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Chemical studies of Pacific Ocean sponges

University of British Columbia

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]

Thesis/Dissertation

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2009-06-02

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http://hdl.handle.net/2429/8555

Chemistry

University of British Columbia

UBCV

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