Natural Products from New Zealand Ascidians Pseudodistoma opacum and Aplidium scabellum

Abstract

New Zealand has a diverse and mostly unexplored marine environment. Ascidians found in New Zealand waters are a previously documented excellent source of bioactive marine natural products. This thesis presents the results of investigation of the secondary metabolite chemistry of two species of New Zealand ascidians, Pseudodistoma opacum, collected in Maori Bay, Muriwai, Auckland and Aplidium scabellum, collected at Great Barrier Island. Four new metabolites, (-)-7-bromohomotrypargine (2.82) and opacalines A-C (2.83-2.85), all belonging to the β-carboline family, were isolated from the ascidian P. opacum. The debromo analogues of opacalines A and C were synthesized and the library was evaluated for growth inhibition properties against a range of neglected disease parasite assays. The β-carbolines tested were found to be non-cytotoxic and display mild antimalarial activity, with IC50 ranging from 5-27 μM towards Trypanosoma brucei rhodesiense and 4-12 μM towards Plasmodium falciparum. A biosynthetic pathway for the four new metabolites is proposed, with arginine and homoarginine undergoing transamination to give the respective α-keto acid precursors, followed by a Pictet-Spengler reaction to form the β- carboline skeleton. Examination of the natural product chemistry of the ascidian Aplidium scabellum led to the isolation of five new natural products, 2-geranyl-6-methoxy-1,4-hydroquinone-4- sulfate (3.57) and scabellones A-D (3.59-3.62), as well as the known chromenol, 8- methoxy-2-methyl-2-(4-methyl-3-pentenyl)-2H-1-benzopyran-6-ol (3.58), and quinone, verapliquinone A (3.63). Results from biomimetic synthesis of scabellones A-D utilizing either 2-methoxy-6-geranyl-1,4-hydroquinone or 2-methoxy-6-geranyl-1,4-benzoquinone as starting material identified the latter as the species necessary for the formation of the scabellones. Unexpected products were also isolated from different biomimetic synthesis attempts, including verapliquinone C and 3-methoxy-7-prenyl-1,4-naphthoquinone. A biosynthesis route for scabellones A-D was proposed based on the results obtained from the biomimetic reactions, with 2-geranyl-1,4-benzoquinone as the starting material and scabellone A as the common intermediate to scabellones B-D. Scabellone B (3.59) was found to exhibit antimalarial properties (IC50 3.4 μM), opening the potential for structureactivity relationship studies. 2-Geranyl-6-methoxy-1,4-hydroquinone-4-sulfate (3.57) was found to inhibit the respiratory burst of human neutrophils and is non-cytotoxic, making this natural product a potential anti-inflammatory agent. In contrast, its desulfated counterpart, 2-geranyl-6-methoxy-1,4-hydroquinone, was found to be an apoptotic cytotoxin.