Book of Abstracts - Ruhr-Universität Bochum

P-10
ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum
Octahedral Ruthenium Complexes as Protein Kinase Inhibitors
Sebastian Blanck a and Erik Meggers* a
a Philipps-Universität Marburg, Fachbereich Chemie, Hans-Meerwein-Straße, 35043 Marburg,
Germany. E-mail: sebastian.blanck@chemie.uni-marburg.de
Protein kinases are an important target in the field of medicinal chemistry. Since protein
phosphorylation represents a key step in many crucial cellular processes, the synthesis of potent and
selective kinase inhibitors has become more and more important. The ATP competitive
indolocarbazole alkaloid staurosporine is a potent but rather unselective inhibitor. Meggers et al. have
pioneered the design of inert and rigid organometallic complexes using staurosporine as a lead
structure (Figure 1). 1
Figure 1: Staurosporine as lead structure for octahedral metal complexes as kinase inhibitors.
By varying the ligands A-D around the metal center the preference for certain kinases can be
changed. 2 Thus it is possible to synthesize a variety of different kinase inhibitors using combinatorial
chemistry. The octahedral complex 1 has been found to be a good inhibitor for the protein kinase
GSK-3. GSK-3 has been shown to be a key component of the signal transduction in the insulin and
wnt signalling pathways. 3 1 is significantly more potent for the α-isoform (IC50 = 8 nM) over the βisoform
(IC50 = 50 nM), which is astonishing because GSK-3α and GSK-3β show 97% sequence
identity in the ATP-binding pocket. By using molecular modeling and structure based drug design it
was possible to increase the potency against GSK-3α by almost an order of magnitude (IC50 = 1 nM),
while the isoform selectivity remained the same. The amino group of the complex is very important
for the binding to the kinase since a protection of the functional group results in a complete loss of
inhibition as in metal complex 3 (Figure 2).
References
Figure 2: 2-(Aminomethyl)pyridine complexes as kinase inhibitors.
1. E. Meggers, G. E Atilla-Gokcumen, H. Bregman, Synlett 2007, 8, 1177.
2. H. Bregman, P. J. Carroll, E. Meggers, J. Am. Chem. Soc. 2006, 128, 877.
3. N. Pagano, J. Maksimoska, E. Meggers, Org. Biomol. Chem. 2007, 5, 1218
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