003-4018. (b) A. F. A. Peacock, P. J. Sadler, Chem. Asian J. 2008, 3, 1890-1899. 3. A. F. A. Peacock, M. Melchart, R. J. Deeth, A. Habtemariam, S. Parsons, P. J. Sadler, Chem. Eur. J. 2007, 13, 2601-2613. 4. O. Nováková, A. A. Nazarov, C. G. Hartinger, B. K. Keppler, V. Brabec, Biochem. Pharmacol. 2009, 77, 364-374. 37
OP-22 ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum Metalloenzymes in the bacterial life on carbon monoxide: A view from structural biology Holger Dobbek,* and Jae-Hun Jeoung Humboldt-Universität zu Berlin, Institute of Biology, Structural Biology/Biochemistry, Unter den Linden 6, 10099, Berlin, Germany. E-mail: holger.dobbek@biologie.hu-berlin.de The biological conversions of small substrates like N2, H2, and CO2 are vital for the biogeochemical cycle and are typically catalyzed by metalloenzymes with complex iron-sulfur clusters. However, only little is known about how these metalloclusters activate their substrates. Carbon monoxide dehydrogenases (CODHases) catalyze the reversible oxidation of carbon monoxide with water, to carbon dioxide, two protons and two electrons. Two principal types of CODHases have been described, which differ in activity, metal composition, amino acid sequence and stability in the presence of oxygen. The Ni, Fe-containing CODHases found in anaerobic microorganisms have a unique Ni- and Fe-containing metal cluster called cluster C. 1 A Cu- and Mo-containing metal site is found in CODHases isolated from aerobic microorganisms. 1 We used a crystallographic approach to gain further insights into the reaction mechanism of Ni, Fe- CODHases. Structural analysis of CODHII from Carboxydothermus hydrogenoformans in several different states showed how substrates are activated by cluster C. 2 Water is bound by an asymmetrically coordinated Fe(II)-ion and carbon dioxide has been shown to act as a bridging ligand between Ni and the Fe(II)-ion. Amino acids in the direct vicinity of the cluster may contribute to catalysis by fast proton transfers and the stabilization of negatively charged intermediates. We further tested the reactivity of cluster C with inhibitors 3 and slow substrates, whose binding mode was resolved at atomic resolution. The structural analysis of ligand binding to cluster C presents a complementary approach to spectroscopic methods describing the electronic changes of cluster C during catalysis. Both approaches converge to a mechanism in which substrate activation and catalysis is mediated by a binuclear Ni-Fe sub site of cluster C. References 1. S. W. Ragsdale, Crit. Rev. Biochem. Mol. Biol. 2004, 39, 165-195. 2. J.-H. Jeoung, H. Dobbek, Science 2007, 318, 1461-1464. 3. J.-H. Jeoung, H. Dobbek, J. Am. Chem. Soc. 2009, 131, 9922-9923. 38
Page 1 and 2: ISBOMC ‘10 5th International Symp
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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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