Book of Abstracts - Ruhr-Universität Bochum

P-45
ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum
Octahedral Ruthenium Complexes as Phosphatidyl-inositol-3-kinase Inhibitors
Stefan Mollin, a Jie Qin, b Ronen Marmorstein b and Eric Meggers *a
a Philipps-Universität Marburg, Fachbereich Chemie, Hans-Meerwein-Straße, 35032, Marburg,
Germany. b The Wistar Institute, 3601 Spruce Street, 19104, Philadelphia, PA, USA.
E-mail: stefan.mollin@chemie.uni-marburg.de
The design of bioactive compounds for applications in medicinal chemistry and chemical biology is
focused predominantly on organic molecules, whereas inorganic compounds are mainly known for
their reactivity (e.g. cisplatin) or imaging properties (e.g. gadolinum complexes in MRI). 1 However, in
recent years, MEGGERS et al. developed a novel strategy, wherein inert ruthenium(II) complexes were
designed as protein kinase inhibitors. 2 Here, the ability of metal complexes is used to organize organic
ligands in three-dimensional space to form structures with unique and defined shapes. Based on the
natural product staurosporine 1, a potent but unselective kinase inhibitor, MEGGERS et al. designed
half-sandwich complexes initially and achieved a number of potent and selective inhibitors.
Phosphatidyl-inositol-3-kinases (PI3Ks) are a family of lipid kinases which act as signal transducers.
They serve phosphatidylinositol-3,4,5-triphosphate (PIP3), an important second messenger which
recruits AKT/PKB. Disruption of the PI3K signaling pathway leads to uncontrolled cell proliferation,
survival, and cell growth. Thus, PI3K is a highly attractive target for the development of therapeutic
agents to treat cancer and other related diseases.
MARMORSTEIN and MEGGERS et al. found that a methylation of the pyridocarbazole-imide leads to a
selectivity switch between protein and lipid kinases. Whereas half-sandwich complexes with free
imides were found as nanomolar GSK-3 and Pim-1 inhibitors, complex 2 shows good selectivity for
PI3Ks. 3 To further increase the potency and selectivity our focus has shifted now to octahedral
compounds 3 with even more defined and rigid shapes. Following this strategy more potent inhibitors
have been synthesized with up to tenfold selectivity between the different isoforms PI3Kα and PI3Kγ.
References
1. C. Orvig, M. J. Abrams, Chem. Rev. 1999, 99, 2201-2204.
2. (a) H. Bregman, P. J. Carroll, E. Meggers, J. Am. Soc. 2006, 128, 877-884. (b) E. Meggers, G. E.
Atilla-Gokcumen, H. Bregman, J. Maksimoska, S. P. Mulcahy, N. Pagano, D. S. Williams, Synlett
2007, 8, 1177-1189.
3. X. Peng, D. S. Williams, G. E. Atilla-Gokcumen, L. Milk, X. Min, K. S. M. Smalley, M. Herlyn, E.
Meggers, R. Marmorstein, ACS Chem. Biol. 2008, 3, 305-316.
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