Biogenesis of axially chiral biaryl alkaloids from plants

GERHARD BRINGMANN
Institut für Organische Chemie der Universität
Am Hubland
D-97074 Würzburg
bringman@chemie.uni-wuerzburg.de
http://www-organik.chemie.uni-wuerzburg.de/

This interdisciplinary project (Natural Product Chemistry - Plant Molecular Biology) aims at the elucidation of the unprecedented biosynthesis of the axially chiral naphthylisoquinoline alkaloids, in collaboration with Prof. Kutchan's group. It is text book knowledge that isoquinolines are formed from aromatic amino acids like L-tryrosine in nature. The naphthylisoquinoline alkaloid dioncophylline A, however, the most prominent representative of this new class of intriguing secondary metabolites from tropical Ancistrocladaceae and Dioncophyllaceae plants, originates from acetate units, exclusively. We have shown that both molecular halves, the isoquinoline part and the naphthalene portion, are formed from identical polyketide precursors. Besides the search for biosynthetic precursors of the alkaloids (including molecular halves and biosynthetic intermediates) in Ancistrocladaceae and Dioncophyllaceae plants by applying modern hyphenated techniques (i.a., LC-NMR, LC-MS/MS, and LC-CD), this project mainly deals with the elucidation of key steps and the characterization of the respective enzymes involved in the construction of the unusual carbon skeleton of those acetogenic naphthylisoquinolines. Combining techniques for isotope labelling synthesis, feeding experiments, and trace analysis of putative intermediates (Bringmann's group) with enzymological and molecular genetic methods (Kutchan's group), the following objectives are in the scope of the project:

(1) Development of synthetic pathways to postulated intermediates (e.g., open-chain polyketones, monocyclic diketones, the free bicyclic isoquinoline and naphthalene moieties, primary coupling products) and search for them in the plants and in cell cultures.

(2) Synthesis of ¹³C and/or ¹⁵N labeled compounds to probe their identity as authentic biosynthetic precursors by feeding experiments.

(3) Collaboration with the Kutchan group concerning the development of test systems for the identification of the respective enzymes, like, e.g., polyketide synthase(s) and enzymes catalyzing the N-incorporation and the C-C phenol-oxidative cross-coupling reaction, and the search for the genes encoding the biosynthetic enzymes.

A second minor project deals with the axially chiral biscarbazole alkaloids from Rutaceae plants, and with their biosynthetic origin from indol or tryptophan involving a prenylation at C-2 and oxidative ring closure, followed by phenol-oxidative coupling to give the intact dimeric alkaloid.

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