An investigation into the chemistry of two species of marine sponges has led to the
isolation of eighteen new and twelve previously known secondary metabolites. The structures of
the new compounds were elucidated by a combination of spectroscopic analysis and chemical
degradation.
A study of the organic extracts of a pink sponge collected of the coast of British
Columbia led to the identification of botanones A to C (55-57), botanicol (58), cadlinolide C
methyl acetal (59), and cadlinoglycine (60). Botanones A to C (55-57) were the first examples
of diterpenoids with the degraded "labdane" skeleton to be isolated from a marine sponge.
Cadlinoglycine (59) and cadlinolide C methyl acetal (60) and were both thought to be isolation
artifacts. The novel secondary metabolites isolated from the pink sponge were useful in
identifying the sponge as a previously undescribed Aplysilla species.
The novel cyclic depsipeptides geodiamolides H to N (89-95) and P (97), as well as the
known cytotoxins geodiamolides A to G (77-83), were isolated during the bioassay guided
fractionation of the cytotoxic extracts of the marine sponge Cymbastela sp. Geodiamolides J to
N (91-95) and P (97) represented the first examples in the geodiamolide family in which a serine
residue had been incorporated.
Extracts of Cymbastela sp. also yielded the novel cytotoxic peptides hemiasterlin A (98),
hemiasterlin B (99), criamide A (100), and criamide B (101), in addition to the known peptide
hemiasterlin (86). Chemical degradation, followed by Marfey's amino acid analysis of
hemiasterlin (86), combined with single crystal X-ray diffraction analysis of hemiasterlin methyl
ester (141), established the absolute configuration of 86. Using a combination of chemical
degradation and C D analysis, the absolute configurations of hemiasterlin A (98) and hemiasterlin
B (99) were also determined. The hemiasterlins were shown to be potently cytotoxic in vitro against several cell lines,
and hemiasterlin (86) demonstrated promising activity in vivo against murine leukemia P388 in
mice. Studies on the mechanism of activity of hemiasterlin A (98) suggested that it exerted its
cytotoxic affects by inhibiting spindle microtubule dynamics. Both hemiasterlin (86) and
hemiasterlin A (98) were more potent cytotoxins and mitotic blockers than the known
microtubule inhibitors paclitaxel (113) and vinblastine (114).
The total synthesis of hemiasterlin (86) was accomplished. Using the methodology
developed in the total synthesis, several analogs were synthesized in the beginning of an
extensive structure activity study. [Molecular Structures]
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:BVAU.2429/8555 |
| Date | 05 1900 |
| Creators | Coleman, John Edward |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Relation | UBC Retrospective Theses Digitization Project [http://www.library.ubc.ca/archives/retro_theses/] |
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