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ABSTRACT: Shortly after the discovery of the proteasome it was proposed that inhibitors could stabilize proteins which ultimately would trigger apoptosis in tumor cells. The essential questions were whether small molecules would be able to inhibit the proteasome without generating prohibitive side effects and how one would derive these compounds. Fortunately, "Mother Nature" has generated a wide variety of natural products that provide distinct selectivities and specificities. The chemical synthesis of these natural products finally provided access to analogues and optimized drugs of which two different classes have been approved for the treatment of malignancies. Despite these achievements, additional lead structures derived from nature are under investigation and will be discussed with regard to their biological potential and chemical challenges.
Angewandte Chemie International Edition 03/2013; · 13.45 Impact Factor
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ABSTRACT: Leading the way: The synthesis of natural products with new biological targets is one of the driving forces for the development of new antibiotics. The synthesis of the two secondary metabolites corallopyronin and myxopyronin have been achieved, which are prominent leads for the inhibition of bacterial RNA polymerase.
Angewandte Chemie International Edition 10/2012; · 13.45 Impact Factor
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09/2012: pages 17-41; , ISBN: 978-1849733618
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Wiebke Zander,
Herbert Irschik,
Hermann Augustiniak,
Martina Herrmann,
Rolf Jansen,
Heinrich Steinmetz,
Klaus Gerth,
Wolfgang Kessler, Markus Kalesse,
Gerhard Höfle,
Rolf Müller
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ABSTRACT: Sulfangolids are the first sulfate ester containing secondary metabolites from myxobacteria. The metabolites 1-4 and the structurally related kulkenon (5) were isolated from different strains of the species Sorangium cellulosum. In the course of isolation all metabolites proved to be rather sensitive due to their conjugated double bond systems and the strong acidic nature of the sulfate ester in sulfangolids. The relative configuration of sulfangolid C (3) was assigned by extensive 1D and 2D NMR analysis and molecular modelling. In addition, the biosynthesis of 3 was studied by feeding experiments.
Chemistry 04/2012; 18(20):6264-71. · 5.93 Impact Factor
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ABSTRACT: The improved synthesis of the antitumor compound (+)-tedanolide is described through an aldol coupling of bis-ketone 7. This modification shortens the synthetic steps in the endgame and provides rapid access to this biologically important natural product. Additionally, it serves as a probe in order to unravel the conformational effects that impede or enable its successful synthesis. Having this way access to des-epoxy-tedanolide, its biological characterization surprisingly unravelled the mode of action to resemble candidaspongiolide rather than deoxytedanolide.
Chemistry 03/2012; 18(16):4946-52. · 5.93 Impact Factor
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ABSTRACT: Southern belles! Simplified analogues of tedanolide, a natural product with picomolar activity against a range of tumor cell lines, were synthesized and evaluated for potency in mammalian cancer cells. The truncated analogues were found to retain significant activity in vitro (23 μmol mL(-1) for the example shown) compared with the parent compound tedanolide (0.33 nmol mL(-1)), and represent potential leads for the development of novel anticancer agents.
ChemMedChem 03/2012; 7(5):771-5. · 3.15 Impact Factor
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ABSTRACT: The challenging synthesis of a quaternary center within the highly oxygenated setting of tedanolide C can be performed via a Kiyooka aldol reaction. Here, the diastereomeric analog of tedanolide C with the configurations between C10 and C20 opposite compared to the proposed structure was chosen as the synthetic target. The tetra-substituted silyl ketene acetal provides the southern hemisphere of tedanolide C in useful selectivities, and the absolute configuration of the newly generated quaternary center was determined by NOE experiments of the corresponding acetonide.
Organic Letters 11/2011; 13(22):6038-41. · 5.86 Impact Factor
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ABSTRACT: Unsaturated aldehydes are exquisite building blocks for further transformations in polyketide synthesis. Besides standard transformations that take advantage of the aldehyde functionality, the conjugate addition of hydrides followed by internal protonation allows access to alpha chiral aldehydes. Even though vinylogous Mukaiyama aldol reactions have been used in natural product syntheses before, the first enantioselective Mukaiyama aldol reaction of aldehyde-derived dienolates is described.
Organic Letters 05/2011; 13(9):2430-2. · 5.86 Impact Factor
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ABSTRACT: The first synthesis of the highly biologically active chivosazole F is described. It features an intramolecular Stille coupling for the macrolactone formation and thereby circumvents the problem of isomerization associated with the tetraene segment. Additionally, the synthesis confirms the structure which has been proposed based solely on a combination of NMR/computational methods and genetic analysis.
Journal of the American Chemical Society 10/2010; 132(39):13610-1. · 9.91 Impact Factor
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Angewandte Chemie International Edition 09/2010; 49(45):8367-9. · 13.45 Impact Factor
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Annalen der Chemie und Pharmacie 08/2010; 2010(27):5155 - 5159. · 3.10 Impact Factor
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Angewandte Chemie International Edition 05/2010; 49(23):3934-8. · 13.45 Impact Factor
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Leila Bülow,
Irina Nickeleit,
Anna-Katharina Girbig,
Tobias Brodmann,
Andreas Rentsch,
Ulrike Eggert,
Florenz Sasse,
Heinrich Steinmetz,
Ronald Frank,
Teresa Carlomagno,
Nisar P Malek, Markus Kalesse
ChemMedChem 03/2010; 5(6):832-6. · 3.15 Impact Factor
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Angewandte Chemie International Edition 02/2010; 49(9):1619-22. · 13.45 Impact Factor
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ABSTRACT: During heme biosynthesis the oxygen-independent coproporphyrinogen III oxidase HemN catalyzes the oxidative decarboxylation of the two propionate side chains on rings A and B of coproporphyrinogen III to the corresponding vinyl groups to yield protoporphyrinogen IX. Here, the sequence of the two decarboxylation steps during HemN catalysis was investigated. A reaction intermediate of HemN activity was isolated by HPLC analysis and identified as monovinyltripropionic acid porphyrin by mass spectrometry. This monovinylic reaction intermediate exhibited identical chromatographic behavior during HPLC analysis as harderoporphyrin (3-vinyl-8,13,17-tripropionic acid-2,7,12,18-tetramethylporphyrin). Furthermore, HemN was able to utilize chemically synthesized harderoporphyrinogen as substrate and converted it to protoporphyrinogen IX. These results suggest that during HemN catalysis the propionate side chain of ring A of coproporphyrinogen III is decarboxylated prior to that of ring B.
Biological Chemistry 11/2009; 391(1):55-63. · 2.96 Impact Factor
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Angewandte Chemie International Edition 12/2008; 48(3):595-8. · 13.45 Impact Factor
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ABSTRACT: The synthesis of the C10-C32 core structure of spirangien A is reported. The pivotal aldol coupling between both key intermediates provides a synthetic challenge in the synthesis of this complex natural product.
Organic Letters 09/2008; 10(19):4371-4. · 5.86 Impact Factor
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Irina Nickeleit,
Steffen Zender,
Florenz Sasse,
Robert Geffers,
Gudrun Brandes,
Inga Sörensen,
Heinrich Steinmetz,
Stefan Kubicka,
Teresa Carlomagno,
Dirk Menche,
Ines Gütgemann,
Jan Buer,
Achim Gossler,
Michael P Manns, Markus Kalesse,
Ronald Frank,
Nisar P Malek
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ABSTRACT: A reduction in the cellular levels of the cyclin kinase inhibitor p27(kip1) is frequently found in many human cancers and correlates directly with patient prognosis. In this work, we identify argyrin A, a cyclical peptide derived from the myxobacterium Archangium gephyra, as a potent antitumoral drug. All antitumoral activities of argyrin A depend on the prevention of p27(kip1) destruction, as loss of p27(kip1) expression confers resistance to this compound. We find that argyrin A exerts its effects through a potent inhibition of the proteasome. By comparing the cellular responses exerted by argyrin A with siRNA-mediated knockdown of proteasomal subunits, we find that the biological effects of proteasome inhibition per se depend on the expression of p27(kip1).
Cancer cell 08/2008; 14(1):23-35. · 25.29 Impact Factor
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Angewandte Chemie International Edition 08/2008; 47(34):6478-82. · 13.45 Impact Factor
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Angewandte Chemie International Edition 02/2008; 47(3):597-9. · 13.45 Impact Factor
