Publications

Download list of publications, May 13th, 2013 (PDF file)

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2013

2013-6: Asymmetric Catalysis with Inert Chiral-At-Metal Iridium Complex

_{L.-A. Chen, W. Xu, B. Huang, J. Ma, L. Wang, J. Xi, K. Harms, L. Gong, E. Meggers, J. Am. Chem. Soc. 2013, DOI: 10.1021/ja403777k}

abstract: The development of a chiral-at-metal iridium(III) complex for the highly efficient catalytic asymmetric transfer hydrogenation of beta, beta’-disubstituted nitroalkenes is reported. Catalysis by this inert, rigid metal complex does not involve any direct metal coordination but operates exclusively through cooperative, weak interactions with functional groups properly arranged in the ligand sphere of the iridium complex. Although the iridium complex only relies on the formation of three hydrogen bonds, it exceeds the performance of most organocatalysts with respect to enantiomeric excess (up to 99% ee) and catalyst loading (down to 0.1 mol%). This work hints towards an advantage of structurally complicated, rigid scaffolds for non-covalent catalysis which especially relies on conformationally constrained, cooperative interactions between catalyst and substrates.

Link to article

2013-5: Method for the Preparation of Non-Racemic Bis-Cyclometalated Iridium(III) Complexes

_{M. Helms, Z. Lin, L. Gong, K. Harms, E. Meggers, Eur. J. Inorg. Chem. 2013, accepted for publication}

abstract: A straightforward method for the synthesis of virtually enantiomerically pure ruthenium(II) polypyridyl complexes [Ru(pp)(pp’)(pp’’)](PF6)2, pp = bidentate polypyridyl has been developed. The synthesis draws from the readily available racemic starting material cis-[Ru(pp)(pp’)Cl2] and the natural amino acids L- or D-proline and relies on a dynamic asymmetric transformation under thermodynamic control.

 

2013-4: Rhenium Complexes with Visible-Light-Induced Anticancer Activity

_{A. Kastl, S. Dieckmann, K. Wähler, T. Völker, L. Kastl, A. L. Merkel, a. Vultur, B. Shannan, K. Harms, M. Ocker, W. Parak, M. Herlyn, E. Meggers, ChemMedChem 2013, published online}

abstract: This publication introduces a new class of potent visible-light-triggered anticancer organometallics based on rhenium(I) indolato complexes. This is unexpected since related rhenium(I) tricarbonyl polypyridyl complexes are well established nontoxic luminescence probles routinely applied for biological imaging.

Link to article

 

 

2013-3: Chiral-Auxiliary-Mediated Asymmetric Synthesis of Ruthenium Polypyridyl Complexes

_{L. Gong, M. Wenzel, E. Meggers, Acc. Chem. Res. 2013, accepted for publications}

abstract: A few years ago our laboratory embarked on a project exploring new and general synthetic strategies for the asymmetric synthesis of inert octahedral transition metal complexes by initially using the example of thermally inert ruthenium polypyridyl complexes. As a result of these efforts, we developed a family of chiral bidentate ligands, including salicyloxazolines, (mercaptophenyl)oxazolines, sulfinylphenols, N-acetylsulfinamides, a phosphinohydroxybinaphthyl, and even the amino acid proline to serve as chiral auxiliaries for asymmetric coordination chemistry. The applications of these auxiliaries for the asymmetric synthesis of non-racemic ruthenium(II) polypyridyl complexes is discussed.

 

2013-2: Thioether-Based Anchimeric Assistance for Asymmetric Coordination Chemistry with Ruthenium(II) and Osium(II)

_{L.-A. Chen, X. Ding, L. Gong, E. Meggers, Dalton Trans. 2013, 42, 5623-5626}

abstract: (R)-4-(Alkylthiomethyl)-5,5-dimethyl-2-(2’-hydroxyphenyl)-2-oxazolines are demonstrated to be highly suitable chiral auxiliaries for the two-step conversion of the half-sandwich complex [Ru(C6H6)(bpy)Cl]Cl, bpy = 2,2’-bipyridine, into delta-configured ruthenium polypyridyl complexes. The tailored thioether substituent at the oxazoline ring is essential for this conversion and not only promotes the removal of the benzene moiety but also controls the absolute metal-centered configuration. Applied to osmium, this strategy resulted in the first highly asymmetric synthesis of delta-[Os(bpy)3](PF6)2.

Link to article

 

 

2013-1: Metal Complex Catalysis in Biological Systems

_{P. K. Sasmal, C. N. Streu, E. Meggers, Chem. Commun. 2013, 49, 1581-1587}

abstract: This Feature article discusses synthetic metal complexes that are capable of catalyzing chemical transformations in living organisms. Over the last few years, significant progress has been made towards the application of non-biological reactions in living systems, ranging from the organoruthenium-catalyzed cleavage of allylcarbamates and a gold-catalyzed intramolecular hydroarylation to palladium-catalyzed Suzuki-Miyaura and Sonogashira cross-couplings within the cytoplasm or on the surface of living cells. The design of bioorthogonal catalyst/substrate pairs, which can passively diffuse into cells, combines the advantages of small molecules with catalysis and promises to provide exciting new tools for future chemical biology studies.

Link to article

2012

2012-14: Proline as Chiral Auxiliary for the Economical Asymmetric Synthesis of Ruthenium(II) Polypyridyl Complexes

_{C. Fu, M. Wenzel, E. Treutlein, K. Harms, E. Meggers, Inorg. Chem. 2012, 51, 10004-10011}

abstract: A straightforward method for the synthesis of virtually enantiomerically pure ruthenium(II) polypyridyl complexes [Ru(pp)(pp’)(pp’’)](PF6)2, pp = bidentate polypyridyl has been developed. The synthesis draws from the readily available racemic starting material cis-[Ru(pp)(pp’)Cl2] and the natural amino acids L- or D-proline and relies on a dynamic asymmetric transformation under thermodynamic control.

Link to article

 

_{N. L. Kilah, E. Meggers, Aust. J. Chem. 2012, 65, 1325-1332}

_{J. K. John, K. H. T. Paraiso, V. W. Rebecca, L. P. Cantini, E. V. Abel, N. Pagano, E. Meggers, R. Mathew, C. Krepler, V. Izumi, B. Fang, J. M. Koomen, J. L. Messina, M. Herlyn, K. S. M. Smalley, J. Investigative Dermatology 2012, published online}

2012-3: About the Art of Filling Protein Pockets Efficiently with Octahedral Metal Complexes

_{S. Blanck, J. Maksimoska, J. Baumeister, K. Harms, R. Marmorstein, E. Meggers, Angew. Chem. Int. Ed. 2012, 51, 5244-5246}

abstract: A very important aspect regarding the design of enzyme inhibitors based on octahedral metal complex scaffolds is the position of the metal within the active site. In this work, two different octahedral scaffolds are compared regarding their binding to the same protein pocket.

Link to article

 

2012-2: Rhodium(III)-Pyridocarbazole Complexes as Protein Kinase Inhibitors

_{S. Dieckmann, R. Riedel, K. Harms, E. Meggers, Eur. J. Inorg. Chem. 2012, 813-821}

abstract: Whereas previous work from our laboratory was predominantly based on ruthenium(II), this study evaluates the suitability of rhodium in the oxidation state III to serve as a structural center for designing inert metal-based enzyme inhibitors. Based on our established staurosporine-inspired metallo-pyridocarbazole scaffold, strategies for the convenient synthesis of rhodium(III)-pyridocarbazole complexes were developed and applied to the synthesis of protein kinase inhibitors.

Link to article





2012-1: Dual Anticancer Activity in a Single Compound: Visible Light-Induced Apoptosis by an Antiangiogenic Iridium Complex

_{A. Kastl, A. Wilbuer, A. L. Merkel, L. Feng, P. Di Fazio, M. Ocker, E. Meggers, Chem. Commun. 2012, 48, 1863-1865}

abstract: A metal complex is identified in which the metal fulfills two independent functions: as a structural scaffold for the specific molecular recognition of protein kinases resulting in antiangiogenic properties, together with a visible-light-induced photoreactivity triggering apopotosis in cancer cells.

Link to article

2011

2011-11: N-Sulfinylcarboximidates as a Novel Class of Chiral Bidentate Ligands: Application to Asymmetric Coordination Chemistry

_{Z. Lin, M. A. Celik, C. Fu, K. Harms, G. Frenking, E. Meggers, Chem. Eur. J. 2011, 17, 12602-12605}

abstract: We have discovered N-acetyl-tert-butanesulfinamide as a novel chiral bidentate ligand and applied it to the asymmetric synthesis of octahedral ruthenium polypyridyl complexes. This auxiliary is highly appealing due to its convenient accessibility from Ellman’s sulfinamide in a single step. To the best of our knowledge, the coordination of N-acetyl-tert-sulfinamide through the formation of a chelating N-sulfinylcarboximidate has not been reported before.

Link to article

 

 

2011-10: On the Structure and Dynamics of Duplex GNA

_{A. T. Johnson, M. K. Schlegel, E. Meggers, L.-O. Essen, O. Wiest, J. Org. Chem. 2011, 76, 7964-7974}

abstract: A herein presented new crystal structure of a GNA duplex at 1.8 Å resolution from self-complementary 3’-CTCBrUAGAG-2’ GNA oligonucleotides reveals an N-type conformation with alternating gauche-anti torsions along its (O3'-C3'-C2'-O2') backbone. To elucidate the conformational state of dsGNA in solution, molecular dynamic simulations over a period of 20 ns were performed with the repertoire of now available structural information from the three crystal structures. Interestingly, dsGNA exists in solution as in conformational states intermediate between experimentally observed backbone conformations: simulated dsGNA shows the all-gauche conformation of the M-type GNA with the higher helical twist observed in N-type GNA structures.

Link to article

2011-9: P-Donor Ligand Containing Ruthenium Half-Sandwich Complexes as Protein Kinase Inhibitors

_{C. Streu, L. Feng, P. J. Carroll, J. Maksimoska, R. Marmorstein, E. Meggers, Inorg. Chim. Acta 2011, 377, 34-41}

abstract: Reported is the design, synthesis, and evaluation of protein kinase inhibition properties of pyridocarbazole half-sandwich complexes containing P-donor ligands. The nature of the monodentate P-donor ligand has a strong effect on protein kinase binding properties, most likely due to a direct interaction with the glycine-rich loop in the ATP-binding site.

Link to article

2011-8: Organometallic Pyridylnaphthalimide Complexes as Protein Kinase Inhibitors

_{S. Blanck, T. Cruchter, A. Vultur, R. Riedel, K. Harms, M. Herlyn, E. Meggers, Organometallics 2011, 30, 4598-4606}

abstract: A new metal-containing scaffold for the design of protein kinase inhibitors is introduced. Key feature is a 3-(2-pyridyl)-1,8-naphthalimide “pharmacophore chelate ligand” which is designed to form two hydrogen bonds with the hinge region of the ATP-binding site and is at the same time capable of serving as a stable bidentate ligand through C-H-activation at the 4-position of the electron-deficient naphthalene moiety. This C-H-activation leads to a reduced demand for coordinating heteroatoms and thus sets the basis for a very efficient three-step synthesis starting from 1,8-naphthalic anhydride. The versatility of this ligand is demonstrated with the discovery of a ruthenium complex that functions as a nanomolar inhibitor for myosin light-chain kinase.

Link to article.

 

2011-7: Size Does Matter. Sterically Demanding Metallocene-Substituted 3-Methylidene-Oxindoles Exhibit Poor Kinase Inhibitory Action

_{J. Spencer, J. Amin, P. Coxhead, J. McGeehan, C. J. Richards, G. J. Tizzard, S. J. Cole, J. P. Bingham, J. A. Hartley, L. Feng, E. Meggers, M. Guille, Organometallics 2011, 33, 3177-3181}

abstract: Bulky oxindole-complexes have been synthesized and tested for anticancer activity and were found to be inactive against a range of kinase targets compared with their simpler, less bulky ferrocene analog. Space-filling models emphasize the dramatic difference in the metal complex bulk around the common oxindole unit, which leads us to conclude that the bulky environment may disfavor binding in the ATP pocket of kinases, including that of PAK1.

Link to article.

 

2011-6: Asymmetric Synthesis of Octahedral Coordination Complexes

_{E. Meggers, Eur. J. Inorg. Chem. 2011, 2911-2926}

abstract: This microreview provides an overview of the asymmetric coordination chemistry of octahedral metal complexes within the historical context, including asymmetric coordination chemistry evolved by Nature, the predetermination of metal-centered chirality with tailored chiral ligands, chiral-anion-mediated and chiral-auxiliary-mediated asymmetric synthesis, and a recent example of the catalytic asymmetric synthesis of an octahedral coordination complex.

Link to article.

2011-5: Structurally Sophisticated Octahedral Metal Complexes as Highly Selective Protein Kinase Inhibitors

_{L. Feng, Y. Geisselbrecht, S. Blanck, A. Wilbuer, G. E. Atilla-Gokcumen, P. Filippakopoulos, K. Kräling, M. A. Celik, K. Harms, J. Maksimoska, R. Marmorstein, G. Frenking, S. Knapp, L.-O. Essen, E. Meggers, J. Am. Chem. Soc. 2011, 133, 5976-5986}

abstract: The generation of synthetic compounds with exclusive target specificity is an extraordinary challenge of molecular recognition and demands novel design strategies, in particular for large and homologous protein families such as protein kinases with more than 500 members. Simple organic molecules often do not reach the necessary sophistication to fulfill this task. Here, we present six carefully tailored, stable metal-containing compounds in which unique and defined molecular geometries with natural-product-like structural complexity are constructed around octahedral ruthenium(II) or iridium(III) metal centers. Each of the six reported metal compounds displays high selectivity for an individual protein kinase, namely GSK3alpha, PAK1, PIM1, DAPK1, MLCK, and FLT4.

Link to article.

2011-4: 2-Diphenylphosphino-2'-hydroxy-1,1'-binaphthyl as a Chiral Auxiliary for Asymmetric Coordination Chemistry

_{L. Gong, C. Müller, M. A. Celik, G. Frenking, E. Meggers, New J. Chem. 2011, 35, 788-793.}

abstract: In this study, the bidentate ligand (R)-2-diphenylphosphino-2'-hydroxy-1,1'-binaphthyl (HO-MOP) was investigated as a chiral auxiliary for the asymmetric synthesis of ruthenium polypyridyl complexes. It was found that (R)-HO-MOP serves as an effective chiral auxiliary starting from different precursor complexes, most notably using the commercially available half-sandwich complex [Ru(C₆H₆)Cl₂]₂.

Link to article.

2011-3: Asymmetric Coordination Chemistry by Chiral-Auxiliary-Mediated Dynamic Resolution under Thermodynamic Control

_{Z. Lin, L. Gong, M. A. Celik, K. Harms, G. Frenking, E. Meggers, Chem. Asian J. 2011, 6, 474-481.}

abstract: Dynamic asymmetric transformation at an octahedral ruthenium center: Chiral (R)-2-(isopropylsulfinyl)phenol (R = H) and preferably a more electron rich methoxy derivative (R = OMe) serve as auxiliaries for the asymmetric synthesis of chiral ruthenium polypyridyl complexes starting from racemic cis-[Ru(pp)₂Cl₂] (pp = 2,2'-bipyridine or 1,10-phenanthroline ligands).

Link to article.

2011-2: From Conventional to Unusual Enzyme Inhibitor Scaffolds: The Ongoing Quest for Target Specificity

_{E. Meggers, Angew. Chem. Int. Ed. 2011, 50, 2442-2448.}

abstract: The enormous challenge of specific molecular recognition of single biomacromolecular targets within complex biological systems demands novel and creative design strategies. This short review discusses some conventional and unusual approaches for the design of target-selective enzyme inhibitors with a focus on the employed underlying chemical scaffolds.

Link to article.

2011-1: Structure of Ruthenium Half-Sandwich Complex Bound to Glycogen Synthase Kinase 3beta

_{G. E. Atilla-Gokcumen, L. Di Costanzo, E. Meggers, J. Biol. Inorg. Chem. 2011, 16, 45-50.}

abstract: The 3.15 Å resolution crystal structure of the (R)-enantiomer of the highly bioactive and antiproliferative half-sandwich ruthenium complex DW12 bound to the ATP-binding site of glycogen synthase kinase 3beta (GSK-3b) is reported and compared with the GSK-3b-binding of staurosporine and other organic inhibitors. The structure reveals a close packing of the organometallic inhibitor in the ATP binding site of GSK-3b via an induced fit mechanism. The molecular structure of (R)-DW12 with the CO-ligand oriented perpendicular to the pyridocarbazole heterocycle allows the complex to stretch the whole distance sandwiched between the faces of the N- and C-terminal lobes and to interact tightly with the flexible glycine-rich loop which is uncommon for the interaction of GSK-3b with organic inhibitors.

Link to interactive 3D complement in proteopedia.

Link to article.

2010

2010-9: Isomerization-Induced Asymmetric Coordination Chemistry: From Auxiliary Control to Asymmetric Catalysis

_{L. Gong, Z. Lin, K. Harms, E. Meggers, Angew. Chem. Int. Ed. 2010, 49, 7955-7957.}

abstract: Catalytic asymmetric coordination chemistry made possible by chirality transfer from an organic ligand with sulfur-centered chirality to a chiral-at-metal octahedral ruthenium complex. (S)-2-(isopropylsulfinyl)phenol and a more electron rich methoxy derivative are capable of inducing and even catalyzing a chirality-generating trans-cis isomerization of two 2,2'-bipyridine ligands in an octahedral coordination sphere of a ruthenium complex. Link to article.

To be featured on cover: Link to cover image.

Featured in: Nature Chemistry (DOI:10.1038/nchem.836 )

Highlighted in ChemCatChem: Link to Early View.

2010-8: Organometallics as Structural Scaffolds for Enzyme Inhibitor Design

_{S. P. Mulcahy, E. Meggers, Top. Organomet. Chem. 2010, 32, 141-153.}

abstract (review): Substitutionally inert metal-containing compounds provide new opportunities as structurally diverse and unique scaffolds for the design of protein binders. This review cites progress in this area by highlighting the use of metal complexes, including truly organometallic compounds, as inhibitors for enzymes of biological interest, such as esterases, proteases, and protein kinases.

download article · 2290K PDF





 

2010-7: Discovery of a Strongly Apoptotic Ruthenium Complex through Combinatorial Coordination Chemistry

_{S. P. Mulcahy, K. Gründler, C. Frias, L. Wagner, A. Prokop, E. Meggers, Acc. Dalton Trans. 2010, 39, 8177-8182.}

abstract: A simple octahedral ruthenium complex with striking apoptotic properties was identified through combinatorial chemistry, subsequent screening, and followed by a brief structure-activity relationship. Link to article.

2010-6: Chiral Salicyloxazolines as Auxiliaries for the Asymmetric Synthesis of Ruthenium Polypyridyl Complexes

_{L. Gong, S. P. Mulcahy, D. Devarajan, K. Harms, G. Frenking, E. Meggers, Inorg. Chem. 2010, 49, 7692-7699.}

abstract: We recently introduced chiral salicyloxazolines as coordinating bidentate chiral ligands which provide excellent control over the metal-centered configuration in the course of ligand substitution reactions and can be removed afterwards in an acid-induced fashion under complete retention of configuration (J. Am. Chem. Soc. 2009, 131, 9602-9603). Herein we report our detailed investigation of this reaction sequence, reveal the scope of this method, and provide a guide to optimal standard reaction conditions. Link to article.

2010-5: Unusual Allene Osmacycle with Apoptotic Properties

_{X. He, L. Gogn, K. Kräling, K. Gründler, C. Frias, R. D. Webster, E. Meggers, A. Prokop, H. Xia, Chem. Bio. Chem. 2010, 11, 1607-1613.}

abstract: The highly apoptotic properties of a structurally unusual organometallic osmacycle is reported. Despite its chemical stability, the complex strongly induces apoptosis in Burkett-like lymphoma cells and we demonstrate that this occurs through the intrinsic mitochondrial pathway of programmed cell death. The presented results indicated that previously not considered organometallics provide untapped opportunities to be exploited for the discovery and development of future drug candidates. Link to article.

2010-4: Synthesis and Properties of the Simplified Nucleic Acid GNA

_{E. Meggers and L. Zhang, Acc. Chem. Res. 2010, 43, 1092-1102.}

abstract: The nucleosides of glycol nucleic acid (GNA)—with the backbone comprising just the three carbons and one stereocenter of propylene glycol (1,2-propanediol)—probably constitute the simplest possible building blocks for a chemically stable nucleic acid that contains phosphodiester bonds. However, it was not until 2005 that the astonishing duplex formation properties of GNA homoduplexes were discovered in our laboratory. This account article summarizes and discusses the surprising duplex formation properties of GNA. Link to article.

 

 

2010-3: Iridium Complex with Antiangiogenic Properties

_{A. Wilbuer, D. H. Vlecken, D. J. Schmitz, K. Kräling, K. Harms, C. P. Bagowski, E. Meggers, Angew. Chem. Int. Ed. 2010, 49, 3839-3842.}

abstract: The discovery of a bioactive octahedral iridium(III) complex, synthesized through oxidative addition as the key synthetic step, is presented. The organometallic compound functions as a nanomolar and selective inhibitor of the protein kinase Flt4 (Fms-related tyrosine kinase 4), also known as VEGFR3 (vascular endothelial growth factor receptor 3). Flt4 is involved in angiogenesis and lymphangiogenesis and it is demonstrated that this nontoxic organoiridium compound can interfere with the development of blood vessels in vivo in two different zebrafish angiogenesis models. Link to article.

Featured in highlight article from C. Kunick and I. Ott: Angew. Chem. Int. Ed. 2010, 49, 5226-5227.

2010-2: Atomic Resolution Structure of the Simplified Nucleic Acid GNA

_{M. K. Schlegel, L.-O. Essen, E. Meggers, Chem. Commun. 2010, 46, 1094-1096.}

abstract: Double helix variations of glycol nucleic acids (GNA) are revealed by the atomic resolution crystal structure of a 6mer GNA duplex containing solely Watson–Crick type hydrogen bonded base pairs. Link to article.

2010-1: Chiral Auxiliaries as Emerging Tools for the Asymmetric Synthesis of Octahedral Metal Complexes

_{E. Meggers, Chem. Eur. J. 2010, 16, 752-758.}

abstract (minireview): New methods for the stereocontrolled synthesis of octahedral metal complexes are needed in order to fully exploit the stereochemical richness of the octahedron in the fields of catalysis, materials sciences, and life sciences. Whereas a large body of work exists regarding the diastereoselective coordination chemistry with chiral ligands, such efforts are restricted to certain carefully designed chiral ligands which remain in the coordination sphere. This short review summarizes reported examples of chiral auxiliaries applied to the asymmetric synthesis of octahedral metal complexes. Link to article.

2009

From Imide to Lactam Metallo-pyridocarbazoles: Distinct Scaffolds for the Design of Selective Protein Kinase Inhibitors

_{N. Pagano, E. Y. Wong, T. Breiding, H. Liu, A. Wilbuer, H. Bregman, Q. Shen, S. L. Diamond, E. Meggers, J. Org. Chem. 2009, 74, 8997-9009.}

abstract: Organometallic pyridocarbazole scaffolds are investigated as protein kinase inhibitors. Whereas our previous designs employed solely a maleimide pharmacophore we have now extended our investigations to include the related lactam metallo-pyridocarbazoles. Lactam lead structures for the inhibition of the protein kinases TrkA and CLK2 are reported.

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Crystal Structure of the PIM2 Kinase in Complex with an Organoruthenium Inhibitor 

_{A. N. Bullock, S. Russo, A. Amos, N. Pagano, H. Bregman, J. E. Debreczeni, W. H.  Lee, F. von Delft, E. Meggers, S. Knapp, PLoS One 2009, 4,  e7112.}

abstract: The serine/threonine kinase PIM2 is highly expressed in human leukemia and lymphomas and has been shown to positively regulate survival and proliferation of tumor cells.  Its diverse ATP site makes PIM2 a promising target for the development of anticancer agents. Here we determined the crystal structure of PIM2 in complex with an organoruthenium complex. 

download article · 734K PDF

 

Chiral-Auxiliary-Mediated Asymmetric Synthesis of Tris-Heteroleptic Ruthenium Polypyridyl Complexes

_{G. Lei, S. P. Mulcahy, K. Harms, E. Meggers, J. Am. Chem. Soc. 2009,  131,  9602-9603.}

abstract: A strategy for the asym. synthesis of chiral-at-metal [Ru(pp)(pp')(pp'')]²⁺ complexes, where pp, pp', and pp'' are achiral 2,2'-bipyridines, is introduced. The method employs isopropyl-2-(2'-hydroxyphenyl)oxazolines as chiral auxiliaries, which serve in their deprotonated forms as strong bidentate ligands that provide excellent asymmetric induction in the course of the coordination chemistry and, importantly, can afterward become substituted with complete retention of configuration in the presence of acid.

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The Crystal Structure of BRAF in Complex with an Organoruthenium Inhibitor Reveals a Mechanism for Inhibition of an Active Form of BRAF Kinase

_{P. Xie, C. Streu, J. Qin, H. Bregman, N. Pagano, E. Meggers, R. Marmorstein, Biochemistry 2009, 48, 5187-5198.}

abstract: Here we report on the identification and subsequent optimization of a potent BRAF inhibitor, CS292, based on an organometallic kinase inhibitor scaffold. A cocrystal structure of CS292 in complex with the BRAF kinase domain reveals that CS292 binds to the ATP binding pocket of the kinase and is an ATP competitive inhibitor. The structure of the kinase-inhibitor complex also demonstrates that CS292 binds to BRAF in an active conformation and suggests a mechanism for regulation of BRAF by phosphorylation and BRAFV600E oncogene-induced activation.

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Toward the Development of a Potent and Selective Organoruthenium Mammalian Sterile 20 Kinase Inhibitor

_{R. Anand, J. Maksimoska, N. Pagano, E. Y. Wong, P. A. Gimotty, A. Phyllis, S. L. Diamond, E. Meggers, R. Marmorstein, J. Med. Chem. 2009, 52,  1602-1611.}

abstract: Mammalian sterile 20 (MST1) kinase, a member of the sterile 20 (Ste-20) family of proteins, is a proapoptotic cytosolic kinase that plays an important role in the cellular response to oxidative stress. In this study, we report on the development of a potent and selective MST1 kinase inhibitor based on a ruthenium half-sandwich scaffold.  We show that the enantiopure organoruthenium inhibitor, has an IC50 value of 45 nM for MST1 and a greater than 25-fold inhibitor selectivity over the related Ste-20 kinases. A cocrystal structure of a related compd. with PIM-1 and a homol. model with MST1 reveals the binding mode of this scaffold to MST1 and provides a starting point for the development of improved MST1 kinase inhibitors for possible therapeutic application. 

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Inert Ruthenium Half-Sandwich Complexes with Anticancer Activity

_{Eric Meggers, G. Ekin Atilla-Gokcumen, Katharina Gründler, Corazon Frias, Aram Prokop, Dalton Trans. 2009, 10882-10888.}

abstract: In this study, we investigate the anticancer properties of an inert half-sandwich metal complex scaffold. The ruthenium complexes DW12 and NP309 do not interact with nucleic acids and their anticancer effects are instead due to the inhibition of protein kinases. DW12 and the even more cytotoxic derivative NP309 are thus members of a new class of anticancer metal complexes in which the metal is not directly involved in the mode of action. NP309 efficiently triggers the mitochondrial pathway of apoptosis and shows promising anticancer activities in some drug resistant cell lines.

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Improved Phosphoramidite Building Blocks for the Synthesis of the Simplified Nucleic Acid GNA

_{M. K. Schlegel, E. Meggers, J. Org. Chem. 2009, 74, 4615-4618.}

abstract: An improved synthesis of glycol nucleic acids is reported using new phosphoramidite building blocks in which the exocyclic amino groups of adenine and guanine are protected as N-dimethylformamidines, whereas the amino group of cytosine is protected via an acetamide.  Besides a more rapid synthesis with higher yields, these phosphoramidites allow the use of a quicker deprotection procedure in the subsequent solid-phase synthesis of GNA oligonucleotides. 

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Targeting Metal Complexes to Proteins
_{E. Meggers, Chem. Commun. 2009, 1001-1010.}
abstract (review): Unique properties of metal complexes, such as structural diversity, adjustable ligand exchange kinetics, fine-tuned redox activities, and distinct spectroscopic signatures, make them exciting scaffolds not only for binding to nucleic acids but increasingly also to proteins as non-traditional targets. This feature article discusses recent trends in this field.

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Metal-Mediated Base Pairing with the Simplified Nucleic Acid GNA
_{M. K. Schlegel, L. Zhang, N. Pagano, E. Meggers, Org. Biomol. Chem. 2009, 7, 476-482.}
abstract: Hydroxypyridone and pyridopurine homo- and hetero-base pairs have been investigated in the context of duplex GNA. The hydroxypyridone homo-base pair and hydroxypyridone-pyridopurine hetero-base pair are particularly well accommodated in the GNA duplex and form copper(II)-dependent base pairs that are more stable compared to a Watson-Crick A:T base pair at the same position by nearly 20 °C and 24 °C, respectively.

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Insight into the High Duplex Stability of the Simplified Nucleic Acid GNA
_{M. Schlegel, X. Xie, L. Zhang, E. Meggers, Angew. Chem. Int. Ed. 2009, 48, 960-963.}
abstract: In this communication we shed light on the reasons for the surprisingly high duplex stability of the simplified nucleic acid GNA. Thermodynamic measurements demonstrate that the entropic penalty for GNA duplex formation is significantly smaller compared to DNA, which is consistent with a strong conformational preorganization of GNA single strands in addition to especially favorable stacking interactions in the corresponding GNA duplex, rendering GNA a preorganized zipper with highly favorable duplex formation properties.

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Strategy for the Stereochemical Assignment of Tris-Hetereoleptic Ru(II) Complexes by NMR Spectroscopy
_{X. Xie, S. P. Mulcahy, E. Meggers, Inorg. Chem. 2009, 48, 1053-1061.}
abstract: The relative stereochem. of tris-heteroleptic ruthenium complexes [Ru(pp)(pp')(pp'')](PF6)2, where pp = 1,10-phenanthroline-4-carboxamide, pp' = 5,6-dimethyl-1,10-phenanthroline, and pp'' = 7,8-di-Me dipyrido[3,2-a:2',3'-c]phenazine, was studied using NMR spectroscopy. The introduction of an additional chiral center to ligand pp by coupling it with L-lysine caused removal of the enantiomerism. Thus, four diastereomers were observed and their relative stereochem. determined.

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2008

Extremely Tight Binding of Ruthenium Complex to Glycogen Synthase Kinase 3

_{G. E. Atilla-Gokcumen, N. Pagano, C. Streu, J. Maksimoska, P. Filippakopoulos, S. Knapp, E. Meggers, ChemBioChem 2008, 9, 2933.}

abstract: An organoruthenium complex with at least low picomolar binding constant for glycogen synthase kinases 3 is reported and its binding to the ATP-binding site analyzed by X-ray crystallography. With a binding constant (K_i) of at most 5 pM, this organometallic compound is by several orders of magnitude more potent than the natural product staurosporine which itself served as an inspiration for the design. The crystal structure of the organoruthenium inhibitor with GSK-3 demonstrates that the metal itself is not involved in any direct interactions with the active site of GSK-3 but soleily serves as a structural center.

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Targeting Large Kinase Active Site with Rigid, Bulky Octahedral Ruthenium Complexes

_{J. Maksimoska, L. Feng, K. Harms, C. Yi, J. Kissil, R. Marmorstein, E. Meggers, J. Am. Chem. Soc. 2008, 130, 15764-15765.} 

abstract: A strategy for targeting protein kinases with large ATP-binding sites by using bulky and rigid octahedral ruthenium complexes as structural scaffolds is presented. A highly potent and selective GSK3 and Pim1 half-sandwich complex NP309 was successfully converted into a PAK1 inhibitor by making use of the large octahedral compounds lambda-FL172 and lambda-FL411 in which the cyclopentadienyl moiety of NP309 is replaced by a chloride and sterically demanding diimine ligands. A cocrystal structure of PAK1 with lambda-FL172 reveals how the large coordination sphere of the ruthenium complex matches the size of the active site and serves as a yardstick to discriminate between otherwise closely related binding sites. 

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Duplex Structure of a Minimal Nucleic Acid

_{Mark K. Schlegel, Lars-Oliver Essen, Eric Meggers,J. Am. Chem. Soc. 2008, 130, 8158-8159.}

abstract: The crystal structure of an 8mer (S)-GNA duplex is presented. As a tool for phasing, the anomalous diffraction of two copper(II) ions within two artificial metallo-base pairs was employed. The antiparallel duplex  structure can be described as a right-handed helical ribbon wrapped around the helix. Most intriguingly, neighboring base pairs slide strongly against each other resulting in extensive interstrand base-base hydrophobic interactions along with unusual hydrophobic intrastrand interactions of nucleobases with their backbone.

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Structure-Based Design of an Organoruthenium Phosphatidyl-inositol-3-kinase inhibitor Reveals a Switch Governing Lipid Kinase Potency and Selectivity

_{Peng Xie, Douglas S. Williams, G. Ekin Atilla-Gokcumen, Leslie Milk, Min Xiao, Keiran S. M. Smalley, Meenhard Herlyn, Eric Meggers, Ronen Marmorstein, ACS Chem. Biol. 2008, 3, 305-316.}

abstract: In this study, we report the design of an organoruthenium half-sandwich complex as a selective inhibitor for PI3K over protein kinases. This selectivity is largely due to a single methyl group.

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Isostructural Ruthenium and Osmium Complexes Display Highly Similar Bioactivities

_{Jasna Maksimoska, Douglas S. Williams, G. Ekin Atilla-Gokcumen, Keiran S. M. Smalley, Patrick J. Carroll, Richard D. Webster, Paganis Filippakopoulos, Stefan Knapp, Meenhard Herlyn, Eric Meggers, Chem. Eur. J. 2008, 14, 4816-4822.}

abstract: In this comprehensive study we probe and verify the concept of designing unreactive bioactive metal complexes by investigating the consequences of replacing ruthenium in a bioactive half-sandwich kinase inhibitor scaffold by its heavier homolog osmium.

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Solid Phase Synthesis of Tris-Heteroleptic Ru(II) Complexes and Application to Acetylcholinesterase Inhibition
_{Seann P. Mulcahy, Shan Li, Ricarda Korn, Xiulan Xie, Eric Meggers, Inorg. Chem. 2008, 47, 5030-5032.}
abstract: A synthetic route with two consecutive coordination chemistry steps on solid support affords tris-heteroleptic ruthenium(II) polypyridyl complexes in high purities and good yields. As an application the identification of a nanomolar acetylcholinesterase inhibitor from a small ruthenium complex library is reported.

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Synthesis of Cyclopentadienyl Ruthenium Complexes Bearing Pendant Chelating Picolinates through an Electrophilic Precursor
_{Craig Streu, Patrick J. Carroll, Rakesh K. Kohli, Eric Meggers, J. Organomet. Chem. 2008, 693, 551-556.}
abstract: This note reports the facile synthesis of two ruthenium cyclopentadienyl half-sandwich complexes functionalized with coordinating alpha-picolinates. The synthetic approach involves the (chloromethylcyclopentadienyl)(benzene)ruthenium(II) cation as a useful common building block for cyclopentadienyl complexes bearing anchored ligands. 
 

 

 

2007

Duplex Formation of the Simplified Nucleic Acid GNA
_{Mark K. Schlegel, Adam E. Peritz, Krisada Kittigowittana, Lilu Zhang, Eric Meggers, ChemBioChem 2007, 8, 927-932.}
abstract: Glycol nucleic acid (GNA) contains an acyclic backbone with propylene glycol nucleosides that are connected by phosphodiester bonds. The fullpaper characterizes the duplex formation properties of this simplified nucleic acid.
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Exploring Chemical Space with Organometallics: Ruthenium Complexes as Protein Kinase Inhibitors
_{Eric Meggers, G. Ekin Atilla-Gokcumen, Howard Bregman, Jasna Maksimoska, Seann P. Mulcahy, Nicholas Pagano, and Douglas S. Williams, Synlett 2007, 8, 1177-1189.}
abstract: ACCOUNT ARTICLE: Complementing organic elements with a metal center provides new opportunities for building three dimensional structures with unique and defined shapes. Such access to unexplored chemical space may lead to the discovery of molecules with unprecedented properties. Along these lines, this account article describes our successful design of highly potent and selective ruthenium-based inhibitors for the protein kinases GSK-3 and Pim-1 by using the class of indolocarbazole alkaloids as a lead structure.
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Ruthenium Half-Sandwich Complexes as Protein Kinase Inhibitors: Derivatization of the Pyridocarbazole Pharmacophore Ligand
_{Nicholas Pagano, Jasna Maksimoska, Howard Bregman, Douglas S. Williams, Richard D. Webster, Feng Xue and Eric Meggers, Org. Biomol. Chem. 2007, 5, 1218-1227.}
abstract: A general route to ruthenium pyridocarbazole half-sandwich complexes was developed and applied to the synthesis of sixteen new compounds, many of which display modulated protein kinase inhibition properties.
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Platinum Complex as Nanomolar Protein Kinase Inhibitor
_{Douglas S. Williams, Patrick J. Carroll, and Eric Meggers, Inorganic Chemistry 2007, 46, 2944-2946.}
abstract: A pyridocarbazole platinum complex, which matches the overall shape of the natural product staurosporine, binds with high affinity at the ATP binding site of glycogen synthase kinase 3.
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An Organometallic Protein Kinase Inhibitor Pharmacologically Activates p53 and Induces Apoptosis in Human Melanoma Cells
_{Keiran S.M. Smalley, Rooha Contractor, Nikolas K. Haass, Angela N. Kulp, G. Ekin Atilla-Gokcumen, Douglas S. Williams, Howard Bregman, Keith T. Flaherty, Maria S. Soengas, Eric Meggers, and Meenhard Herlyn, Cancer Research 2007, 67, 209-217.}
abstract: We describe an organometallic glycogen synthase kinase 3ß (GSK3ß) inhibitor (DW1/2) as a potent activator of p53 and inducer of cell death in otherwise highly chemoresistant melanoma cells.
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2006

Synthesis and cyclometalation of a pyrido[3,2-e]-2,10b-diaza-cyclopenta[c] fluorene-1,3-dione scaffold
_{S. P. Mulcahy, P. J. Carroll, E. Meggers, Tetrahedron Lett. 2006, 47, 8877-8880.}
abstract: The synthesis of a pyrido[3,2-e]-2,10b-diaza-cyclopenta[c]fluorene-1,3-dione scaffold is disclosed, which was synthesized using a Suzuki cross-coupling reaction and an intramolecular Heck cyclization as the key steps. This heterocyclic system can serve as a bidentate ligand as demonstrated by the formation and structural analysis of a derived ruthenium complex. The new scaffold constitutes an interesting candidate for the development of organometallic protein kinase inhibitors.
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Ruthenium Half-Sandwich Complexes as Protein Kinase Inhibitors: An N-Succinimidyl Ester for Rapid Derivatizations of the Cyclopentadienyl Moiety
_{H. Bregman and E. Meggers, Org. Lett. 2006, 8, 5465-5468.}
abstract: Cyclopentadienyl half-sandwich ruthenium complexes have been demonstrated to be promising scaffolds as protein kinase inhibitors. In order to rapidly identify derivatives which display modified pharmacological properties, we developed the synthesis of an organoruthenium compound bearing an N-succinimidyl ester at the cyclopentadienyl moiety. The quenching of this activated ester with a library of primary amines, followed by testing of the resulting amide library, led to the identification of inhibitors with improved potencies and kinase selectivities.
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Ruthenium-Induced Allylcarbamate Cleavage in Living Cells
_{C. Streu and Eric Meggers, Angw. Chem. Int. Ed. 2006, 5645-5648.}
abstract: Towards the goal of designing catalytic organometallics as tools for cellular chemical biology, a ruthenium catalyzed release of amines from their respective allylcarbamates is disclosed which tolerates the combination of water, air, and thiols, and it is demonstrated that this reaction can be performed inside living mammalian cells.
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Organometallic Compounds with Biological Activity: A Very Selective and Highly Potent Cellular Inhibitor for Glycogen Synthase Kinase 3
_{G. E. Atilla, D. S. Williams, H. Bregman, N. Pagano, E. Meggers, ChemBioChem 2006, 1443-1450.}
abstract: Like an organic molecule! A chemically inert ruthenium complex acts as metallopharmaceutic inhibitor of the protein kinase GSK-3 by targeting its ATP-binding site. It is shown to switch on the Wnt signal transduction pathway inside living cells and in Xenopus embryos, which developed a hyperdorsalized phenotype on administration of the complex.
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Synthesis of Glycol Nucleic Acids
_{L. Zhang, A. E. Peritz, P. J. Carroll, E. Meggers, SYNTHESIS 2006, 645-653.}
abstract: Starting from glycidol, the synthesis of dimethoxytritylated glycol nucleoside phosphor-amidites of adenine (A), thymine (T), uracil (U), guanine (G), and cytosine (C) is reported. These phosphoramidites are the building blocks for the automated solid phase synthesis of GNA oligonucleotides and it is demonstrated that derived GNA duplexes with completely acyclic backbones considerably exceed the thermal stabilities of analogous DNA duplexes.
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Ruthenium Half-Sandwich Complexes Bound to Protein Kinase Pim-1
_{J. É. Debreczeni, A. N. Bullock, G. E. Atilla, D. S. Williams, H. Bregman, S. Knapp, E. Meggers, Angewandte Chemie Int. Ed. 2006, 45, 1580-1585.}
abstract: Like an organic molecule! A chemically inert ruthenium complex acts as metallopharmaceutic inhibitor of the protein kinase GSK-3 by targeting its ATP-binding site. It is shown to switch on the Wnt signal transduction pathway inside living cells and in Xenopus embryos, which developed a hyperdorsalized phenotype on administration of the complex.
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Rapid Access to Unexplored Chemical Space by Ligand Scanning Around a Ruthenium Center: Discovery of Potent and Selective Protein Kinase Inhibitors
_{H. Bregman, P. J. Carroll, E. Meggers, J. Am. Chem. Soc. 2006, Volume 128, 877-884.}
abstract: An important objective for the discovery of compounds with unique biological activities is the development of methods for the synthesis of molecular scaffolds with defined three-dimensional shapes. In this paper we present a strategy that allows a rapid scanning of ligands around a ruthenium center in the search for ligand spheres that are complementary in shape and functional group presentation to ATP binding sites of protein kinases. Following this approach, we have identified octahedral ruthenium complexes as potent inhibitors for the protein kinases Pim1, MSK1, and GSK3a.
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2005

Switching on a Signaling Pathway with an Organoruthenium Complex
_{D. S. Williams, G. E. Atilla, H. Bregman, A. Arzoumanian, P. S. Klein, and E. Meggers, Angewandte Chemie Int. Ed. 2005, Volume 117, 1984-1987.}
abstract: Like an organic molecule! A chemically inert ruthenium complex acts as metallopharmaceutic inhibitor of the protein kinase GSK-3 by targeting its ATP-binding site. It is shown to switch on the Wnt signal transduction pathway inside living cells and in Xenopus embryos, which developed a hyperdorsalized phenotype on administration of the complex.
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An Extremely Stable and Orthogonal DNA Base Pair with a Simplified Three-Carbon Backbone
_{L. Zhang and E. Meggers; J. Am. Chem. Soc. 2005, Volume 127, 74-75.}
abstract: A nucleotide C3HQ with a minimal three-carbon backbone displays unprecedented pairing strength and orthogonality in a homopair C3HQ:C3HQ in the presence of one equivalent of Cu²⁺. The pairing stability in DNA even exceeds the related base pair having the regular 2'-deoxyribose backbone. This discovery of a synergy between an artificial backbone and base-pairing scheme opens new avenues for the economical design of modified oligonucleotides with tailored properties.
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Pyrido[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6 H)-diones: Synthesis, Cyclometalation, and Protein Kinase Inhibition
_{H. Bregman, D. S. Williams, E. Meggers; SYNTHESIS, 2005, 1521-1527.}
abstract: Synthetic routes to pyrido[2,3-a]pyrrolo[3,4-c]carba-zole-5,7(6H)-diones are disclosed and examples for their subsequent transformations into cyclometalated protein kinase inhibitors are presented.
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A Simple Glycol Nucleic Acid
_{L. Zhang, A. Peritz, E. Meggers; J. Am. Chem. Soc. 2005, Volume 127, 4174-4175.}
abstract: A glycol nucleic acid (GNA) with an acyclic propylene glycol phosphodiester backbone forms stable antiparallel duplexes following the Watson-Crick base pairing rules.
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2004

An Organometallic Inhibitor for Glycogen Synthase Kinase 3
_{H. Bregman, D. S. Williams, G. E. Atilla, P. J. Carroll, E. Meggers; J. Am. Chem. Soc. 2004, Volume 126, 13594-13595.}
abstract: Replacing natural products with kinetically inert metal complexes may lead to a new class of therapeutics in which a metal center plays the role of an innocent bystander, organizing the orientation of the organic ligands in the receptor space. As an example of this approach, a ruthenium complex is described that copies the binding mode of indolocarbazole protein kinase inhibitors and serves as a reversible, low-nanomolar inhibitor for glycogen synthase kinase 3 (GSK-3).
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Ruthenium Complexes as Protein Kinase Inhibitors
_{L. Zhang, P. J. Carroll, E. Meggers; Organic Letters 2004, Volume 6, 521-523.}
abstract: Replacing complex natural products with simple metal complexes could lead to a new class of metallopharmaceuticals in which the metal center plays mainly a structural role. A strategy is introduced for the creation of Ru complex-based protein kinase inhibitors, morphed out of the class of indolocarbazole inhibitors with the alkaloid staurosporine as its most prominent member.
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Selected Earlier Publications

Structure of a Copper-Mediated Base Pair in DNA
_{S. Atwell, E. Meggers, G. Spraggon, P. G. Schultz; J. Am. Chem. Soc. 2001, Volume 123, 12364-12367.}
abstract: This paper reports the first crystal structure of a metallo-base pair within a DNA duplex.

 

 

A Novel Copper-Mediated DNA Base Pair
_{E. Meggers, P. L. Holland, W. B. Tolman, F. E. Romesberg, P. G. Schultz; J. Am. Chem. Soc. 2000, Volume 122, 10714-10715.}
abstract: This publication is the first report of a designed metallo-base pair in a DNA duplex. The results demonstrate that interbase metal coordination can replace the hydrogen bonding schemes found in the natural base Watson-Crick base pairs.

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Sequence Dependent Hole Transfer in DNA
_{E. Meggers, M. E. Michel-Beyerle, B. Giese; J. Am. Chem. Soc. 1998, Volume 120, 12950-12955.}
abstract: A guanine radical cation was site-selectively generated in double stranded DNA and the charge transfer in different oligonucleotide sequences was investigated. It was discovered, that the overall charge transport in a mixed strand is a multistep hopping process between G bases where the individual steps contribute to the overall rate. The distance dependence is no longer described by the beta-value of the superexchange mechanism.

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