| Summary: | 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]
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