Study of Biologically Active Marine Natural Products - Discorhabdins and Ascidiathiazones

Abstract

Structure-activity relationship (SAR) and mechanism of action studies of biologically active marine natural products are needed to assess potential drug leads or biochemical tools for future development. This thesis describes the SAR study of two families of such compounds, the discorhabdins and ascidiathiazones, incorporating synthesis or semisynthesis and biological assay results. Discorhabdin C, extracted from Latrunculia du Bocage sponges, was previously proposed as a novel anti-tumour agent, showing selective cytotoxicity towards human colon tumour and leukaemia subpanels at the National Cancer Institute. A library of C-3 and N-13 modified analogues, some of which incorporated fluorescent chromophores, were semisynthesised for SAR study. The low cytotoxic potency of C-3 modified analogues suggested the spiro-enone ring on discorhabdin C was a crucial pharmacophore for the discorhabdin family of compounds. Biomimetic reactions with discorhabdins B and C revealed the spiro-enone moiety to be highly electrophilic, readily reacting with cellularlike nucleophiles. These findings prompted a reinvestigation of the sponge Latrunculia (Latrunculia) trivetricillata leading to the characterisation of a new natural product, discorhabdin 1, a possible dimer of discorhabdin C. Modification of discorhabdin C at N- 13 yielded a series of cytotoxic analogues which exhibited excellent differential cytotoxic profiles. The N-13 fluorescent analogues, synthesised for cellular localisation studies failed to demonstrate in vitro cytotoxicity, suggesting only small non-polar subtituents may be successfully incorporated at the N-13 position. Ascidiathiazone A extracted from the New Zealand ascidian Aplidium sp. was previously found to exhibit both in vitro and in vivo anti-inflammatory activities. In order to more fully explore the SAR, a library of analogues was prepared that incorporated a variety of amido sidechain substituents, or contained changes to the core heterocyclic scaffold of the natural product. Biological evaluation of the new analogues revealed an improvement of anti-inflammatory activity for several library members with AI50's of 0.09-0.16 μM. Antiparasitic testing of the analogues also identified this class of alkaloids to have high selectivity against malaria; the low cytotoxicity of these compounds has made these alkaloids a potential new drug lead as antimalarial agents.