Abstract:
Marine natural products have inspired the development of novel therapeutic agents. Marine habitats harbour a vast variety of structurally diverse and unique chemicals, and New Zealand waters are previously documented as an excellent source of bioactive marine natural products. This thesis presents the results of investigation of the secondary metabolites isolated from the New Zealand marine invertebrates Bugula flabellata (bryozoan) and Pseudodistoma opacum (ascidian), and a structure-antimalarial relationship study of the New Zealand ascidian metabolites didemnidine B and orthidine F. Examination of the natural product chemistry of Bugula flabellata (collected in Stewart Island, Southland) led to the isolation of janolusimide B (128), a tripeptide with 5 stereogenic centres. Janolusimide B is an N-methyl analogue of janolusimide (129), previously isolated from the Mediterranean nudibranch Janolus cristatus, a bryozoan preydator. Base hydrolysis of janolusimide B afforded ester 163 and known pyrrolidinedione 160. The absolute configuration of janolusimide B was resolved with the aid of an 11-step synthesis towards the acetylated ester 192, which involved crotylation of Boc-L-alaninal, and amide coupling of Boc-N-methyl-L-alanine as key steps. Two new metabolites, 7-bromohomotrypargine N-hydroxylamine (281), and distaminolyne A (282) were isolated from the ascidian Pseudodistoma opacum, collected in Ti Point, Northland. Compound 281 is the N-hydroxylamine of 7-bromohomotrypargine, which was reported previously from the same species. Distaminolyne A (282) is the first acetylene-containing amino alcohol isolated from nature. The absolute configuration of distaminolyne A was determined as 2S, from analysing the CD spectra of the dibenzolyated derivative. Distaminolyne A displayed mild antimicrobial activities towards Escherichia coli and Staphylococcus aureus. In an extension of previous research into polyamine-derived antimalarials, thirty novel analogues bearing di-substituted indole capping acids were designed, synthesised, and evaluated against malarial Plasmodium falciparum. All analogues tested exhibited better activity than the prototypical ascidian metabolite didemnidine B (41), with three analogues (421, 430, 433) exhibiting IC50 values in nM ranges. Analogue 421 (92 nM, SI > 1200) was selected for in vivo antimalarial evaluation in P. berghei infected mice, however, no increase in mean survival time was observed.