Natural products from some marine invertebrates

Abstract

This thesis describes the chemical investigation of several marine organisms from Eastern Australia waters. A sponge of the genus Haliclona collected from the Great Barrier Reef was shown to contain the bioactive tertiary alkaloids, haliclonacyclamines A-C (116,118 and 121, respectively). The structure of haliclonacyclamine A was unambiguously determined by high field NMR methods and low temperature single crystal structure analysis to be a tetracyclic alkaloid containing two hexahydropyridine rings in a trans arrangement in the central core. The relative stereochemistry of haliclonacyclamine A was partially deduced from NMR studies while the complete relative stereochemistry, and the position of the double bonds at C15-C16 and C25-C26, were determined by X-ray crystal structure analysis. The complete structure of haliclonacyclamine B was determined by modem NMR techniques revealing it to be a tetracylic alkaloid with double bonds at C15-C16 and C29-C30, and hence an isomer of haliclonacyclamine A. The X-ray crystal structure investigation of haliclonacyclamine B gave incomplete data, however sufficient data was obtained to confirm the relative stereochemistry of the methine protons in the central core and the position of the double bond at C15-C16. Methylation of haliclonacyclamine A and B provided the bismethiodide derivatives 117 and 119, respectively. Derivative 119 was used to complete the structure elucidation of 118 mainly by the use of DQFCOSY and the recently developed geHSQC and geHMBC NMR experiments. Interpretation of the NMR data of derivative 119 was used to provide complementary evidence for the structure of haliclonacyclamine B. Hydrogenation of 116 and 118 provided a single tetrahydro product 120 and confirmed that 116 and 118 had identical ring stereochemistry. The partial structure of haliclonacyclamine C was shown by NMR methods to be a dihydro analogue of 116 and 118.The biological activities and structure-activity relationships of haliclonacyclamines A-C, and selected derivatives of 116 and/or 118 in P388, anti-microbial and anti-fungal cell lines are described. The tertiary amines were found to be cytotoxic and displayed potent activity in all the assays. In contrast the tetrahydro, bismethiodide, bis-epoxidebis-N-oxide and dibromo derivatives were generally found to be less active in all the bioassays. Cell separation experiments by density gradient centrifugation methods have indicated that haliclonacyclamines A-C can be attributed to the sponge and not a dinoflagellate symbiont, morphologically similar to Symbiodinium microadriaticum, which was found to be present in the sponge.Investigation of a verongiid sponge, Pseudoceratina durrissima, resulted in the isolation of hexadellin A (142) and uranidine (144) and another sponge of the genus Ectyodoryx yielded the carotenoid astaxanthin (145).Polypropionate derived metabolites were isolated from two opisthobranch molluscs Bulla vernicosa and Bulla angasi. The known compounds niuhinone-B (159) and 5,6-dehydroaglajne-3 (160) were isolated from B. vernicosa while B. angasi yielded the two new compounds niuhinol-1 (163) and niuhinol-3 (165). All the polypropionate metabolites were structurally characterised by NMR spectroscopy, including 2D NMR methods. A 4-bromophenylcarbamate derivative (164) of niuhinol-1 is described as well as the oxidation product of niuhinol-1; The double bond stereochemistries of all the polypropionate metabolites were established by 1H and 13C NMR spectroscopy. The absolute stereochemistry in 163 and 165 at one of the chiral centres, C16, is S.