Publications
Download list of publications (PDF file)2010
M. K. Schlegel, L.-O. Essen, E. Meggers, Chem.
Commun. 2010, published online.
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.
Chiral Auxiliaries as Emerging Tools for the Asymmetric Synthesis of Octahedral Metal Complexes
E. Meggers, Chem. Eur. J. 2010, Early
View.
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. The emerging strategy of chiral-auxiliary-mediated asymmetric synthesis holds promise to solve the problem of controlling relative and absolute configuration in octahedral metal complexes in a general fashion, thus hopefully in the future providing access to any desired optical active octahedral metal complex without the need for chiral separations. This short review summarizes reported examples of chiral auxiliaries applied to the asymmetric synthesis of octahedral metal complexes.
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.
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.
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.
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.
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.
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. UV melting
experiments with duplex DNA and 1H-NMR experiments with 9-ethylguanine
reveal that the apoptotic ruthenium complex DW12 does not interact with
DNA. On the other hand, diminishing the kinase inhibition properties of
DW12 by methylating the maleimide nitrogen (DW12-Me) abolishes the
anticancer activity. Furthermore, the incorporation of a fluorine into
the pyridine moiety (NP309) improves the IC50 value for glycogen
synthase kinase 3 (GSK-3) and at the same time the cytotoxicity,
implying that the anticancer activity correlates with the inhibition of
GSK-3 and maybe other not yet identified kinases. We demonstrate in
Burkitt-like lymphoma (BJAB) cells that NP309 is not necrotic but
induces apoptosis and that this apoptosis is mediated by a loss of the
mitochondrial membrane potential, caspase-9 processing, and is partly
dependent on Bcl-2 expression. In addition, NP309 efficiently induces
apoptosis in vincristine- and cytarabine-resistant human B-cell
precursor cell lines.
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.
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.
download article · 1300K PDF
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.
download article · 281K PDF
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.
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.
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 (Ki) 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.
download article · 4451K PDFdownload coverpicture · 907K PDF
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.
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 duplex structure confirms a canonical Watson-Crick base pairing scheme of GNA with antiparallel strands. The duplex secondary structure is distinct from canonical A- and B-form nucleic acids and can be described as a right-handed helical ribbon wrapped around the helix axis resulting in a large hollow core. 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.
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.
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.
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.
download article · 700K PDF
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.
download article · 700K PDF
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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338K PDF
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.
download article · 159K
PDF
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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PDF
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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PDF
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.
download article · 217K
PDF
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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article · 642K PDF
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.
download article ·
602K PDF
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.
download article · 63K
PDF
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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article · 902K PDF
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.
download article · 396K
PDF
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.
download article ·
223K PDF
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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397K PDF
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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PDF
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.
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.
