Publications
Duplex Formation of the Simplified Nucleic Acid GNA
Mark K. Schlegel, Adam E. Peritz, Krisada Kittigowittana, Lilu Zhang, Eric Meggers
abstract Glycol nucleic acid (GNA) contains an acyclic backbone with propylene glycol nucleosides that are connected by phosphodiester bonds. The paper characterizes the duplex formation properties of this simplified nucleic acid. Although single and multiple GNA nucleotides are highly destabilizing if incorporated into DNA duplexes, the two enantiomeric oligomers (S)-GNA and (R)-GNA form antiparallel homoduplexes which are thermally and thermodynamically significantly more stable than analogous duplexes of DNA and RNA. Salt-dependence and Watson-Crick pairing fidelity of GNA duplexes are similar to duplexes of DNA but, apparently, the 2’-deoxyribonucleotide and the propylene glycol backbone are not compatible with each other. This conclusion is further supported by crosspairing experiments. Accordingly, both (S)-GNA and (R)-GNA strands generally do not pair with DNA. However, (S)-GNA, but not (R)-GNA, forms stable heteroduplexes with RNA in sequences which are poor in their G:C content. All together, the high stability and fidelity of GNA duplex formation in combination with the economical accessibility of propylene glycol building blocks for oligonucleotide synthesis render GNA an attractive candidate for the design of self-assembling materials. It furthermore suggests to consider GNA as a potential candidate for a predecessor of RNA during the evolution of life on Earth.
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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, in press
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. The described ruthenium complexes are kinetically inert scaffolds in which the ruthenium has the function to organize the orientation of the organic ligands in the three-dimensional space.
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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. Using RNA interference and pharmacologic approaches, we show that p53 is required for the cytotoxic effects of this organometallic inhibitor. The DW1/2 compound was barely able to induce cell death in melanoma cells with p53 mutations, further confirming the requirement for p53-WT in the cytotoxic effects of the GSK3ß inhibition. Mechanistic analysis of the p53-dependent cell death indicated an apoptotic mechanism involving depolarization of mitochondrial membrane potential, caspase cleavage, and elevated NOXA expression. The effect of p53 was not simply due to passive up-regulation of protein expression as adenoviral-mediated overexpression of p53 was not able to induce cell death. Treatment of melanoma cells with DW1/2 was instead found to decrease levels of Mdm2 and Mdm4. The importance of Mdm2 down-regulation in DW1/2-induced apoptosis was confirmed by treating the p53-WT cells with the p53/Mdm2 antagonist Nutlin-3. Taken together, our data provide a new strategy for the pharmacologic activation of p53 in melanoma, which may be a viable approach for overcoming apoptotic resistance in melanoma and offer new hope for rational melanoma therapy.
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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
abstractThe 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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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(6H)-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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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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