Potential anti-tumour compounds from marine sources
Degree GrantorUniversity of Canterbury
Degree NameDoctor of Philosophy
The search for potential anti-tumour compounds from marine sources has covered many areas of research. Initial investigations were made to ascertain any drug mode of action information contained in the readings of our in-house antiviral/cytotoxicity assays. These results, utilising clinical drugs with known modes of action, failed to indicate any obvious correlations. The extract of a New Zealand ascidian, Aplidium species D, was studied because extracts prepared from it always exhibited a wide range of biological activities. Bioassay directed fractionation led to the isolation of a novel metabolite cis-5-hydroxy-4-(4'-hydroxy-3'-methoxyphenyl)-4-(2"-imidazolyl)-1,2,3-trithiane, trithiane A. The structure was solved by extensive use of mass and NMR spectroscopy. The compound was found to be stable in acidified solutions, but under alkaline conditions was observed to interconvert to the 4-epi derivative, trithiane B and to decompose to 2-vanilloyl imidazole. Two competing base catalysed mechanisms were proposed to account for these observations. The relative stereochemistries of trithiane A and B were established by ¹H NMR NOE experiments, application of the modified Karplus equation and molecular mechanics modelling. Numerous attempts were made to crystallise trithiane A and to make crystalline derivatives. Only one reaction, oxidation to the monosulphoxide, gave any isolable products. The trithianes were found to be cytotoxic to both BSC monkey kidney cells and P388 leukemia cells and modestly inhibitory to bacteria and fungi. No efficacy against in vitro viruses was observed. A study based upon the chemical modification of discorhabdin C was carried out in order to produce compounds with more effective in vivo activity than discorhabdin C and to explore the structural features that could be responsible for the observed bioactivities of the discorhabdins. To this end, a new discorhabdin, E, was isolated and identified and six new derivatives were synthesised and characterised. Analysis of the biological activities of the discorhabdin derivatives suggested that structural features of ring E and possibly electron distribution changes in the iminoquinone moiety were responsible for the observed bioactivities.