CHEMICAL BIOLOGY AND MEDICINAL CHEMISTRY WITH INERT METAL
Our research group is focusing on the design and discovery of novel bioactive organometallic compounds and their application as tools in chemical biology and lead structures for the development of future medicines. Key aspect is to exploit the unique structural opportunities provided by chemically inert metal complexes, in particular octahedral coordination geometries, and apply them to unsolved problems of biomolecular recognition. Along these lines, we reported over the last few years a series of inert organometallic compounds as highly potent and selective inhibitors for protein and lipid kinases, some of which also display promising anticancer activities.
Protein and lipid kinases as a proof-of-principle class of
targets: We chose protein kinases as the principal target
because mutations and deregulation of protein kinases play causal roles
in many human diseases, making kinases an important therapeutic target.
Over the last 5 years, our group reported highly potent organometallic
inhibitors for the kinases GSK-3, Pim-1, MSK-1, PAK-1, and PI3K, thus
demonstrating the generality of the design strategy. Together with
collaborators, we deposited multiple cocrystal structures of metal
complexes with kinases in the PDB (Pim-1 with Ru: 2BZH, 2BZI, 2OI4, 2
BZJ; Pim-2 with Ru: 2IWI; PI3Kg with Ru: 2CST; Pim-1 with Os: 3BWF). In
all these crystal structures, the metal exerts a purely structural
role. Some of the published inhibitors belong to the most potent and
selective compounds known for their respective kinases. We hypothesize
that the high selectivities are caused by the rigidities of these
scaffolds. The complex EA1 and derivatives thereof have also
been demonstrated to display promising anticancer activities in several
cancer cell lines and in a melanoma spheroid model. See, for example:
Meggers, Chem. Commun. 2009, 1001-1010, and references
"Natural product-like" complicatedness of octahedral metal complexes: Whereas the initial years (2003-2007) were dedicated to use half-sandwich complexes as scaffolds, our focus has now shifted to truly octahedral coordination geometries. Note that this research is based on the hypothesis that octahedral coordination geometries are superior structural centers for the design small molecules with globular and defined shapes. Strikingly, the octahedron permits a much larger structural complicatedness than the tetrahedron which can be illustrated by the number of possible stereoisomers; a tetrahedron is capable of building a maximum of two enantiomers, in comparison to an octahedron which can form up to 30 stereoisomers, 15 diastereomers as pairs of enantiomers. Since unfortunately Nature did not provide us with stable octahedral carbon coordination spheres, we are instead using substitutionally inert transition metal centers, currently especially ruthenium and iridium.
New synthetic methodology urgently needed! In order to fully exploit the immense structural opportunities provided by octahedral coordination spheres, need synthetic methodology is needed for controlling the relative and absolute stereochemistry. Along these lines, in 2009 we reported the first general method available for the asymmetric synthesis of tris-heteroleptic ruthenium polypyridyl complexes by using salicyloxazolines as chiral auxiliaries. See: G. Lei, S. P. Mulcahy, K. Harms, E. Meggers, J. Am. Chem. Soc. 2009, 131, 9602-9603.
These efforts are currently ongoing in our laboratory:
- Designing kinase inhibitors which display complete selectivity in the human kinome.
- Investigation of the properties of selected kinase inhibitors in
- Expanding our design concept to other protein targets.
- Developing synthetic methodology for the stereoselective synthesis of complicated octahedral metal complexes.