Medical Impact of Polynuclear Cluster Compounds

Polynuclear metal compounds may have considerable potential as metallic drugs. The most prominent representatives are polyoxometalates which have been investigated since the last third of the 19^th century. In addition to applications in catalysis, separation, analysis, and as electron-dense imaging agents, some of these substances have been shown to exhibit biological activity in vitro as well as in vivo ranging from anti-cancer, antibiotic, and antiviral to anti-diabetic effects.¹
Polymetalates represent a diverse ensemble of nanostructures with an almost infinite variability of chemical, physical and biological properties. The size of typical covalent bridged cluster compounds is in the range from 1 to 3 nm. The attachment of special surface groups on the periphery of cluster compounds may result in self-assembled non-covalent organized structures larger than 5 nm which are characteristic for bio-molecules, such as enzymes. Cells of mammalian organisms are typically 10 to 30 µm. However, sub-cellular organelle dimensions are smaller and range in sub-µm sizes. This comparison of size dimension illustrates that polymetalates are small enough to allow the cell membrane to be penetrated without too much interference. Evidently, some types of polymetalates are able to be transported into cells, particularly into mitochondria. Our aim is focused on the development of novel cluster compounds with improved chemical and metabolic stability. Furthermore, increased recognition of target biomolecules - such as enzymes - shall be achieved.
On the way to explore the biological activity of polynuclear cluster compounds, we recently recognised polyoxometalates as a new class of potent enzyme inhibitors.² Certain polymetalates are able to inhibit E-NTPDases (ecto-nucleoside triphosphate diphosphohydrolases) that are surface-located nucleotide-hydrolyzing enzymes involved in the regulation of signaling cascades by activating P2 (nucleotide) receptors. The most potent compound - described to date – is K₆H₂[TiW₁₁CoO₄₀] I exhibiting IC₅₀ values which are significantly lower than those of known standard inhibitors. Some compounds are also able to directly interact with P2 receptors. A further promising new class of cluster compounds to permit selective inhibition of E-NTPDases are hexanuclear rhenium complexes with bridging sulfur, selenium and/or tellurium atoms. In this perspective, a broad ensemble of water-soluble octahedral rhenium cluster compounds II becomes available by ligand exchange reactions.³
The paper will give a brief overview about the potential of inorganic cluster compounds in medicine as well as a survey of recent progress that was achieved on E-NTPDase inhibition and P2 receptor antagonism with polymetalates.

[1] J. T. Rhule, C. L. Hill, D. A. Judd, R. F. Schinazi, Chem. Rev.1998, 98, 327-357.
[2] C. E. Müller, J. Iqbal, Y. Baqi, H. Zimmermann, A. Röllich, H. Stephan, Bioorg. Med. Chem. Lett. 2006, 16, 5943-5947.
[3] K. A. Brylev, Y. V. Mironov, S. Kozlova, V. E. Fedorov, S.-J. Kim, H.-J. Pietzsch,
H. Stephan, A. Ito, S. Ishizaka, N. Kitamura, Inorg. Chem. 2009, 48, 2309-2315.