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KIRSCHNING GROUP

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Latest publications

T. Busch, G. Dräger, E. Kunst, H. Benson, F. Sasse, K. Siems, A. Kirschning:

Synthesis and antiproliferative activity of new tonantzitlolone-derived diterpene derivatives

Org. Biomol. Chem. 2016, 14, 9040-9045.

tonantzitlolone350.jpgThe synthesis of the diterpene (+)-tonantzitlolone A and a series of derivatives is reported. The study includes the determination of their antiproliferative activities against selected cancer cell lines.

 

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J. Hoepfner, M. Kleinsorge, O. Papp, M. Ackermann, S. Alfken, U. Rinas, W. Solodenko, A. Kirschning, M. Sgodda, T. Cantz:

Biphasic modulation of Wnt signaling supports efficient foregut endoderm formation from human pluripotent stem cells

Cell Bio. Int. 2016, 40, 534-548.

Pluripotent stem cells (embryonic stem cells and induced pluripotent stem cells) are of great promise in regenerative medicine, including molecular studies of disease mechanisms, if the affected cell type can be authentically generated during in vitro differentiation. Most existing protocols aim to mimic embryonic development steps by the supplementation of specific cytokines and small molecules, but the involved signaling pathways need further exploration. In this study, we investigated enhanced initial activation of Wnt signaling for definitive endoderm formation and subsequent rapid shutdown of Wnt signaling for proper foregut endoderm specification using 3 μM CHIR99021 and 0.5 μg/mL of secreted frizzled-related protein 5 (sFRP-5) for biphasic modulation of the Wnt pathway. The definitive endoderm and foregut endoderm differentiation capabilities of Wnt pathway-modulated cells were determined based on the expression levels of the endodermal transcription factors SOX17 and FOXA2 and those of the transcription activator GATA4 and the α-fetoprotein (AFP) gene, respectively. Furthermore, the resulting biphasic Wnt pathway modulation was investigated at the protein level by analyzing phosphorylation of glycogen synthase kinase 3 beta (GSK3β) and β-catenin. Finally, Wnt target gene expression was determined using an improved lentiviral reporter construct that enabled robust T-cell transcription factor 4 (TCF4)/lymphoid enhancer-binding factor 1 (LEF1)-mediated luciferase expression in differentiating pluripotent stem cells. In conclusion, we demonstrated robust, homogeneous, and efficient derivation of foregut endodermal cells by inducing a biphasic modulation of the Wnt signaling pathway.

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P. M. Perin, S. Haid, R. J. P. Brown, J. Doerrbecker, K. Schulze, C. Zeilinger, M. von Schaewen, B. Heller, K. Vercauteren, E. Luxenburger, Y. M. Baktash, F. W. R. Vondran, S. Speerstra, A. Awadh, F. Mukhtarov, L. M. Schang, A. Kirschning, R. Müller, C. A. Guzman, L. Kaderali, G. Randall, P. Meuleman, A. Ploss,  T. Pietschmann:

Flunarizine prevents hepatitis C virus membrane fusion in a genotype-dependent manner by targeting the potential fusion peptide within E1

Hepatology 2016, 63, 49-62.

To explore mechanisms of hepatitis C viral (HCV) replication we screened a compound library including licensed drugs. Flunarizine, a diphenylmethylpiperazine used to treat migraine, inhibited HCV cell entry in vitro and in vivo in a genotype-dependent fashion. Analysis of mosaic viruses between susceptible and resistant strains revealed that E1 and E2 glycoproteins confer susceptibility to flunarizine. Time of addition experiments and single particle tracking of HCV demonstrated that flunarizine specifically prevents membrane fusion. Related phenothiazines and pimozide also inhibited HCV infection and preferentially targeted HCV genotype 2 viruses. However, phenothiazines and pimozide exhibited improved genotype coverage including the difficult to treat genotype 3. Flunarizine-resistant HCV carried mutations within the alleged fusion peptide and displayed cross-resistance to these compounds, indicating that these drugs have a common mode of action. Conclusion: These observations reveal novel details about HCV membrane fusion; moreover, flunarizine and related compounds represent first-in-class HCV fusion inhibitors that merit consideration for repurposing as a cost-effective component of HCV combination therapies.

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F. Gille, A. Kirschning:

Studies on the synthesis of peptides containing dehydrovaline and dehydroisoleucine based on copper-mediated enamide formation

Beilstein J. Org. Chem. 2016, 12, 564-570.

graph-abstract-buchwald-beilstein-franziska-gille-350_1.jpgThe preparation of peptide fragments containing dehydrovaline and dehydroisoleucine moieties present in the antibiotic myxovalargin is reported. Peptide formation is based on a copper-mediated C–N cross-coupling protocol between an acyl amide and a peptidic vinyl iodide. The presence of a neighboring arginine in the vinyl iodide posed a challenge with respect to the choice of the protecting group and the reaction conditions. It was found that ornithine – a suitable precursor – is better suited than arginine for achieving good yields for the C–N cross-coupling reaction. The optimized conditions were utilized for the synthesis of peptides 32, 33, 39 and 40 containing a neighboring ornithine as well as for the tripeptide 44 containing dehydroisoleucine with the correct stereochemistry.

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J. Hartwig, A. Kirschning:

Flow Synthesis in Hot Water: Synthesis of the Atypical Antipsychotic Iloperidone

Chem. Eur. J.  2016, 22, 3044-3052.

janantipsychotic350.jpgInductively heated steel reactors continuously perform organic transformations in water under high temperature conditions, utilizing the unique physiochemical properties of water at subcritical conditions. We demonstrated the power of this set-up in the continuous synthesis of the atypical antipsychotic drug iloperidone, in which we performed four out of five steps under aqueous conditions.

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T. J. Pfeffer, F. Sasse, C. F. Schmidt, S. Lakämper, A. Kirschning, T. Scholz:

The natural diterpene tonantzitlolone A and its synthetic enantiomer inhibit cell proliferation and kinesin-5 function

Eur. J. Med. Chem. 2016, 113, 164-170.

tonantzitlolone-homepage-teaser-352.jpgTonantzitlolone A, a diterpene isolated from the Mexican plant Stillingia sanguinolenta, shows cytostatic activity. Both the natural product tonantzitlolone A and its synthetic enantiomer induce monoastral spindle formation in cell experiments which indicates inhibitory activity on kinesin-5 mitotic motor molecules. These inhibitory effects on kinesin-5 could be verified in in vitro single-molecule motility assays, where both tonantzitlolones interfered with kinesin-5 binding to its cellular interaction partner microtubules in a concentration-dependent manner, yet with a larger effect of the synthetic enantiomer. In contrast to kinesin-5 inhibition, both tonantzitlolone A enantiomers did not affect conventional kinesin-1 function; hence tonantzitlolones are not unspecific kinesin inhibitors. The observed stronger inhibitory effect of the synthetic enantiomer demonstrates the possibility to enhance the overall moderate anti-proliferative effect of the lead compound tonantzitlolon A by chemical modification.

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I. Bulyszko, G. Dräger, A. Klenge, A. Kirschning:

Evaluation of the Synthetic Potential of an AHBA Knockout Mutant of the Rifamycin Producer Amycolatopsis mediterranei

Chem. Eur. J. 2015, 21, 19231-19242.

ilona.jpgSupplementing an AHBA(−) mutant strain of Amycolatopsis mediterranei, the rifamycin producer, with a series of benzoic acid derivatives yielded new tetraketides containing different phenyl groups. These mutasynthetic studies revealed unique reductive properties of A. mediterranei towards nitro- and azidoarenes, leading to the corresponding anilines. In selected cases, the yields of mutaproducts (fermentation products isolated after feeding bacteria with chemically prepared analogs of natural building blocks) obtained are in a range (up to 118 mg L−1) that renders them useful as chiral building blocks for further synthetic endeavors. The configuration of the stereogenic centers at C6 and C7 was determined to be 6R,7S for one representative tetraketide. Importantly, processing beyond the tetraketide stage is not always blocked when the formation of the bicyclic naphthalene precursor cannot occur. This was proven by formation of a bromo undecaketide, an observation that has implications regarding the evolutionary development of rifamycin biosynthesis.

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A. Kirschning, F. Gille, M. Wolling:

Brook Rearrangement as the Key Step in Domino Reactions

Applications of Domino Transformations in Organic Synthesis Vol. 1 (Science of Synthesis), Georg Thieme Verlag Stuttgart•New-York, 2015, 355-448.

brook-umlagerung-350.jpgThe Brook rearrangement has lost its Cinderella status over the past twenty years since being embedded into cascade reaction sequences. The powerful formation of carbanions through silyl migration has been exploited for the development of many new methodol- ogies and has been used as a key transformation in complex natural product syntheses. Now, the Brook rearrangement belongs to the common repertoire of synthetic organic chemists. 

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