Book of Abstracts - Ruhr-Universität Bochum

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.
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