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Novel nitrogenous metabolites from marine sponges

University of British Columbia

An investigation into the chemistry of four species of marine sponges has led to the isolation of twenty-two new natural products. The structures of these novel compounds were determined by spectroscopic analysis and chemical interconversion. The metabolites were tested in a variety of bioassays. Methanol extracts of the marine sponge Xestospongia ingens were found to be cytotoxic against murine leukemia P388. Fractionation of the crude extract led to the identification of two classes of biologically active alkaloids with novel heterocyclic skeletons. Ingenamine (27) is the first example of a new class of cytotoxic pentacyclic alkaloids that appears to arise biogenetically from an intramolecular [4+2] cycloaddition reaction. The discovery of the ingenamine type compounds strongly supported Baldwin and Whitehead's proposal for the biosynthesis of the manzamines, since the ingenamine skeleton corresponded to their proposed pentacyclic intermediate. Ingenamine showed in vitro cytotoxicity against murine leukemia P388 with an ED₅₀ value of 1 μg/mL. Madangamine A (30) represented the first example of another new class of pentacyclic alkaloids. It was proposed that the biosynthesis of madangamine involves the rearrangement of an ingenamine type precursor. Madangamine A also showed in vitro cytotoxicity against murine leukemia P388 (ED₅₀ 0.93 μg/mL), human lung A549 (ED₅₀ 14 μg/mL), brain U373 (ED₅₀ 5.1 μg/mL), and breast MCF-7 (ED₅₀ 5.7 μg/mL) cancer cell lines. The structures of ingenamine (27) and madangamine A (30) were elucidated by extensive analyses of spectroscopic data. The absolute configuration of ingenamine was determined by Mosher's ester methodology. Eight additional 'ingenamine' alkaloids (31 - 34, 36 - 39) and four additional 'madangamine' alkaloids (48 - 51) were also isolated from this sponge. Examination of the Norwegian sponge Polymastia boletiformis collected off the Korsnes Peninsula on Fanafjiord south of Bergen, Norway yielded six new metabolites, the steroid/amino acid conjugates, polymastiamides A-F (65, 68, 70, 72, 74, 76). The structure of polymastiamide A (65), isolated as the natural product, was elucidated by spectroscopic analysis as well as chemical degradation. The relative stereochemistry of the steroidal nucleus was obtained by comparison with previously reported data. The remaining analogs, polymastiamides B-F (68, 70, 72, 74, 76), were hydrolyzed to remove the sulfate groups and then converted to methyl esters in order to exploit the convenience and efficiency of normal phase HPLC separation and purification techniques. Polymastiamide A (65) exhibited in vitro antimicrobial activity against various human and plant pathogens [MIC's in a 1/4-in. disk assay: Staphylococcus aureus (100μg/disk), Candida albicans (75 μg/disk) andpythium ultimum (25 μg/disk)]. The study of two Papua New Guinea sponges led to the isolation and identification of two new peptides. A novel cyclic heptapeptide pseudaxinellin (87) was isolated from Pseudaxinella massa. Pseudaxinellin (87) contained standard protein amino acid residues with the L configuration. A new cyclic depsipeptide, geodiamolide G (111), was obtained from the sponge Cymbastela sp., together with the known metabolites geodiamolides A-F (89 - 94). [chemical compound diagrams]

Thesis/Dissertation

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2009-04-15

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http://hdl.handle.net/2429/7151

Chemistry

University of British Columbia

UBCV

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