Chemical and Biological Aspects of Secondary Metabolites from Tongan Marine Sponges

<p>This thesis describes the isolation and structural elucidation of 17 new secondary metabolites from Tongan marine sponges including examples of alkaloids, polyketides and terpenoids. In the process of this work, 19 sponge specimens were subjected to preliminary NMR-guided investigation. Nine organisms were selected for further analysis on the basis of the structural novelty perceived within the HMBC spectrum of crude fractions generated by the first chromatographic purification of their crude extracts, and the apparent rarity of the specimen. Investigation of two different demosponge specimens afforded the γ-hydroxybutenolide sesterterpenes (23 and 24), and small quantities of the potently cytotoxic alkaloid 14-bromohomofascaplysin (29). The analysis of two samples of a dictyoceratid sponge yielded the new labdane diterpenes luakuliides A–C (33–36), characterised by a bridging hemi-acetal function on the B-ring of the labdane bicycle. Luakuliide A (33) and its methyl acetal derivative 34 were found to display interesting immunomodulatory activity. Seven new α-pyrone polyketides, lehualides E–K (69–75), were isolated from a Plakortis sp. Lehualides H–K (72–75) display a range of sulfur functionalities, the natures of which were determined by spectroscopic comparison with synthesised model compounds. Another plakinid sponge specimen contained four new polyketides (95–98), all of which possess different cyclic peroxide moieties. Cyclic peroxides 95, 97 and 98 displayed potent cytoxicity against human promyelocytic leukemia cells (HL- 60). Chemical genetic and phenoytypic profiling studies of 95 were undertaken in Saccharomyces cerevisiae yeast using the homozygous diploid and heterozygous diploid deletion libraries. These studies indicate that 95 acts to disrupt Ca2+ homeostasis, leading to elevation of intracellular Ca2 levels.</p>

Chemical and Biological Aspects of Secondary Metabolites from Tongan Marine Sponges

<p>This thesis describes the isolation and structural elucidation of 17 new secondary metabolites from Tongan marine sponges including examples of alkaloids, polyketides and terpenoids. In the process of this work, 19 sponge specimens were subjected to preliminary NMR-guided investigation. Nine organisms were selected for further analysis on the basis of the structural novelty perceived within the HMBC spectrum of crude fractions generated by the first chromatographic purification of their crude extracts, and the apparent rarity of the specimen. Investigation of two different demosponge specimens afforded the γ-hydroxybutenolide sesterterpenes (23 and 24), and small quantities of the potently cytotoxic alkaloid 14-bromohomofascaplysin (29). The analysis of two samples of a dictyoceratid sponge yielded the new labdane diterpenes luakuliides A–C (33–36), characterised by a bridging hemi-acetal function on the B-ring of the labdane bicycle. Luakuliide A (33) and its methyl acetal derivative 34 were found to display interesting immunomodulatory activity. Seven new α-pyrone polyketides, lehualides E–K (69–75), were isolated from a Plakortis sp. Lehualides H–K (72–75) display a range of sulfur functionalities, the natures of which were determined by spectroscopic comparison with synthesised model compounds. Another plakinid sponge specimen contained four new polyketides (95–98), all of which possess different cyclic peroxide moieties. Cyclic peroxides 95, 97 and 98 displayed potent cytoxicity against human promyelocytic leukemia cells (HL- 60). Chemical genetic and phenoytypic profiling studies of 95 were undertaken in Saccharomyces cerevisiae yeast using the homozygous diploid and heterozygous diploid deletion libraries. These studies indicate that 95 acts to disrupt Ca2+ homeostasis, leading to elevation of intracellular Ca2 levels.</p>