Michael Goebel - Academia.edu (original) (raw)

Papers by Michael Goebel

Proceedings of the National Academy of Sciences of the United States of America, Apr 9, 2002

Chemistry: A European Journal, Jan 21, 2020

Nature relieso nr eading and synthesizingt he genetic codew ith high fidelity.N ucleic acid build... more Nature relieso nr eading and synthesizingt he genetic codew ith high fidelity.N ucleic acid building blocks that are orthogonal tot he canonical AT and G-C base-pairs are therefore uniquely suitable to facilitate position-specific labeling of nucleic acids. Here, we employ the orthogonal kappa-xanthosine-base-pair for in vitro transcription of labeled RNA. We devised an improved synthetic route to obtain the phosphoramidite of the deoxy-version of the kappa nucleoside in solid phase synthesis. From this DNA template, we demonstrate the reliable incorporation of xanthosined uring in vitro transcription. Using NMR spectroscopy,w eshowt hat xanthosine introduces only minor structural changes in an RNA helix. We furthermore synthesized a clickable 7-deaza-xanthosine, which allowst os ite-specifically modify transcribed RNA molecules with fluorophores or other labels.

Journal of Back and Musculoskeletal Rehabilitation, 2009

Arkivoc, 2022

Nucleophilic catalysis by N-acetyl cysteine permits the smooth reaction of 1,2-diarylethylene-1,2... more Nucleophilic catalysis by N-acetyl cysteine permits the smooth reaction of 1,2-diarylethylene-1,2-diamines with 1,2-dicyanobenzene forming chiral bisamidines in yields up to 94% in a single step. Such bisamidines can be used as Brønsted bases or, in the protonated state, as electrophilic catalysts to promote Diels-Alder reactions with medium levels of enantioselectivity.

Bioconjugate Chemistry, 2020

Quinone methide precursors 2 and 3 were protected with a photoreactive 2-nitrobenzyl group and co... more Quinone methide precursors 2 and 3 were protected with a photoreactive 2-nitrobenzyl group and conjugated to peptide nucleic acids (PNA) using a Huisgen click reaction. After brief irradiation at 365 nm, crosslinking with com-plementary RNA strands started and was analysed with an ALFexpress sequencer. When using this method, the gel temperature had a major influence on apparent rates. Quinone methides are known to form transient as well as stable bonds with nucleotides. While both were detected at 25 °C, analysis at 57 °C only recorded the stable types of crosslinks suggesting much slower alkylation kinetics. Linker 11 allowed us to attach quinone methides to internal positions of the PNA/RNA duplex and to capture a model of miR-20a with good efficiency.

Angewandte Chemie International Edition, 2021

SARS‐CoV‐2 contains a positive single‐stranded RNA genome of approximately 30 000 nucleotides. Wi... more SARS‐CoV‐2 contains a positive single‐stranded RNA genome of approximately 30 000 nucleotides. Within this genome, 15 RNA elements were identified as conserved between SARS‐CoV and SARS‐CoV‐2. By nuclear magnetic resonance (NMR) spectroscopy, we previously determined that these elements fold independently, in line with data from in vivo and ex‐vivo structural probing experiments. These elements contain non‐base‐paired regions that potentially harbor ligand‐binding pockets. Here, we performed an NMR‐based screening of a poised fragment library of 768 compounds for binding to these RNAs, employing three different 1H‐based 1D NMR binding assays. The screening identified common as well as RNA‐element specific hits. The results allow selection of the most promising of the 15 RNA elements as putative drug targets. Based on the identified hits, we derive key functional units and groups in ligands for effective targeting of the RNA of SARS‐CoV‐2.

Angewandte Chemie, 2009

Die Inhibierung der ATPase-Aktivität des Kinomchaperons Hsp90 (Kinom = alle Proteine mit Kinase-D... more Die Inhibierung der ATPase-Aktivität des Kinomchaperons Hsp90 (Kinom = alle Proteine mit Kinase-Domänen) ist ein wohlbekannter Ansatz für Krebstherapien. Cdc37, ein Cochaperon von Hsp90 in Säugerzellen, bindet an Proteinkinasen, und seine Expressionsrate ist in einer Reihe von Krebszellen erhöht. [1, 2] Der Komplex der beiden Proteine weist einen K D-Wert von 1.2 mm auf. Allgemein wird angenommen, dass dieser Komplex die Karzinogenese erhöht, indem er eine Reihe von onkogenen Kinasen in bösartigen Krebszellen stabilisiert. Darüber hinaus üben zumindest in Hefe Cdc37 und Hsp90 auch jeweils allein diese Funktion aus. Mehrere Liganden mit niedrigem Molekulargewicht wurden vor kurzem als Inhibitoren von Cdc37 allein oder dem Hsp90-Cdc37-Komplex und damit als neue Klasse von Tumortherapeutika vorgeschlagen. [3, 4] Aus Gen-basierten Expressionsprofilierungen wurde abgeleitet, dass das Triterpen Celastrol zu einer neuen Klasse von nicht-ATP-kompetitiven Hsp90-Inhibitoren gehört. [5] Auf der Basis von Immunpräzipitationsexperimenten mit Zelllinien der Bauchspeicheldrüse und von Strukturen, die mittels molekularer Docking-Algorithmen ermittelt wurden, wurde vorgeschlagen, dass Celastrol seine antiproliferierende Aktivität durch Binden an die N-terminale Domäne von Hsp90 (Hsp90 N) ausübt, was das Binden von Hsp90 N an Cdc37 unterdrückt. [6] In vivo inhibiert Celastrol das Tumorwachstum in von Prostata-oder Bauchspeicheldrüsenkrebs befallenen Nacktmäusen signifikant. [6, 7] Wir stellen hier unsere detaillierten Studien zur Beantwortung der Frage vor, wie Celastrol den Hsp90-Cdc37-Komplex inhibiert. Dabei wurden die Sequenzen der humanen Proteine untersucht. Mit 1 H, 15 N-HSQC-NMR-Experi

ChemBioChem, 2009

Target TAR by NMR: Tripeptides containing arginines as terminal residues and non-natural amino ac... more Target TAR by NMR: Tripeptides containing arginines as terminal residues and non-natural amino acids as central residues are good leads for drug design to target the HIV trans-activation response element (TAR). The structural characterization of the RNA-ligand complex by NMR spectroscopy reveals two specific binding sites that are located at bulge residue U23 and around the pyrimidine-stretch U40-C41-U42 directly adjacent to the bulge.

Physical Chemistry Chemical Physics, 2013

Figure S1. Time-of-flight fsMPI mass spectra of the 4APM-1MT (a) and 4APM-M4PMN (b) systems. 9MA ... more Figure S1. Time-of-flight fsMPI mass spectra of the 4APM-1MT (a) and 4APM-M4PMN (b) systems. 9MA (m/z=149) indicates 9-methyladenine impurity.

Angewandte Chemie, 2015

Gerhard Quinkert, emeritus professor at the University of Frankfurt, passed away on May 6, 2015. ... more Gerhard Quinkert, emeritus professor at the University of Frankfurt, passed away on May 6, 2015. The chemistry community has lost a passionate teacher and a researcher with foresight, and independent, firm opinions who argued from early on that organic chemistry should open up to address questions in biology.

Beilstein Journal of Organic Chemistry, 2008

C 2-symmetric bisamidines 8 have been tested as chiral Brønsted bases in the Diels-Alder reaction... more C 2-symmetric bisamidines 8 have been tested as chiral Brønsted bases in the Diels-Alder reaction of anthrones and N-substituted maleimides. High yields of cycloadducts and significant asymmetric inductions up to 76% ee are accessible. The proposed mechanism involves proton transfer between anthrone and bisamidine, association of the resulting ions and finally a cycloaddition step stereoselectively controlled by the chiral ion pair.

Angewandte Chemie International Edition, 2009

The Journal of Organic Chemistry, 2007

The chiral bisamidine 5 has been prepared in just two steps from malonodinitrile. In the monocati... more The chiral bisamidine 5 has been prepared in just two steps from malonodinitrile. In the monocationic form this compound adopts a planar conformation with an almost convergent orientation of two N-H groups. Ketones, aldehydes, and nitro compounds are assumed to bind to this strongly polar cleft via hydrogen bonds, resulting in a Lewis-acid-like activation of the carbonyl groups. A broad scope of reactions (Diels-Alder, hetero-Diels-Alder, Friedel-Crafts) can be catalyzed. The observed accelerations surpass the rate effects of neutral hydrogen-bond donors such as thioureas or TADDOLs. SCHEME 1. Ionic Hydrogen-Bond Donors in Catalysis: Axially Chiral Amidine 1 and C 2-Symmetric Bisamidine 2 (TFPB: tetrakis[3,5-bis(trifluoromethyl)phenyl]borate) 5618

Molecules, 2020

The RNA cleaving catalyst tris(2-aminobenzimidazole) when attached to the 5’ terminus of oligonuc... more The RNA cleaving catalyst tris(2-aminobenzimidazole) when attached to the 5’ terminus of oligonucleotides cuts complementary RNA strands in a highly site-specific manner. Conjugation was previously achieved by the acylation of an amino linker by an active ester of the catalyst. However, this procedure was low yielding and not reliable. Here, a phosphoramidite building block is described that can be coupled to oligonucleotides by manual solid phase synthesis in total yields around 85%. Based on this chemistry, we have now studied the impact of LNA (locked nucleic acids) nucleotides on the rates and the site-specificities of RNA cleaving conjugates. The highest reaction rates and the most precise cuts can be expected when the catalyst is attached to a strong 5’ closing base pair and when the oligonucleotide contains several LNA units that are equally distributed in the strand. However, when placed in the 5’ position, LNA building blocks tend to diminish the specificity of RNA cleavage.

Beilstein Journal of Organic Chemistry, 2018

TEMPO spin labels protected with 2-nitrobenzyloxymethyl groups were attached to the amino residue... more TEMPO spin labels protected with 2-nitrobenzyloxymethyl groups were attached to the amino residues of three different nucleosides: deoxycytidine, deoxyadenosine, and adenosine. The corresponding phosphoramidites could be incorporated by unmodified standard procedures into four different self-complementary DNA and two RNA oligonucleotides. After photochemical removal of the protective group, elimination of formic aldehyde and spontaneous air oxidation, the nitroxide radicals were regenerated in high yield. The resulting spin-labeled palindromic duplexes could be directly investigated by PELDOR spectroscopy without further purification steps. Spin–spin distances measured by PELDOR correspond well to the values obtained from molecular models.

Beilstein Journal of Organic Chemistry, 2016

Starting from (S)-β-phenylalanine, easily accessible by lipase-catalyzed kinetic resolution, a ch... more Starting from (S)-β-phenylalanine, easily accessible by lipase-catalyzed kinetic resolution, a chiral triamine was assembled by a reductive amination and finally cyclized to form the title compound 10. In the crystals of the guanidinium benzoate salt the six membered rings of 10 adopt conformations close to an envelope with the phenyl substituents in pseudo-axial positions. The unprotonated guanidine 10 catalyzes Diels–Alder reactions of anthrones and maleimides (25–30% ee). It also promotes as a strong Brønsted base the retro-aldol reaction of some cycloadducts with kinetic resolution of the enantiomers. In three cases, the retro-aldol products (48–83% ee) could be recrystallized to high enantiopurity (≥95% ee). The absolute configuration of several compounds is supported by anomalous X-ray diffraction and by chemical correlation.

Bioconjugate Chemistry, 2015

Electropherograms obtained with a DNA sequencer displaying the cleavage kinetics of RNA 3 by PNAz... more Electropherograms obtained with a DNA sequencer displaying the cleavage kinetics of RNA 3 by PNAzyme 2. (S2) 2) Electropherograms showing the substrate specificity of PNAzyme 2. No cleavage takes place when 2 is incubated with non-complementary RNA sequences 5 and 6. (S3) 3) Electropherograms of kinetic studies for catalytic turnover properties of PNAzyme 2. (S4) 4) Graphs displaying cleavage kinetics of substrate 3 in the presence of PNAzyme 2 at different pH. (S5) 5) Graph displaying cleavage kinetics of substrate 4 in the presence of PNAzyme 2. (S5) 6) Comment on the influence of water treated with DEPC. (S6) 7) Analytical chromatogram of PNAzyme 2 after HPLC purification. (S7) 8) MALDI-TOF MS of PNAzyme 2 after HPLC purification. (S8)

Beilstein Journal of Organic Chemistry, 2015

Tris(2-aminobenzimidazole) conjugates with antisense oligonucleotides are effective site-specific... more Tris(2-aminobenzimidazole) conjugates with antisense oligonucleotides are effective site-specific RNA cleavers. Their mechanism of action is independent of metal ions. Here we investigate conjugates with peptide nucleic acids (PNA). RNA degradation occurs with similar rates and substrate specificities as in experiments with DNA conjugates we performed earlier. Although aggregation phenomena are observed in some cases, proper substrate recognition is not compromised. While our previous synthesis of 2-aminobenzimidazoles required an HgO induced cyclization step, a mercury free variant is described herein.