CHEMICAL BIOLOGY, MEDICINAL CHEMISTRY, AND CATALYSIS WITH ORGANOMETALLICS
Our research group is exploring organometallics as tools in chemical biology, lead structures for the development of future medicines, and scaffolds for the design of highly efficient asymmetric catalysts. Key focus of the Meggers lab is to exploit the unique structural opportunities provided by chemically inert metal complexes, in particular octahedral coordination geometries (up to 30 stereoisomers possible!), and apply them to difficult problems of biomolecular recognition and catalysis. 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. We also demonstrated recently that octahedral chiral-at-metal metal complexes can serve as highly efficient "organocatalysts" for asymmetric transformations.
A continued progress in this area of organometallic and inorganic medicinal chemistry also requires the development of strategies for the stereocontrolled synthesis of octahedral metal complexes. We therefore recently started a research program that aims in developing synthetic methods such as solid phase, combinatorial, diastereoselective, and asymmetric synthesis of complicated metal-containing compounds.
- Highly efficient asymmetric catalyst relying exclusively on octahedral metal-centered chirality! J. Am. Chem. Soc. 2013, DOI: 10.1021/ja403777k.
- Gold standard for the design of structurally sophisticated metal-based enzyme inhibitors: J. Am. Chem. Soc. 2011, 133, 5976-5986.
- First example of catalytic asymmetric coordination chemistry!
Featured in Nature Chemistry.
Link to article.
Link to cover picture.
Atomic resolution structure of a GNA duplex containing solely Watson–Crick hydrogen bonded base pairs solved in collaboration with Prof. Dr. L.-O. Essen: Helical twist due to alternating syn & anti conformations of the vicinal CO bonds: Chem. Commun.2010, 46, 1094-1096.
Chiral auxiliaries as emerging tools for the asymmetric synthesis of octahedral metal complexes: Chem. Eur. J. 2010, 16, 752-758 (minireview).
- First iridium complex as kinase inhibitor: Angew. Chem. Int. Ed. 2010, 49, 3839-3842.
Asymmetric coordination chemistry! First example of asymmetric synthesis of enantiopure ruthenium complex with the help of a chiral auxiliary: J. Am. Chem. Soc. 2009, 131, 9602-9603.
- Kinase selectivity through size and rigidity: Bulky octahedral
ruthenium complex as selective PAK1 inhibitor: J. Am. Chem. Soc. 2008,
- Close to a world record? Ultra-high affinity organometallic
inhibitor for protein kinase GSK-3: ChemBioChem 2008, 9,
- Finally solved: Structure of a duplex of the simplified nucleic acid GNA: J. Am. Chem. Soc. 2008, 130, 8158.
- Solid phase synthesis of ruthenium complexes: Cover art for the issue 12 of Inorganic Chemistry.
- Replacing the metal has virtually no effect on the biological properties of an organometallic scaffold! Chem. Eur. J. 2008, 14, 4816.
- Discovery of an organometallic lead structure which is selective
for lipid over protein kinases: ACS Chem. Biol. 2008,
More information on current areas of research:
I.) Metals as Building Blocks for the Design of
Ruthenium complexes have been developed as protein and lipid kinase inhibitors. See the Figure below:a) Staurosporine as the lead structure for the design of metal complexes. b) Cocrystal structure of protein kinase PAK1 with the octahedral inhibitor lambda-FL172. Displayed are the most important H-bonding interactions and a surface view demonstrating the shape match between active site and coordination sphere. c) A selection of potent and selective ruthenium-based kinase inhibitors.
For technology transfer of metal-containing kinase inhibitors, see following link. E-mail: email@example.com
II.) New Synthetic Methodology for Metal-Containing
Compounds: Asymmetric Coordination Chemistry
Most of our metal-containing enzyme inhibitors are chiral and, as expected, typically only one enantiomer has the desired properties, whereas the optical antipode often displays undesired different target selectivities. We recently developed a number of bidentate ligands that serve as chiral auxiliaries and in one case even as a catalyst for controlling the metal-centered configuration in octahedral ruthenium complexes.
- L. Gong, S. P. Mulcahy, K. Harms, E. Meggers, J. Am. Chem.
Soc. 2009, 131, 9602-9603. Link
- L. Gong, Z. Lin, K. Harms, E. Meggers, Angew. Chem. Int.
Ed. 2010, 49, 7955-7957.
Link to article.
- L. Gong, S. P. Mulcahy, D. Devarajan, K. Harms, G. Frenking, E.
Meggers, Inorg. Chem. 2010, 49,
- E. Meggers, Chem. Eur. J. 2010, 16, 752-758 (minireview). Link to article.
III.) Organometallic Catalysis in Living Cells
The exceptional ability of organometallic compounds to catalyze a wide variety chemical transformations has not yet been sufficiently exploited for chemical biology, but could yield bioactive molecules with novel properties. For example, such catalysts could eventually be used to amplify signals by turning over a substrate multiple times, catalytically label or deactivate target biomolecules, or release prodrugs, and all this in a cellular environment. However, designing catalysts which work under physiological conditions is a significant challenge due to the combined presence of air, water, and a plethora of cellular components such as millimolar concentrations of thiols that are prone to poison organometallic catalysts, especially under protic and aerobic conditions. With respect to this new aspect of bioorganometallic chemistry, we recently demonstrated a ruthenium-catalyzed release of amines from their allylcarbamates that tolerates the combination of water, air, and thiols, and we demonstrated the utility of this cleavage reaction in living mammalian cells: Streu and Meggers, Angew. Chem. Int. Ed. 2006, 45, 5645-5648.
- THE MINIMAL NUCLEIC ACID GNA: We recently discovered a minimal nucleic acid backbone (GNA, glycol nucleic acid). Due to its unique combination of high duplex stability, base pairing fidelity, and easy synthetic access of its nucleotides, GNA comprises a promising scaffold for future nucleic-acid-based nanotechnology. Furthermore, GNA is structurally the most simplified solution for a phosphodiester-containing nucleic acid backbone and thus constitutes a candidate for initial genetic molecules of life. See: L. Zhang, A. Peritz, E. Meggers, J. Am. Chem. Soc. 2005, 127, 4174-4175. For the crystal structure of a GNA duplex, see: M. K. Schlegel, L.-O. Essen, E. Meggers, J. Am. Chem. Soc. 2008, 130, 8158-8159.
- METAL-MEDIATED BASE PAIRING: In 2000, Meggers, Romesberg, and Schultz demonstrated for the first time that interbase metal coordination can replace the hydrogen bonding schemes found in the natural base Watson-Crick base pairs by reporting an artificial copper(II)-mediated base pair between pyridine and pyridine-2,6-dicarboxylate nucleotides. Metal-mediated base pairing (metallo-base pairing) will find potential applications in nucleic-acid-derived nanoelectronics or molecular motors and for the design of metal ion sensors and switches. See: E. Meggers, P. L. Holland, W. B. Tolman, F. E. Romesberg, P. G. Schultz, J. Am. Chem. Soc. 2000, 122, 10714-10715. For the first crystal structure of metal-mediated base pairs in a DNA duplex, see: S. Atwell, E. Meggers, G. Spraggon, P. G. Schultz, J. Am. Chem. Soc. 2001, 123, 12364-12367.
LONG-RANGE HOLE TRANSPORT IN DNA BY G-HOPPING: During the late 1990s we developed a technique that enabled us to generate single guanine radical cations site-selectively in double stranded DNA and to monitor the charge transport in different oligonucleotide systems. From our investigations we concluded that the overall transport of positive charge in a DNA duplex is a multistep hopping process between G bases where the individual steps contribute to the overall rate. The distance dependence is therefore no longer described by a single beta-value of the superexchange mechanism. This G-hopping mechanism can explain the transport of positive charge in DNA over long distances. See: E. Meggers, M. E. Michel-Beyerle, B. Giese; J. Am. Chem. Soc. 1998, 120, 12950-12955.
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein Strasse, D-35032 Marburg
Phone: ++49 6421 282 1534 Fax.: ++49 6421 282 2189 firstname.lastname@example.org