Extending structure-activity-relationship studies of bioactive natural products by novel iminonitroso cycloaddition chemistry

Abstract number: 1733_1585

Miller M., Moellmann U., Li F., Yang B., Zoellner T., Gebhardt P., Dahse H., Miller P.

Objectives: Healthcare problems caused by multidrug-resistant microbes are increasing constantly. However, the pipeline for novel drug candidates is substantially unfilled. Natural products and their derivatives remain a significant source of molecular diversity for drug discovery. However, the development of highly efficient and versatile natural product derivatisation methods remains a challenge. Classical derivatisation methods are often limited to standard modification of nucleophilic or electrophilic functional groups and selectivity is problematic.

Here we report the use of stabilised iminonitroso Diels-Alder reactions for derivatisation of complex diene-containing natural products. This totally atom economical cycloaddition reaction produces conformationally restricted analogs and introduces new functionality to rarely modified centres, diene or polyene components, of bioactive natural products in a highly regio- and stereoselective and chemically efficient fashion.

Methods: Six natural products (turimycin H3, ergosterol, reductiomycin, isoforocidin, colchicine and thebaine) were selected for our initial studies using nitrosopyridine Diels-Alder reactions. The configuration of cycloadducts was assigned based on 1D and 2D high resolution NMR studies, 1H NMR analysis, NOE correlations from ROESY experiments and X-ray crystallographic analyses. Bioactivity of the cycloadducts was studied against bacteria, yeast and fungi. Different cell lines were used for antiproliferative and cytotoxicity assays.

Results: The reactions with nitroso dienophiles proceeded in 10–20 min to afford the corresponding oxazine cycloadducts as single isomers in ~90% yield and with excellent regio- and stereoselectivity for all of the substrates examined.

Incorporation of the oxazine heterocycles altered the biological activity profile of the corresponding parent natural products. While the cycloaddition products of turimycin retained reduced, but did not eliminate, antibacterial activity, antiproliferative activity was introduced. Biological activity studies of related cycloadducts of all of the other natural products mentioned will be presented as well.

Conclusion: The methodology presented herein provides a highly efficient and atom economical tool for derivatisation and functionalisation of complex diene-containing bioactive natural products at rarely modified centres. It provides a new basis towards structural diversity for drug discovery.

Session Details

Date: 31/03/2007
Time: 00:00-00:00
Session name: European Society of Clinical Microbiology and Infectious Diseases
Location: ICC, Munich, Germany
Presentation type:
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