New Zealand Ascidians: Masters of Amino Acid-Derived Secondary Metabolites

Abstract

A survey of 34 New Zealand ascidians was performed for the purpose of investigating the biological and chemical properties of ascidians from New Zealand waters. The crude extracts were assayed for biological activity and were also analyzed by HPLC with photodiode array capability for comparison of absorption spectra. In this manner, biological profiles of the cytotoxicity and antimicrobial activities of the crude extracts were obtained, as well as a UV metabolic profile. The (-)-enantiomer of the known compound 1,2,3-trithiane was isolated from the ascidian Hypsistozoa fasmeriana, and the (+)-enantiomer from the ascidian Distaplia stylifera, a member of the same family (Holozoidiae). The (+)-enantiomer was originally isolated from the New Zealand ascidian Aplidium sp.D and appears to be unique to New Zealand waters. A new class of compound, the fasmerianamines A and B, derivatives of 1,2,3-trithiane, were isolate from a second collection of Hypsistozoa fasmeriana. Another new class of metabolite, the fluorescent, biologically inactive distomadines A and B were discovered in the ascidian Pseudodistoma aureum. A previously unknown trimethylated purine, N2,N2,7-trimethylguanine as well as other known purine bases were detected and isolated. Much of the biological activity of the ascidian extracts could be attributed to the presence of unsaturated long-chain amino alcohol-type compounds. The presence of the pyridoacridine class of compound, a large class of aromatic polycyclic alkaloids of worldwide distribution, was detected in a New Zealand ascidian for the first time. The pyridoacridone alkaloid ascididemin possesses a wide range of biological activity and progressed as far as in vivo xenograft antitumoural assays at the NCI, in addition to exhibiting potency against Mycobacterium tuberculosis, revealing its value as a lead compound. The antitumoural activity of ascididemin is attributed to the intercalative ability of its planar pentacyclic structure. The synthetic strategy for another natural pyridoacridone, kuanoniamine A was optimized, and the synthetic compound also showed not only good human solid tumour selectivity, progressing as far as in vivo hollow fibre testing at the NCI, but also potency against Mycobacterium tuberculosis. Three other synthetic ring A-modified analogues were prepared. Two, combining either a furan or a thiophene A ring with a carboxylic acid methyl ester substituent in position two on ring A, were tested at the NCI and were found to be inactive. This indicated that the carboxylic acid methyl ester substituent modification had a detrimental effect on cytotoxicity. The disruption of the planarity of the heterocyclic ring system with subsequent inability to intercalate into DNA might be a factor. An isoxazole ring A-modified analogue was found to be too unstable for evaluation purposes.