Dirk Menche

University of Bonn, Bonn, North Rhine-Westphalia, Germany

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Publications (84)420.62 Total impact

  • Sebastian Essig · Dirk Menche
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    ABSTRACT: Full details on the design, development and application of a highly stereoselective strategy for the synthesis of isochromanones are reported. The method is based on an asymmetric ortholithiation with aldehyde electrophiles and utilizes the chiral memory of a preoriented atropisomeric amide axis for stereocontrol. For direct transformation of sterically hindered amides to isochromanones efficient and mild one-pot protocols involving either O-alkylation or acidic microwave activation were developed. The procedures may be applied also to highly functionalized as well as stereochemically complex and sensitive substrates and demonstrate a high protective group tolerance. Furthermore, asymmetric crotylborations of axially chiral amides were studied in detail. These methodologies enable a general access to all possible stereoisomers of hydroxyl-isochromanones with up to three contiguous stereocenters. True applicability of our approach was finally demonstrated by synthesis of the authentic anti,anti-configured isochromanone core of the ajudazols, highly potent inhibitors of the mitochondrial respiratory chain from myxobacteria.
    No preview · Article · Jan 2016 · The Journal of Organic Chemistry
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    ABSTRACT: Full details on the evaluation and application of an easily feasible and generally useful method for configurational assignments of isolated methyl-bearing stereocenters are reported. The analytical tool relies on a bioinformatic gene cluster analysis, utilizes a predictive enoylreductase alignment and its feasibility was demonstrated by the full stereochemical determination of the ajudazols, highly potent inhibitors of the mitochondrial respiratory chain. Furthermore, a full account on our strategies and tactics that culminated in the total synthesis of ajudazol B, the most potent and least abundant of these structurally unique class of myxobacterial natural products, is presented. Key features include an application of an asymmetric ortholithiation strategy for synthesis of the characteristic anti-configured hydroxyl-isochromanone core bearing three contiguous stereocenters, a modular oxazole formation, a flexible cross-metathesis approach for terminal allyl amide synthesis and a late-stage Z,Z-selective Suzuki coupling. This total synthesis unambiguously proves the correct stereochemistry which was further corroborated by comparison with reisolated natural material. Finally, 5-lipoxygenase was discovered as an additional molecular target of ajudazol B. Activities against this clinically validated key enzyme of the biosynthesis of proinflammatory leukotrienes were in the range of the approved drug zileuton which further underlines the biological importance of this unique natural product.
    No preview · Article · Jan 2016 · The Journal of Organic Chemistry

  • No preview · Article · Dec 2015 · Synthesis
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    ABSTRACT: Vacuolar-type H+-ATPases (V-ATPases) have gained recent attention as highly promising anticancer drug targets, and therefore detailed structural analyses and studies of inhibitor interactions are very important research objectives. Spin labeling of the V-ATPase holoenzyme from the tobacco hornworm Manduca sexta and V-ATPase in isolated yeast (Saccharomyces cerevisiae) vacuoles was accomplished by two novel methods involving the covalent binding of a (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) derivative of N,N′-dicyclohexylcarbodiimide (DCC) to the essential glutamate residue in the active site and the noncovalent interaction of a radical analogue of the highly potent inhibitor archazolid, a natural product from myxobacteria. Both complexes were evaluated in detail by electron paramagnetic resonance (EPR) spectroscopic studies and double electron–electron resonance (DEER) measurements, revealing insight into the inhibitor binding mode, dynamics, and stoichiometry as well as into the structure of the central functional subunit c of these medicinally important hetero-multimeric proton-translocating proteins. This study also demonstrates the usefulness of natural product derived spin labels as tools in medicinal chemistry.
    No preview · Article · Dec 2015 · ChemMedChem
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    ABSTRACT: // Siwei Zhang 1 , Lina S. Schneider 1 , Binje Vick 2,4 , Michaela Grunert 2 , Irmela Jeremias 2,3,4 , Dirk Menche 5 , Rolf Müller 6 , Angelika M. Vollmar 1 and Johanna Liebl 1 1 Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University, Munich, Germany 2 Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany 3 Department of Oncology/Hematology, Dr. von Haunersches Kinderspital, Munich, Germany 4 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany 5 Kekulé-Institut für Organische Chemie und Biochemie der Universität Bonn, Bonn, Germany 6 Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Department of Pharmaceutical Biotechnology, Saarland University, Saarbrücken, Germany Correspondence to: Johanna Liebl, email: // Keywords : Archazolid, leukemia, natural compounds Received : May 20, 2015 Accepted : October 07, 2015 Published : October 19, 2015 Abstract Prognosis for patients suffering from T-ALL is still very poor and new strategies for T-ALL treatment are urgently needed. Our study shows potent anti-leukemic effects of the myxobacterial V-ATPase inhibitor Archazolid A. Archazolid A reduced growth and potently induced death of leukemic cell lines and human leukemic samples. By inhibiting lysosomal acidification, Archazolid A blocked activation of the Notch pathway, however, this was not the mechanism of V-ATPase inhibition relevant for cell death induction. In fact, V-ATPase inhibition by Archazolid A decreased the anti-apoptotic protein survivin. As underlying mode of action, this work is in line with recent studies from our group demonstrating that Archazolid A induced S-phase cell cycle arrest by interfering with the iron metabolism in leukemic cells. Our study provides evidence for V-ATPase inhibition as a potential new therapeutic option for T-ALL.
    Full-text · Book · Oct 2015
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    ABSTRACT: Several natural compound interfere with microtubules or the actin cytoskeleton. Compounds interfering with the microtubules like Vinca-alkaloids or taxanes, are extensively used for cancer therapy. In contrast, knowledge about pharmacological properties of actin binding drugs is poor and drugs interfering with actin are far from clinical use. Rhizopodin is a natural compound that strongly affects the actin cytoskeleton at nanomolar concentrations. Initial work revealed interesting anti-bacterial and cytotoxic effects, but the cellular effects and pharmacological properties of rhizopodin have not been characterized. We hypothesized that rhizopodin might exert anti-cancer activity. Therefore, the aim of this study was to characterize the cellular and pharmacological effects of rhizopodin in cancer. Effects of rhizopodin demonstrated prominent effects on the actin cytoskeleton as shown in the actin-pyrene assay and by immunostaining of cancer cells. To investigate cellular effects of rhizopodin, we analyzed cell proliferation, cell death induction by propidium iodide exclusion and western blot, as well as migration by impedance measurement using the xCELLligence device in MDA-MB-231 breast cancer and T24 bladder cancer cell lines. Rhizopodin inhibited proliferation and induced cell death of MDA-MB-231 and T24 cells at nanomolar concentrations. PARP cleavage by rhizopodin suggests caspase-dependent cell death induction. Importantly, rhizopodin potently inhibited MDA-MB-231 and T24 cancer cell migration at subtoxic doses where no actin aggregation was observed, indicating a specific underlying signaling of rhizopodin. In summary, our study elucidates rhizopodin as actin-binding natural compound that exerts potent anti-cancer effects. Therefore, our work provides the basis for further in depth characterization of rhizopodin as an antitumoral agent.
    No preview · Article · Sep 2015 · Pharmazie
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    ABSTRACT: Inspired by the bioactive natural metabolites leupyrrin A1 and B1 , two novel stereoselective methods for the highly concise synthesis of densely substituted α-chiral butyrolactones are reported. The first approach relies on an innovative three-step Ti(III) -catalyzed radical reaction that proceeds with excellent chemo-, regio-, and stereoselectivity. The alternative route utilizes sequential asymmetric alkylations and enables asymmetric synthesis of the authentic α-tetrasubstituted butyrolactone motif of the leupyrrins in only four steps from commercially available substrates.
    No preview · Article · Sep 2015 · Chemistry - A European Journal
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    ABSTRACT: A general new method for the highly concise synthesis of C-1-alkylated tetrahydroisoquinolines (THIQ) is reported. The CuCl2-catalyzed procedure is based on a coupling of nonfunctionalized THIQs with organozinc reagents under aerobic conditions. It proceeds in high yields and is broadly applicable to a wide range of substrates. It relies on a regioselective sp(3) C-H bond activation allowing for an sp(3)-sp(3) bond union under mild reaction conditions in a rapid and effective manner. Mechanistically it involves an iminium ion intermediate that is formed via an organic radical involving a single-electron-transfer process. For the first time for this type of reaction a radical intermediate has been proven by EPR spectroscopy.
    No preview · Article · Aug 2015 · Organic Letters
  • Björn Schmalzbauer · Dirk Menche
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    ABSTRACT: A concise synthesis of the tricyclic core 2 of the structurally unique marine myxobacterial natural product salimabromide has been developed. Compound 2 contains the tetraline subunit including the two quaternary centers and the eight-membered ring of salimabromide. Major features for its synthesis include a Lewis base catalyzed Denmark-crotylation for stereoselective construction of the highly hindered quaternary stereocenter, an innovative iodine/selectfluor induced endo-carbocylization, and a unique chemoselective carbonylative lactonization of the eight-membered ring.
    No preview · Article · May 2015 · Organic Letters
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    ABSTRACT: Generalized strategies to improve breast cancer treatment remain of interest to develop. In this study, we offer preclinical evidence of an important metabolic mechanism underlying the antitumor activity of inhibitors of the vacuolar-type ATPase (V-ATPase), a heteromultimeric proton pump. Specifically, our investigations in the 4T1 model of metastatic breast cancer of the V-ATPase inhibitor archazolid suggested that its ability to trigger metabolic stress and apoptosis associated with tumor growth inhibition related to an interference with hypoxia inducible factor-1α signaling pathways and iron metabolism. As a consequence of disturbed iron metabolism, archazolid caused S-phase arrest, double stranded DNA breaks and p53 stabilization leading to apoptosis. Our findings link V-ATPase to cell cycle progression and DNA synthesis in cancer cells, and highlight the basis for the clinical exploration of V-ATPase as a potentially generalizable therapy for breast cancer. Copyright © 2015, American Association for Cancer Research.
    No preview · Article · May 2015 · Cancer Research
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    ABSTRACT: The stereochemical determination of the potent antifungal agents leupyrrin A1 and B1 and the total synthesis of leupyrrin A1 are reported. The relative and absolute configuration was determined by a combination of high field NMR studies, molecular modeling and chemical derivatization. The expedient total synthesis involves a one-pot sequential Zr-mediated oxidative diyne-cyclization/regioselective opening sequence for preparation of the unique dihydrofuran ring, a highly stereoselective one-pot approach to the butyrolactone, a challenging sp2-sp3-Suzuki coupling and a high-yielding Shiina macrolactonization.
    No preview · Article · Mar 2015 · Journal of the American Chemical Society
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    ABSTRACT: The natural products rhizopodin and bistramide belong to an elite class of highly potent actin binding agents. They show powerful antiproliferative activities against a range of tumor cell lines, with IC50 values in the low-nanomolar range. At the molecular level they disrupt the actin cytoskeleton by binding specifically to a few critical sites of G-actin, resulting in actin filament stabilization. The important biological properties of rhizopodin and bistramide, coupled with their unique and intriguing molecular architectures, render them attractive compounds for further development. However, this is severely hampered by the structural complexity of these metabolites. We initiated an interdisciplinary approach at the interface between molecular modeling, organic synthesis, and chemical biology to support further biological applications. We also wanted to expand structure–activity relationship studies with the goal of accessing simplified analogues with potent biological properties. We report computational analyses of actin–inhibitor interactions involving molecular docking, validated on known actin binding ligands, that show a close match between the crystal and modeled structures. Based on these results, the ligand shape was simplified, and more readily accessible rhizopodin–bistramide mimetics were designed. A flexible and modular strategy was applied for the synthesis of these compounds, enabling diverse access to dramatically simplified rhizopodin–bistramide hybrids. This novel analogue class was analyzed for its antiproliferative and actin binding properties.
    No preview · Article · Jan 2015 · ChemMedChem
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    ABSTRACT: The macrolide archazolid inhibits vacuolar-type H(+)-ATPase (V-ATPase), a proton-translocating enzyme involved in protein transport and pH regulation of cell organelles, and potently suppresses cancer cell growth at low nanomolar concentrations. In view of the growing link between inflammation and cancer, we investigated whether inhibition of V-ATPase by archazolid may affect primary human monocytes that can promote cancer by sustaining inflammation through the release of tumor-promoting cytokines. Human primary monocytes express V-ATPase, and archazolid (10 to 100nM) increases the vesicular pH in these cells. Archazolid (10nM) markedly reduced the release of pro-inflammatory (TNF-α, interleukin-6 and -8) but also of anti-inflammatory (interleukin-10) cytokines in monocytes stimulated with LPS, without affecting cell viability up to 1000nM. Of interest, secretion of interleukin-1β was increased by archazolid. Comparable effects were obtained by the V-ATPase inhibitors bafilomycin and apicularen. The phosphorylation of p38 MAPK and ERK-1/2, Akt, SAPK/JNK or of the inhibitor of NFκB (IκBα) as well as mRNA expression of IL-8 were not altered by archazolid in LPS-stimulated monocytes. Instead, archazolid caused endoplasmic reticulum (ER) stress response visualized by increased BiP expression and accumulation of IL-8 (and TNF-α) at the ER, indicating a perturbation of protein secretion. In conclusion, by interference with V-ATPase, archazolid significantly affects the secretion of cytokines due to accumulation at the ER which might be of relevance when using these agents for cancer therapy.
    No preview · Article · Aug 2014 · Biochemical Pharmacology
  • Thomas Debnar · Dirk Menche
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    ABSTRACT: Polyketides are prevalent structural features in numerous natural products with a broad range of biological activities and pharmacological properties and polyketide antibiotics, antifungals, cytostatics, antiparasitics, and natural insecticides are in commercial use. Biosynthetically, they are derived by iterative condensations of acetyl and propionyl subunits giving rise to diverse assemblies of methyl and hydroxyl-bearing stereogenic centers and thus enabling very large numbers of stereochemical permutations and structures with very complexity and diversity. Despite impressive accomplishments and progress in the synthesis of these structures in recent years, there remains a high need for the development of more efficient synthetic methods to assemble these structures in a more direct and convergent manner. Sequential catalytic sequences are particularly desirable as they combine several synthetic transformations in a one-pot process and thus enable the rapid assembly of complex architectures. Herein, the design, development, and application of innovative sequential concepts are reported, including a novel domino reaction relying on a combination of a nucleophilic addition and a Tsuji–Trost reaction and a sequence relying on an oxidative diyne cyclization and regioselective opening of the intermediate metallacycles. These methods enable a highly concise synthesis of key structural elements of complex polyketides.
    No preview · Chapter · Jun 2014
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    ABSTRACT: Covering: the literature up to 2012This review presents recent advances in sequential catalytic methods developed in our group for the rapid and stereoselective synthesis of key structural features of complex polyketides. These include a novel domino reaction, based on a combination of a nucleophilic addition and a Tsuji-Trost reaction, an innovative sequence relying on an oxidative diyne cyclization and regioselective opening, as well as sequential cross coupling strategies. The design and scope of these methods are discussed and applications in complex target syntheses presented.
    No preview · Article · Dec 2013 · Natural Product Reports
  • Sebastian Essig · Dirk Menche
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    ABSTRACT: Polyketides are a very diverse family of natural products with an extremely broad range of biological activities and pharmacological properties, including antiproliferative, antibiotic, antifungal, or antiplasmodial activities, and in many cases specific targets are addressed at the molecular level. Their structures are characterized by diverse assemblies of methyl- and hydroxyl-bearing stereogenic centers enabling large numbers of stereochemical permutations, which are often embedded into macrolide rings. This complexity renders the stereochemical assignment and directed total synthesis challenging tasks. Within this review, we will detail practicable approaches for the stereochemical determination of diverse complex polyketides of myxobacterial origin by using computational and NMR methods in combination with novel procedures based on bioinformatics. Furthermore, we have developed efficient preparative strategies for the synthesis of these compounds, which have culminated in several first total syntheses. Key aspects of these various endeavors, which will also focus on the importance of conformational bias in complex polyketide analysis and synthesis, will be discussed within this review in the realm of the potent macrolide antibiotics etnangien and rhizopodin. Along these lines, we will also summarize novel methods for the rapid assembly of key structural elements of polyketides including a novel domino concept relying on a combination of a nucleophilic addition and a Tsuji-Trost reaction.
    No preview · Article · Oct 2013 · ChemInform
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    ABSTRACT: A highly convergent total synthesis of the potent polyketide macrolide rhizopodin has been achieved in 29 steps by employing a concise strategy that exploits the molecule's C2 symmetry. Notable features of this convergent approach include a rapid assembly of the macrocycle through a site-directed sequential cross-coupling strategy and the bidirectional attachment of the side chains by means of Horner-Wadsworth-Emmons (HWE) coupling reactions. During the course of this endeavor, scalable routes for synthesis of three main building blocks of similar complexity were developed that allowed for their stereocontrolled construction. This modular route will be amenable to the development of syntheses of other analogues of rhizopodin.
    No preview · Article · Oct 2013 · Chemistry - A European Journal
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    ABSTRACT: The aldol addition of an enol(ate) to a carbonyl compound is one of the most powerful and versatile C-C bond forming reactions. In complex target synthesis the coupling of two chiral partners may complicate the stereochemical outcome by multiple stereoinductions. Here, we report studies on pivotal aldol couplings employed in the rhizopodin synthesis, detailing the various directing effects exerted by the stereogenic centers present in this sterically hindered connection.
    No preview · Article · Aug 2013 · Synthesis
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    ABSTRACT: Marine myxobacteria (Enhygromyxa, Plesiocystis, Pseudoenhygromyxa, Haliangium) are phylogenetically distant from their terrestrial counterparts. Salimabromide is the first natural product from the Plesiocystis/Enhygromyxa clade of obligatory marine myxobacteria. Salimabromide has a new tetracyclic carbon skeleton, comprising a brominated benzene ring, a furano lactone residue, and a cyclohexane ring, bridged by a seven-membered cyclic moiety. The absolute configuration was deduced from experimental and calculated CD data. Salimabromide revealed antibiotic activity towards Arthrobacter cristallopoietes.
    No preview · Article · Jul 2013 · Chemistry - A European Journal
  • Liang Wang · Dirk Menche
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    ABSTRACT: Pd-catalyzed treatment of unsaturated alcohols of type (I) with nitro olefins provides a new and efficient approach to multisubstituted tetrahydropyrans, which are of synthetic and biological interest.
    No preview · Article · Jun 2013 · ChemInform

Publication Stats

1k Citations
420.62 Total Impact Points


  • 2011-2015
    • University of Bonn
      • Kekulé Institute of Organic Chemistry and Biochemistry
      Bonn, North Rhine-Westphalia, Germany
  • 2008-2012
    • Universität Heidelberg
      • Institute of Organic Chemistry
      Heidelburg, Baden-Württemberg, Germany
  • 2007-2011
    • Helmholtz Centre for Infection Research
      • • Department of Chemical Biology (CBIO)
      • • Department of Medicinal Chemistry (MCH)
      Brunswyck, Lower Saxony, Germany
  • 2004-2005
    • University of Cambridge
      Cambridge, England, United Kingdom
  • 2003
    • University of Cologne
      • Institute of Organic Chemistry
      Köln, North Rhine-Westphalia, Germany