Studies on marine natural products

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Author
Date
1995Permanent Link
http://hdl.handle.net/10092/7850Thesis Discipline
ChemistryDegree Grantor
University of CanterburyDegree Level
DoctoralDegree Name
Doctor of PhilosophyThe halichondrins are a series of polyether macrolides displaying potent in vitro and in vivo antitumour activities and, as such, represent important leads as anticancer drugs. These compounds had previously been isolated from a number of unrelated marine sponges, such as Lissodendoryx sp., a high yielding deep-water sponge located off the Kaikoura coast of New Zealand. Structure-activity relationships in the halichondrin senes have now been investigated. Hemi-synthetic modifications of selected naturally-occurring halichondrins have produced over fourteen new analogues. The biological activities of twelve of these analogues have been assessed in an in-house P388 in vitro assay and in the National Cancer Institute's (USA) in vitro sixty cell-line human tumour panel. An analysis of these data has shown that the lactone ring (C1-C30), the olefinic functionalities (C19 and C26), the natural C38 stereochemistry and the tricyclo ring system (C-E rings) are essential structural features of the halichondrins. The characterisation of the hemi-synthetic derivatives has been facilitated by the full NMR spectroscopic assignments of halichondrin B and homohalichondrin B. The future progress of the halichondrins as anticancer drugs will have been assisted by the development of an understanding of the general chemistry of the halichondrins.