Ulrich Groth

Universität Konstanz, Constance, Baden-Württemberg, Germany

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Publications (47)136.4 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The mitotic spindle, a highly dynamic structure composed of microtubules, mediates the segregation of the previously duplicated genome into the two nascent daughter cells. Errors in this process contribute to pathology including tumor formation. Key for the shape and function of the mitotic spindle are kinesins, molecular motor proteins that convert chemical energy into mechanical work. Due to their fast mode of action, small molecules are valuable tools to dissect the dynamic functions of kinesins during mitosis. In this study, we report the identification of optimized small molecule inhibitors of the mitotic kinesin Kif18A. Using BTB-1, the first identified Kif18A inhibitor, as lead compound we synthesized a collection of derivatives. We demonstrate that some of the synthesized derivatives potently inhibited the ATPase activity of Kif18A with a half maximal inhibitory concentration (IC50) value in the low micromolar range. In vitro analysis of a panel of Kif18A-related kinesins revealed that the two most potent compounds show improved selectivity compared to BTB-1. Structure-activity relationship studies identified substituents mediating undesired inhibitory effects on microtubule polymerization. In summary, our study provides key insights into the mechanism of action of BTB-1 and its analogs which will have a great impact on the further development of highly selective and bioactive Kif18A inhibitors. Since Kif18A is frequently overexpressed in solid tumors, such compounds are not only of great interest for basic research but have also the potential to open up new strategies for the treatment of human diseases.
    ACS Chemical Biology 11/2014; 10(2). DOI:10.1021/cb500789h · 5.36 Impact Factor
  • Johannes Drexler · Ulrich Groth
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    ABSTRACT: Adenosine analogue nucleosides are a fundamental part of medicinal chemistry. Tubercidin is a well-known example, but its application is limited due to high toxicity. The development of less toxic synthetic analogues is therefore highly desirable. Here we show the synthesis of fluorinated nucleosides based on the pyrrolo[2,3-d]pyrimidine (7-deazapurine) motif. The synthetic approach is based on an easily accessible trifluoromethylated acetoacetate and several amidines, as building blocks. This allows for simultaneous introduction of a CF3 group as well as a variety of C2 substituents for the synthesis of the heterocyclic part, including alkyl, aryl, SMe, Cl, N3 and NH2 moieties. Glycosylation of the fully pre-functionalized heterocycles proceeds with excellent β-selectivity. Cytotoxicities were determined using an AlamarBlue assay with HeLa S3 and Hep G2 cancer cell lines. The effect of C2 substitution was explored and a lead structure candidate with IC50 values of 90 ± 49 nM (HeLa S3) and 28 ± 9 nM (Hep G2) was identified.
    European Journal of Organic Chemistry 10/2014; 2014(28). DOI:10.1002/ejoc.201402755 · 3.15 Impact Factor
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    ABSTRACT: – A general strategy encompassing a Directed ortho Metalation (DoM) – Suzuki-Miyaura cross coupling and Directed remote Metalation (DreM) sequence for the synthesis of 5H-chromeno[4,3-c]pyridin-5-ones 5a-j, 5H-chromeno[3,4-b]pyridin-5-ones 6a-j, 5H-chromeno[3,4-c]pyridin-5-ones 13a-d, 12H-benzo[7,8]chromenopyridin-12-ones 16a-c, 17a-c, and pyrido[3',4':4,5]pyrano[2,3-e]indazol-5(1H)-one analogues 18, 28 is reported. Thus, using the powerful directed metalation group properties of aryl O-carbamates 9a-h, 14a-c metalation-boronation followed by Suzuki-Miyaura coupling with 3-bromopyridine affords a variety of azabiaryls 7a-i, 8a-b, 12a-c, 15a-c which, upon DreM reaction leads to several series of chromenopyridinones 5a-j, 6a-j, 13a-d and pyridonaphthopyrones 16a-c, 17a-c. The synthesis of an unusual pyridopyranoindazolone 18 is also described.
    Heterocycles 11/2012; 86(2). DOI:10.3987/COM-12-S(N)131 · 0.91 Impact Factor
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    ABSTRACT: We present HiTSEE (High-Throughput Screening Exploration Environment), a visualization tool for the analysis of large chemical screens used to examine biochemical processes. The tool supports the investigation of structure-activity relationships (SAR analysis) and, through a flexible interaction mechanism, the navigation of large chemical spaces. Our approach is based on the projection of one or a few molecules of interest and the expansion around their neighborhood and allows for the exploration of large chemical libraries without the need to create an all encompassing overview of the whole library. We describe the requirements we collected during our collaboration with biologists and chemists, the design rationale behind the tool, and two case studies on different datasets. The described integration (HiTSEE KNIME) into the KNIME platform allows additional flexibility in adopting our approach to a wide range of different biochemical problems and enables other research groups to use HiTSEE.
    BMC Bioinformatics 05/2012; 13 Suppl 8(Suppl 8):S4. DOI:10.1186/1471-2105-13-S8-S4 · 2.67 Impact Factor
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    ABSTRACT: Multicomponent reactions involving polyfunctional 4-amino-5-carboxamido-1,2,3-triazole and cyclic carbonyl-containing CH-acids were studied under conventional thermal heating, microwave and ultrasonic irradiation. The features of the reactions studied were discussed and the optimized procedures for the synthesis of final triazolopyrimidines were elaborated. In contrast to the similar MCRs of numerous other aminoazoles, a change of direction of the heterocyclizations in the case of 4-amino-5-carboxamido-1,2,3-triazole was not observed when microwave or thermal heating was substituted by ultrasonication at ambient temperature.
    Beilstein Journal of Organic Chemistry 01/2012; 8:2100-5. DOI:10.3762/bjoc.8.236 · 2.80 Impact Factor
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    ABSTRACT: We present HiTSEE (High-Throughput Screening Exploration Environment) a visualization tool for the analysis of large chemical screens for the analysis of biochemical processes. The tool supports the analysis of structure-activity relationships (SAR analysis) and, through a flexible interaction mechanism, the navigation of large chemical spaces. Our approach based on the projection of one or few molecules of interest and the expansion around their neighborhood allows for the exploration of large chemical libraries without the need to create an all encompassing overview of the whole library. We describe the requirements we collected during our collaboration with biologists and chemists, the design rationale behind the tool, and two case studies.
  • Synfacts 09/2010; 2010(09):1058-1058. DOI:10.1055/s-0030-1257902
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    ABSTRACT: A fast, efficient, general and environmentally friendly method for preparation of highly fluorescent derivatives containing the pyrrolodiazine moiety using microwave (MW) irradiation, in liquid phase, is reported. Under MW irradiation the yields are much higher, sometimes substantially (by almost double) and, the amount of solvent used is at least 5-fold less. The pyrrolopyridazine (PP) derivatives are very intense blue emitters and have high quantum yields (up to 90%) while pyrrolophthalazine (PHP) compounds are still intense blue emitters but the quantum yield is negligible. A certain influence of the substituents concerning fluorescence was found, those ones at the 7 position being crucial for fluorescence. The number of the substituents from the pyrrolo ring seems not to play an important role in regard with the fluorescence but, with an increasing number of substituents a certain hypsochromic shift in the absorption spectra was found. (C) 2010 Elsevier Ltd. All rights reserved.
    Tetrahedron 06/2010; 66(24-24):4298-4306. DOI:10.1016/j.tet.2010.04.050 · 2.82 Impact Factor
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    ABSTRACT: The articles which report about the synthesis of chroman-4-ones by hydrogenation/reduction of the corresponding chromones are reviewed. The following methods of synthesis are reviewed: hydrogenation over palladium, platinum, Raney-nickel, catalytic transfer hydrogenation, homogeneous hydrogenation, reduction by complex hydrides, by DIBALH and some special methods. For every appropriate reaction yield, the duration and some additional information is given (if available). Moreover, many exceptions and interesting transformations are described.
    Current Organic Synthesis 05/2010; 7(3):276-309. DOI:10.2174/157017910791163002 · 2.44 Impact Factor
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    ABSTRACT: A general and efficient directed ortho metalation (DoM)-halogen dance (HD)-electrophile quench sequence for the synthesis of trisubstituted pyridyl O-carbamates is described. A second HD sequence furnishes highly functionalized tetrasubstituted pyridines. Furthermore, a hitherto unobserved double HD rearrangement is reported. Under similar LDA conditions, aromatic O-carbamates with OMe, Cl, and F substituents (4a-c) undergo either a HD-electrophile quench sequence, 4a-c --> 18-20, or a HD-anionic ortho Fries rearrangement, 4a-c --> 6a-c, respectively.
    Organic Letters 05/2010; 12(10):2198-201. DOI:10.1021/ol100493v · 6.32 Impact Factor
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    ABSTRACT: The scientific literature detailing the synthesis of chroman- 2-ones by hydrogenation/reduction of the corresponding coumarins is reviewed. The following methods are described: hydrogenation on palladium, platinum, nickel, catalytic transfer hydrogenation, homogeneous hydrogenation, reduction by complex hydrides, reduction by metals, and electrochemical reduction. For each appropriate reaction, the yield, duration and some additional information is given (if available). Moreover, many exceptions and interesting transformations are described.
    Synthesis 11/2009; DOI:10.1055/s-0029-1218153 · 2.44 Impact Factor
  • ChemInform 09/2009; 40(39). DOI:10.1002/chin.200939167
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    ABSTRACT: Here we report the synthesis, investigation as well as surface deposition of a truly axial symmetry Mn12-diphenylphosphinate (Mn12-phn) single molecule magnet. Out of 16 acetate ligands encapsulating the Mn12O12 core, 12 ligands were exchanged by diphenylphosphinate in this compound. Mn12-phn shows well-defined magnetic hysteresis curves indicating a very high crystal quality. A monolayer of Mn12-phn was chemically grafted on a functionalized Au(111) surface via ligand exchange reaction and studied by means of scanning tunneling microscopy and spectroscopy. Via distance–voltage spectroscopy we determine the real-space height of the Mn12-phn molecules with high accuracy. A large spread in the measured molecular heights obtained from the distance–voltage spectra indicates the absence of preferential orientation of Mn12-phn molecules with respect to the surface which we attribute to the equal anchoring probability of all diphenylphosphinate ligands in Mn12-phn while none of the four acetate ligands are exchanged. These results are compared with the experimental data obtained from a different Mn12 derivative containing 16 thiophenecarboxylate ligands. In general, we show that the substitution of the ligand shell may have a major impact on the surface orientation of the Mn12 clusters deposited on Au, i.e. on the orientation of the easy magnetization axis.
    Polyhedron 06/2009; 28. DOI:10.1016/j.poly.2008.11.028 · 2.05 Impact Factor
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    ABSTRACT: Abstract A highly efficient procedure for glucosylation of flavonoids by acetobromoglucose is described. Glucosylation is carried out in a two-phase system CHCl3/H2O over 96 h using tetrabutylammonium bromide as phase-transfer catalyst. A purification procedure can be performed without column chromatography, and the yields of the glucosylated flavonoids are mostly quantitative. Acetylated glucosides were deprotected with sodium methanolate to afford the desired glucosides of flavonoids. Graphical Abstract
    Monatshefte fuer Chemie/Chemical Monthly 06/2009; 140(12):1503-1512. DOI:10.1007/s00706-009-0207-6 · 1.35 Impact Factor
  • S. Voss · M. Fonin · F. Zinser · M. Burgert · U. Groth · U. Rüdiger
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    ABSTRACT: The possibility to use the Au(100)/Fe(100)/MgO(100) system as a substrate for future spin-polarized transport measurements on Mn12 single molecule magnets has been investigated by means of scanning tunneling microscopy and X-ray photoelectron spectroscopy at room temperature. In particular, the stability of the iron layer during a wet chemical preparation of Mn12 monolayers was studied. The results demonstrate that Mn12 can be deposited on Au(100)/Fe(100)/MgO(100) while preserving the metallic nature of the ferromagnetic iron layer which is required as a possible source of spin-polarized electrons in future studies.
    Polyhedron 06/2009; 28(9):1606-1609. DOI:10.1016/j.poly.2008.10.007 · 2.05 Impact Factor
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    ABSTRACT: The 2-aryl-2,3,5,6,7,8-hexahydro[1]benzothieno[2,3-d]pyrimidin-4(1H)-ones and 2-aryl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-ones have been diversified by alkylation reactions, applying benzylchlorides and N-substituted 2-chloroacetamides as alkylating agents. Under the found uniform conditions the substitution direction does not depend on the structure of the alkylating agent and gives monoalkylated products in high yields with simple workup. The alkylation of the 2,3-dihydropyrimidin-4(1H)-one derivatives proceeds onto the N1-position; however, in the case of pyrimidin-4(3H)-ones the O-alkylated products are formed selectively. An alternative strategy for the synthesis of the N1-benzyl-2,3-dihydropyrimidin-4(1H)-one derivatives is also developed. It applies the redaction of N2-substituted Gewald's amides with aromatic aldehydes and allows simple introduction of various substituents in the final molecule.
    Journal of Combinatorial Chemistry 05/2009; 11(3):508-14. DOI:10.1021/cc9000373 · 4.93 Impact Factor
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    ABSTRACT: An efficient and versatile one-step method for the synthesis of heterocyclic analogues of neoflavonoids, such as pyrazolyl-, isoxazolyl-, pyrimidinyl-substituted 4-phenyl-2H-chromen-2-ones and fused 4-phenyl-2H,6H-pyrano[3,2-g]chromene-2,6-diones and 4-phenyl-2H,10H-pyrano[2,3-f]chromene-2,10-diones, using the corresponding enamino ketones is described.
    Synthesis 04/2009; DOI:10.1055/s-0028-1088030 · 2.44 Impact Factor
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    ABSTRACT: The stability of single crystals and monolayers of Mn12 single molecule magnets under the influence of X-ray radiation and other possibly disruptive influences has been investigated by means of synchrotron radiation. Clear evidence for radiation induced sample degradation was found for both single crystals and monolayers. The comparison with spectra obtained after damaging the molecules by Ar+ sputtering, metal evaporation or water moistening indicates a possibility to distinguish between radiation damage and other external influences. The results clarify some of the previous conflicting reports on the integrity of Mn12 molecules deposited on surfaces and are linked to the investigations aiming at studies of the electronic and magnetic properties of individual Mn12 clusters.
    Applied Physics A 03/2009; 94(3). DOI:10.1007/s00339-008-4911-6 · 1.69 Impact Factor
  • ChemInform 02/2009; 40(8). DOI:10.1002/chin.200908158
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    ABSTRACT: Catalytic homogeneous hydrogenation of 7-methoxy-3-phenylchromone and other substrates was achieved in the presence of cationic iridium complexes and base as co-catalyst. Contrary to common alkene hydrogenation, which is inactivated by base, the hydrogenation of the above set of electron-deficient alkenes turned out to be base-activated.
    Synlett 01/2009; 2009(2). DOI:10.1055/s-0028-1087513 · 2.46 Impact Factor