UBC Theses and Dissertations

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UBC Theses and Dissertations

New cytotoxic natural products from North-Eastern Pacific marine invertebrates Pika, Jana


An investigation into the chemistry of four species of marine invertebrates which were found to produce cytotoxic crude extracts (ED50 against the L1210 murine leukemia cell line 5 30 pg/mL) led to the isolation of nine new and eleven previously known secondary metabolites. The structures of the novel compounds were elucidated by a combination of spectroscopic analysis and chemical interconversion. The metabolites were tested against the in vitro L1210 murine leukemia, the drug-sensitive MCF-7, or the drug-resistant MCF-7 Adr breast cancer cell lines. Investigation of the cytotoxic extracts of the marine sponge Aplysilla glacialis led to the identification of the novel 9, 11-secosteroids glaciasterol A (100) and glaciasterol B (101). These compounds are the first examples of secosteroids isolated from a sponge of the genus Aplysilla. Glaciasterol A (100) proved active in vitro against theMCF-7 human breast cancer cell line at an ED50 of 19 pg/mL. The ED50 for Glaciasterol A (100) against the drug-resistant MCF-7 Adr breast cancer cell line was 18 tig/mL. The structures of the glaciasterols were determined by aseries of chemical interconversions in addition to extensive analysis of spectroscopic data. Glaciasterol B diacetate (107) was one of the derivatives synthesized and it proved to be the most active in the cytotoxicity assays.Glaciasterol B diacetate was active against both the MCF-7 and the drug-resistant MCF-7 Adr cell lines with ED50values of 1.8 pg/mL. A study of the metabolites of a gray-white sponge collected off the coast of Vancouver Island yielded the new cytotoxic secosteroid blancasterol (102). Blancasterol (102) was found to be active against the MCF-7 and drug-resistant MCF-7 Adr breast cancer cell lines with ED50 values of 3 g.ig/mL and 10.6 pg/mL, respectively. The new sesquiterpenes 0-methyl 9-oxofurodysinin lactone (72), 2-oxomicrocionin-2 lactone (73), 0-methyl2-oxomicrocionin-2 lactone (74) as well as seven previously reported sesquiterpenes (35, 36, 56, 57, 41, 43, and 44)were also isolated from the sponge extract. An understanding of the secondary metabolism of the invertebrate was useful in identifying the sponge as a Pleraplysilla species, the first found off the west coast of North America. Langarin (142) proved to be the cytotoxic component of the extract of an undescribed species of Aplidium, a compound tunicate found in the waters off the Queen Charlotte Islands. Langarin (142) was active in vitro againstL1210 murine leukemia cells with an ED50 of 0.44g/mL. Examination of extracts of the colonial tunicate Aplidium californicum resulted in the isolation of two new prenylated hydroquinone derivatives (160 and 161) as well as the known compounds 149, 150, 152, and 158. Compound 152 was tested in vitro against the L1210 murine leukemia cell line and found to be cytotoxic with anED50 value of 3.9 pg/mL.

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