Sonderforschungsbereich 630

    A2 Bringmann

    Project Part A2

    A New Class of Agents against Pathogens of Tropical Diseases

    Prof. Dr. Dr. h.c. mult. Gerhard Bringmann

    Institute for Organic Chemistry

    As a rich source of novel natural products and promising agents against infectious diseases we have identified the Ancistrocladaceae (i.e., hooked-twig plants) and the Dioncophyllaceae (i.e., clawed-leaves plants). These are – also botanically intriguing – lianas from the tropical rainforests of Africa and Asia, which are used in the traditional medicine of their countries of origin. As an example, the West African liana Triphyophyllum peltatum produces dioncophylline A and C,  and a plethora of further related so-called naphthylisoquinoline alkaloids. Of these natural products ca. 130 representatives are known today (most of them originally detected in Würzburg!). They are unique by their stereochemically interesting (since rotationally hindered) biaryl axis between the two molecular halves and by their unprecedented biosynthetic origin from acetate units. But in particular, these alkaloids are pharmaceutically most promising: they exhibit an interesting spectrum of excellent in vitro activities against protozoan pathogens like plasmodia, leishmania and trypanosoma. Recently, a novel type of such alkaloids has been discovered, viz., the first N,C-coupled naphthylisoquinoline alkaloids like ancistrocladinium A und B. They possess as an unusual structural feature a yet unprecedented iminium-nitrogen-aryl axis. In addition, they were shown to have promising antileishmanial activities with a comparably low cytotoxicity against mammalian cells.

    Project A2 aims at the identification, isolation, and structural elucidation of antiinfective naphthylisoquinoline alkaloids, the development of new strategies towards the syntheses of naphthylisoquinolines and structurally simplified analogs and at the evaluation of their antiinfective activities in cooperation with our partners within the SFB and with external partners, by structure-activity relationship studies (SAR studies) and by investigations on the mode of action of these compounds. For this purpose, we have developed a broad array of methods, which includes chromatographic and spectroscopic techniques, among them a most efficient analytical triad consisting of the three coupling methods HPLC-MS/MS, HPLC-NMR, and HPLC-CD, as well as methods for the chemical degradation, computer-assisted theoretical calculations, and novel principles for the directed synthetic construction of these bioactive compounds.

    Selected, SFB-relevant Publications

    M. Lödige, M. D. Lewis, E. S. Paulsen, H. L. Esch, G. Pradel, L. Lehmann, R. Brun, G. Bringmann, A. K. Mueller; A primaquine-chloroquine hybrid with dual activity against Plasmodium liver and blood stages. Int J Med Microbiol 2013. doi:10.1016/j.ijmm.2013.07.005

    G. Bringmann, K. Thomale, S. Bischof, C. Schneider, M. Schultheis, T. Schwarz, H. Moll, U. Schurigt; A Novel Leishmania major Amastigote Assay in 96-Well Format for Rapid Drug Screening and its Use for the Discovery and Evaluation of a New Class of Leishmanicidal Quinolinium Salts. Antimicrob Agents Chemother 2013. 57, 3003-30011. doi:10.1128/AAC.02201-12

    G. Bringmann, G. Zhang, T. Büttner, G. Bauckmann, T. Kupfer, H. Braunschweig, R. Brun, V. Mudogo; Jozimine A2: the first dimeric Dioncophyllaceae-type naphthylisoquinoline alkaloid, with three chiral axes and high antiplasmodial activity. Chemistry 2013, 19, 916-923. doi:10.1002/chem.201202755

    G. Bringmann, B. K. Lombe, C. Steinert, K. N. Ioset, R. Brun, F. Turini, G. Heubl, V. Mudogo; Mbandakamines A and B, Unsymmetrically Coupled Dimeric Naphthylisoquinoline Alkaloids, from a Congolese Ancistrocladus Species. Org Lett 2013, 15, 2590-2593. doi:10.1021/ol4005883

    G. Bringmann, G. Zhang, T. Olschläger, A. Stich, J. Wu, M. Chatterjee, R. Brun; Highly selective antiplasmodial naphthylisoquinoline alkaloids from Ancistrocladus tectorius. Phytochemistry 2012.

    B. B. Messi, K. Ndjoko-Ioset, B. Hertlein-Amslinger, A. M. Lannang, A. E. Nkengfack, J. L. Wolfender, K. Hostettmann, G. Bringmann; Preussianone, a new flavanone-chromone biflavonoid from Garcinia preussii Engl. Molecules 2012, 17, 6114-6125. doi:10.3390/molecules17056114

    C. Almeida, Y. Hemberger, S. M. Schmitt, S. Bouhired, L. Natesan, S. Kehraus, K. Dimas, M. Gutschow, G. Bringmann, G. M. Konig; Marilines A-C: novel phthalimidines from the sponge-derived fungus Stachylidium sp. Chemistry 2012, 18, 8827-8834. doi:10.1002/chem.201103278

    S. M. Pimentel-Elardo, V. Buback, T. A. Gulder, T. S. Bugni, J. Reppart, G. Bringmann, C. M. Ireland, T. Schirmeister, U. Hentschel; New tetromycin derivatives with anti-trypanosomal and protease inhibitory activities. Mar Drugs 2011, 9, 1682-1697.

    L. Liu, T. Bruhn, L. Guo, D. C. Gotz, R. Brun, A. Stich, Y. Che, G. Bringmann; Chloropupukeanolides C-E: cytotoxic pupukeanane chlorides with a spiroketal skeleton from Pestalotiopsis fici. Chemistry 2011, 17, 2604-2613.

    E. Kugelmann, C. R. Albert, G. Bringmann, U. Holzgrabe; Fenton's oxidation: a tool for the investigation of potential drug metabolites. J Pharm Biomed Anal 2011, 54, 1047-1058.

    A. Cecil, C. Rikanovic, K. Ohlsen, C. Liang, J. Bernhardt, T. A. Oelschlaeger, T. Gulder, G. Bringmann, U. Holzgrabe, M. Unger, T. Dandekar; Modeling antibiotic and cytotoxic effects of the dimeric isoquinoline IQ-143 on metabolism and its regulation in Staphylococcus aureus, Staphylococcus epidermidis and human cells. Genome Biol 2011, 12, R24.

    C. Buchold, Y. Hemberger, C. Heindl, A. Welker, B. Degel, T. Pfeuffer, P. Staib, S. Schneider, P. J. Rosenthal, J. Gut, J. Morschhauser, G. Bringmann, T. Schirmeister; New cis-configured aziridine-2-carboxylates as aspartic acid protease inhibitors. ChemMedChem 2011, 6, 141-152.

    G. Bringmann, B. Hertlein-Amslinger, I. Kajahn, M. Dreyer, R. Brun, H. Moll, A. Stich, K. N. Ioset, W. Schmitz, L. H. Ngoc; Phenolic analogs of the N,C-coupled naphthylisoquinoline alkaloid ancistrocladinium A, from Ancistrocladus cochinchinensis (Ancistrocladaceae), with improved antiprotozoal activities. Phytochemistry 2011, 72, 89-93.

    G. Bringmann, T. Gulder, T. A. Gulder, M. Breuning; Atroposelective total synthesis of axially chiral biaryl natural products. Chem Rev 2011, 111, 563-639.

    G. Bergner, C. R. Albert, M. Schiller, G. Bringmann, T. Schirmeister, B. Dietzek, S. Niebling, S. Schlucker, J. Popp; Quantitative detection of C-deuterated drugs by CARS microscopy and Raman microspectroscopy. Analyst 2011, 136, 3686-3693.

    G. Bringmann, G. Lang, T. Bruhn, K. Schäffler, S. Steffens, R. Schmaljohann, J. Wiese, J.F. Imhoff; Sorbifuranones A-C, sorbicillinoid metabolites from Penicillium strains isolated from Mediterranean sponges. Tetrahedron 2010, doi:10.1016/J.tet.2010.10.057.

    A. Ponte-Sucre, T. Gulder, T.A.M. Gulder, G. Vollmers, G. Bringmann, H. Moll; Alterations to the structure of Leishmania major induced by N-arylisoquinolines with compound accumulation and disposition. J Med Microbiol 2010, 59, 69-75.

    M. Xu, T. Bruhn, B. Hertlein, R. Brun, A. Stich, J. Wu, G. Bringmann; Shuangancistrotectorines A-E, dimeric naphthylisoquinoline alkaloids with three chiral biaryl axes from the Chinese plant Ancistrocladus tectorius. Chem Eur J 2010, 16, 4206-4216 (with cover picture).

    G. Bringmann, S.K. Bischof, S. Müller, T. Gulder, C. Winter, A. Stich, H. Moll, M. Kaiser, R. Brun, J. Dreher, K. Baumann; QSAR-guided synthesis of simplified antiplasmodial analogs of naphthylisoquinoline alkaloids. Eur J Med Chem 2010, 45, 5370-5383.

    G. Bringmann, T. Gulder, B. Hertlein, Y. Hemberger, F. Meyer; Total synthesis of the N,C-coupled naphthylisoquinoline alkaloids ancistrocladinium A and B and related analogues. J Am Chem Soc 2010, 132, 1151-1158.

    G. Fan, Z. Li, S. Shen, Y. Zeng, Y. Yang, M. Xu, T. Bruhn, H. Bruhn, J. Morschhäuser, G. Bringmann, W. Lin; Baculiferins A-O, O-sulfated pyrrole alkaloids with anti-HIV activity, from the Chinese marine sponge Iotrochota baculifera. Bioorg Med Chem 2010, 18, 5466-5474.

    U. Hentschel, G. Bringmann; Marine Schwämme: Füllhorne der Meere. Suche nach neuen Wirkstoffen aus der Natur. Pharm Unserer Zeit 2010, 39, 62-66.

    A. Ponte-Sucre, T. Gulder, A. Wegehaupt, C. Albert, C. Rikanović, L. Schaeflein, A. Frank, M. Schultheis, M. Unger, U. Holzgrabe, G. Bringmann, H. Moll; Structure-activity relationship and studies on the molecular mechanism of leishmanicidal N,C-coupled arylisoquinolinium salts. J Med Chem 2009, 52, 626-636.

    G. Bringmann, T. Bruhn, K. Maksimenka, Y. Hemberger; The assignment of absolute stereostructures through quantum chemical circular dichroism calculations. Eur J Org Chem 2009, 2717-2727.

    G. Bringmann, K. Maksimenka, T. Bruhn, M. Reichert, T. Harada, R. Kuroda; Quantum chemical CD calculations of dioncophylline A in the solid state. Tetrahedron 2009, 65, 5720-5728.

    G. Bringmann, S. Rüdenauer, T. Bruhn, L. Benson, R. Brun; Total synthesis of the antimalarial naphthylisoquinoline alkaloid 5-epi-4‘-O-demethylancistrobertsonine C by asymmetric Suzuki cross-coupling. Tetrahedron 2008, 64, 5563-5568.

    S.M. Pimentel-Elardo, T.A.M. Gulder, U. Hentschel, G. Bringmann; Cebulactams A1 und A2, new macrolactams isolated from Saccharopolyspora cebuensis, the first obligate-marine strain of the genus Saccharopolyspora. Tetrahedron Lett 2008, 49, 6889-6892.

    G. Bringmann, M. Kaiser, R. Brun, S. Neumann; Synthesis and antitrypanosomal activities of simplified analogs of naphthylisoquinoline alkaloids. Eur J Med Chem 2008, 43, 32-42.

    G. Bringmann, J. Spuziak, J.H. Faber, T. Gulder, I. Kajahn, M. Dreyer, G. Heubl, R. Brun, V. Mudogo; Six naphthylisoquinoline alkaloids and a related benzopyranone from a Congolese Ancistrocladus species related to Ancistrocladus congolensis. Phytochemistry 2008, 69, 1065-1075.

    K.F. Schwedhelm, M. Horstmann, J.H. Faber, Y. Reichert, M. Büchner, G. Bringmann, C. Faber; Spin state of chloroquine-heme complexes: formation of a hemin tetramer adduct. Open Spectrosc J 2008, 2, 10-18.

    G. Bringmann, S. Rüdenauer, A. Irmer, T. Bruhn, R. Brun, T. Heimberger, T. Stühmer, R. Bargou, M. Chatterjee; Antitumoral and antileishmanial dioncoquinones and ancistroquinones from cell cultures of Triphyophyllum peltatum (Dioncophyllaceae) and Ancistrocladus abbreviatus (Ancistrocladaceae). Phytochemistry 2008, 69, 2501-2509.

    G. Bringmann, T.A.M. Gulder, M. Reichert, T. Gulder; The online assignment of the absolute configuration of natural products: HPLC-CD in combination with quantum chemical CD calculations. Chirality 2008, 20, 628-642.

    A. Ponte-Sucre, J.H. Faber, T. Gulder, I. Kajahn, S.E.H. Pedersen, M. Schultheis, G. Bringmann, H. Moll; Activities of naphthylisoquinoline alkaloids and synthetic analogs against Leishmania major. Antimicrob. Agents Chemother. 2007, 51, 188-194.

    T. Frosch, M. Schmitt, T. Noll, G. Bringmann, K. Schenzel, J. Popp; Ultrasensitive in situ tracing of the alkaloid dioncophylline A in the tropical liana Triphyophyllum peltatum by applying deep-UV resonance Raman microscopy. Anal. Chem. 2007, 79, 986-993.

    T. Frosch, M. Schmitt, G. Bringmann, W. Kiefer, J. Popp; Structural analysis of the anti-malaria active agent chloroquine under physiological conditions. J. Phys. Chem. B 2007, 111, 1815-1822.

    K.F. Schwedhelm, M. Horstmann, J.H. Faber, Y. Reichert, G. Bringmann, C. Faber; The novel antimalarial compound dioncophylline C forms a complex with heme in solution. ChemMedChem 2007, 2, 541-548.

    G. Bringmann, C.M. Gampe, Y. Reichert, T. Bruhn, J.H. Faber, M. Mikyna, M. Reichert, M. Leippe, R. Brun, C. Gelhaus; Synthesis and pharmacological evaluation of fluorescent and photoactivatable analogues of antiplasmodial naphthylisoquinolines. J. Med. Chem. 2007, 50, 6104-6115.

    S. Cîntă-Pînzaru, N. Peica, B. Küstner, S. Schlücker, M. Schmitt, T. Frosch, J. H. Faber, G. Bringmann, J. Popp; FT-Raman and NIR-SERS characterization of the antimalarial drugs chloroquine and mefloquine and their interaction with hematin. J. Raman Spectrosc. 2006, 37, 326-334.

    G. Bringmann, T. Gulder, M. Reichert, F. Meyer; Ancisheynine, the first N,C-coupled naphthylisoquinoline alkaloid: total synthesis and stereochemical analysis. Org. Lett. 2006, 8, 1037-1040.

    T. Frosch, M. Schmitt, K. Schenzel, J.H. Faber, G. Bringmann, W. Kiefer, J. Popp; In vivo localization and identification of the antiplasmodial alkaloid dioncophylline A in the tropical liana Triphyophyllum peltatum by a combination of fluorescence, near infrared fourier transform Raman microscopy, and density functional theory calculations. Biopolymers 2006, 82, 295-300.

    P. Kapková, E. Heller, E. Kugelmann, J. Faber, G. Bringmann, U. Kessler, G. Folkers, U. Holzgrabe; Random chemistry as a new tool for the generation of small-compound libraries. Arch. Pharm. Chem. Life Sci. 2006, 339, 489-497.

    G. Bringmann, H. Scharl, K. Maksimenka, K. Radacki, H. Braunschweig, P. Wich, C. Schmuck; Atropodiastereoselective cleavage of configurationally unstable biaryl lactones with amino acid esters. Eur. J. Org. Chem. 2006, 4349-4361.

    M. Sieber, W. Dekant, J.H. Faber, G. Bringmann; Biotransformation and pharmacokinetics of the antiplasmodial naphthylisoquinoline alkaloid dioncophylline A. Xenobiotica 2006, 36, 750-762.

    M. Scheuermayer, T.A.M. Gulder, G. Bringmann, U. Hentschel; Rubritalea marina gen. nov., sp. nov., a marine respresentative of the phylum ‘Verrucomicrobia’, isolated from a sponge (Porifera). Int. J. Syst. Evol. Microbiol. 2006, 56, 2119-2124.

    K. Felgentreff, C. Beisswenger, M. Griese, T. Gulder, G. Bringmann, R. Bals; The antimicrobial peptide cathelicidin interacts with airway mucus. Peptides 2006, 27, 3100-3106.

    G. Bringmann, I. Kajahn, M. Reichert, S.E.H. Pedersen, J.H. Faber, T. Gulder, R. Brun, S.B. Christensen, A. Ponte-Sucre, H. Moll, G. Heubl, V. Mudogo; Ancistrocladinium A and B, the first N,C-coupled naphthyldihydroisoquinoline alkaloids, from a Congolese Ancistrocladus species. J. Org. Chem. 2006, 71, 9348-9356.

    G. Bringmann, M. Dreyer, H. Kopff, H. Rischer, M. Wohlfarth, H.A. Hadi, R. Brun, H. Meimberg, G. Heubl; ent-Dioncophylleine A and related dehydrogenated naphthylisoquinoline alkaloids, the first Asian Dioncophyllaceae-Type alkaloids, from the 'new' plant species Ancistrocladus benomensis.J. Nat. Prod. 2005, 68, 686-690.

    *G. Bringmann, A.J. Price Mortimer, P.A. Keller, M.J. Gresser, J. Garner, M. Breuning; Atroposelective synthesis of axially chiral biaryl compounds. Angew. Chem. 2005, 117, 5518-5563; Angew. Chem. Int. Ed. 2005, 44, 5384-5427.

    E. Sauer, M. Merdanovic, A. Price Mortimer, G. Bringmann, J. Reidl; PnuC and the utilization of the nicotinamide riboside analog 3-aminopyridine in Haemophilus influenza. Antimicrob. Agents Chemother. 2004, 48, 4532-4541.

    G. Bringmann, R.-M. Pfeifer, P. Schreiber, K. Hartner, N. Kocher, R. Brun, K. Peters, E.-M. Peters, M. Breuning; Synthesis and antitrypanosomal activity of 2-aminomethyl-1-(2-oxyphenyl)naphtha-lenes. Tetrahedron 2004, 60, 6335-6344.

    G. Bringmann, M. Dreyer, M. Michel, F.S.K. Tayman, R. Brun; Ancistroheynine B and two further 7,3'-coupled naphthylisoquinoline alkaloids from Ancistrocladus heyneanus. Phytochemistry 2004, 65, 2903-2907.

    G. Bringmann, M. Dreyer, J.H. Faber, P.W. Dalsgaard, D. Stærk, J.W. Jaroszewski, H. Ndangalasi, F. Mbago, R. Brun, S. Brøgger Christensen; Ancistrotanzanine C and related 5,1'- and 7,3'-coupled naphthylisoquinoline alkaloids from Ancistrocladus tanzaniensis. J. Nat. Prod. 2004, 67, 743-748.

    G. Bringmann, M. Dreyer, H. Rischer, K. Wolf, H.A. Hadi, R. Brun, H. Meimberg, G. Heubl; Ancistrobenomine A, the first naphthylisoquinoline oxygenated at Me-3, and related 5,1'-coupled alkaloids, from the "new" plant species Ancistrocladus benomensis. J. Nat. Prod. 2004, 67, 2058-2062.

    M. Unger, M. Dreyer, S. Specker, S. Laug, M. Pelzing, C. Neusüß, U. Holzgrabe, G. Bringmann; Analytical characterisation of crude extracts from an African Ancistrocladus species using high-performance liquid chromatography and capillary electrophoresis coupled to ion trap mass spectrometry. Phytochem. Anal. 2004, 15, 21-26.

    N. Stiefl, G. Bringmann, C. Rummey, K. Baumann; Evaluation of extended parameter sets for the 3D-QSAR technique MaP: Implications for interpretability and model quality exemplified by antimalarially active naphthylisoquinoline alkaloids. J. Comput.-Aided Mol. Des. 2003, 17, 347-365.

    G. Bringmann, C. Schneider, U. Möhler, R.-M. Pfeifer, R. Götz, L. Aké Assi, E.-M. Peters, K. Peters; Two atropisomeric N-methyldioncophyllines A and N-methylphylline, their naphthalene-free heterocyclic moiety, from Ancistrocladus barteri. Z. Naturforsch. 2003, 58b, 577-584.

    G. Bringmann, K. Messer, B. Schwöbel, R. Brun, L. Aké Assi; Habropetaline A, an antimalarial naphthylisoquinoline alkaloid from Triphyophyllum peltatum. Phytochemistry 2003, 62, 345-349.

    G. Bringmann, A. Hamm, M. Schraut; Atroposelective biaryl coupling with chiral catalysts: total synthesis of the antileishmanial naphthylisoquinoline alkaloids ancistrotanzanine B and ancistroealaine A. Org. Lett. 2003, 5, 2805-2808.

    G. Bringmann, M. Dreyer, J.H. Faber, P.W. Dalsgaard, D. Stærk, J.W. Jaroszewski, H. Ndangalasi, F. Mbago, R. Brun, M. Reichert, K. Maksimenka, S.
    Brøgger Christensen; Ancistrotanzanine A, the first 5,3'-coupled naphthylisoquinoline alkaloid, and two further, 5,8'-linked related compounds from the newly described species Ancistrocladus tanzaniensis. J. Nat. Prod. 2003, 66, 1159-1165.

    C.T. Pabel, J. Vater, C. Wilde, P. Franke, J. Hofmeister, B. Adler, G. Bringmann, J. Hacker,
    U. Hentschel; Antimicrobial activities and matrix-assisted laser desorption/ionization mass spectrometry of Bacillus isolates from the marine sponge Aplysina aerophoba. Marine Biotechnol. 2003, 5, 424-434.

    G. Bringmann, V. Hoerr, U. Holzgrabe, A. Stich; Antitrypanosomal naphthylisoquinoline alkaloids and related compounds. Pharmazie 2003, 58, 343-346.