Book of Abstracts - Ruhr-Universität Bochum

P-83
ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum
Iridium Complex with Antiangiogenic Properties
Alexander Wilbuer, a D. H. Vlecken, b D. J. Schmitz, b C. P. Bagowski, b and Erik Meggers* a
a Philipps Universität Marburg, Fachbereich Chemie, Hans-Meerwein Str., 35032 Marburg,
Germany. b Leiden University, Institute of Biology, Wassenaarseweg 64,
2333 AL Leiden, The Netherlands. Wilbuer@chemie.uni-marburg.de
Substitutionally inert metal complexes are promising emerging scaffolds for targeting enzyme active
sites. 1 Our group has demonstrated over the last five years that inert ruthenium(II) complexes can
serve as highly selective nanomolar and even picomolar inhibitors of protein kinases. 2 Octahedral
metal coordination geometries in particular offer new gateways to design rigid, globular molecules
with defined shapes that can fill protein pockets such as enzyme active sites in a unique fashion. 3
Although most of our previous efforts were focused on ruthenium(II) complexes, we envisioned that
octahedral iridium(III) complexes might be interesting scaffolds for two reasons: First, coordinative
bonds with Ir(III) tend to be very inert 4 and therefore Ir(III) complexes should be able to serve as
stable scaffolds for the design of enzyme inhibitors. 5 Second, octahedral Ir(III) complexes can be
accessed from square planar Ir(I) complexes by stereospecific oxidative addition reactions. 6 Here we
present the discovery of an octahedral iridium(III) complex, synthesized through oxidative addition as
the key synthetic step. The organometallic compound functions as a low nanomolar and highly
selective inhibitor of the protein kinase Flt4, also known as VEGFR-3 (vascular endothelial growth
factor receptor 3). Flt4 is involved in angiogenesis and lymphangiogenesis and we were able to
demonstrate that this iridium complex can indeed interfere with the development of blood vessels in
vivo in two different zebrafish angiogenesis models.
References
1. E. Meggers, Curr. Opin. Chem. Biol. 2007, 11, 287-292.
2. E. Meggers, G. E. Atilla-Gokcumen, H. Bregman, Synlett 2007, 8, 1177-1189.
3. J. Maksimoska, L. Feng, K. Harms, J. Am. Chem. Soc. 2008, 130, 15764-15765.
4. J. Burgess, Inorg. React. Mechanism 1972, 2, 140-195.
5. T.-H. Kwon, J. Kwon, J.-I. Hong, J. Am. Chem. Soc. 2008, 130, 3726-3727.
6. J. U. Mondal, D. M. Blake, Coord. Chem. Rev. 1982, 47, 205-238.
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