Australian Ascidian Research Articles

Anti-prion Butenolides and Diphenylpropanones from the Australian Ascidian Polycarpa procera.

A library of 500 Australian marine invertebrate extracts was screened for anti-prion activity using a yeast-based assay, and this resulted in an extract from the ascidian Polycarpa procera showing potent activity. Purification of this extract led to the isolation of six new butenolide metabolites, the procerolides 1-4 and two related diphenylpropanones, the procerones 5 and 6, as the bioactive components. The structures of 1-6 were elucidated from the analysis of 1D/2D NMR and MS data, and their absolute configurations determined from comparison of experimental and computed ECD data. Compounds 1-6 were tested for anti-prion activity in a yeast-based assay, and 1 and 5 displayed potent bioactivity (EC50 of 23 and 29 μM, respectively) comparable to the potently active anti-prion compound guanabenz. The procerolides and procerones are the first anti-prion compounds to be reported from ascidians, indicating that ascidians may be an untapped source of new lead anti-prion compounds.

Taxonomic and Metabolite Diversity of Actinomycetes Associated with Three Australian Ascidians

Actinomycetes are known to be the most prolific producers of biologically active metabolites. Here, we investigated the host species-specificity and the related secondary metabolites of actinomycetes that are associated with three different Australian ascidians, namely Symplegma rubra, Aplidium solidum, and Polyclinum vasculosum. Results indicated that while isolates from the genera Streptomyces and Micromonospora were highly diverse in the ascidian samples, only two culturable actinomycete Operational Taxonomic Units (OTUs) overlapped between all of the ascidians, pointing to some degree of host species-specificity of the isolates and selective acquisition of microbial associates by the host from the surrounding environment. LC-MS/MS profiling of extracts obtained from the ascidians and their actinomycete associates revealed many overlapping ions between hosts and actinomycetes, indicating that these compounds were likely to be synthesised by the microbial associates. Laboratory cultures of the actinomycetes displayed even more diverse metabolomes than those of their ascidian hosts; thus, making ascidian-associated actinomycetes an excellent target for natural product drug discovery and biotechnology.

Pteridine-, thymidine-, choline- and imidazole-derived alkaloids from the Australian ascidian, Leptoclinides durus

Four new acylated pteridine alkaloids, duramidines A-D, two new acylated thymidine alkaloids, leptoclinidines A and B, two new 1-acylglyceryl-3-(O-carboxyhydroxymethylcholine) alkaloids, durabetaines A and B, three new 1,3-dimethyl-5-methylsulfanylimidazole alkaloids, leptoclinidamines D-F, and the known alkaloids leptoclinidamines B and C and 6-bromo-1H-indolo-3-yl-oxoacetic acid methyl ester were isolated from the Australian ascidian Leptoclinides durus. The duramidines are the first pteridine alkaloids, possessing a three carbon side chain esterified at C-1' with a 4-hydroxy-2'-methoxycinnamic acid, and are either hydroxylated or sulfated at C-2'. The leptoclinidines are the first 3'-indole-3-carboxylic acid ester derivatives of thymidine to be reported in the literature. The durabetaines are the first glyceryl-3-(O-carboxyhydroxymethylcholine) alkaloids to be reported from an animal source and are also the only known derivatives from this class to be acylated with aromatic carboxylic acids. MS and NMR data analysis established the structures of the new compounds. All compounds were shown to be inactive when tested for cytotoxic activity against prostate (LNCaP) and breast (MDA-MB-231) cancer cell lines and antimicrobial activity against Pseudomonas aeruginosa and Staphylococcus aureus.

Kinase Inhibitor Scaffolds against Neurodegenerative Diseases from a Southern Australian Ascidian, Didemnum sp.

Screening a library of Southern Australian and Antarctic marine invertebrates and algae for inhibitors of neurodegenerative disease kinase targets casein kinase 1 (CK1δ), cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β) identified a Western Australian Didemnum species (CMB-02127) as a high-priority specimen. Chemical fractionation returned the known aromatic alkaloids ningalins B-D as the major metabolites, together with six minor metabolites, the new ningalins E-G and the known hexacyclic pyrrole alkaloids lamellarins Z, G and A6. All structures were assigned by detailed spectroscopic analysis and literature comparisons, and the structural assignments were supported by biosynthetic considerations. The ningalins showed potent and broad inhibition across the three kinases, while the lamellarins were generally more selective for CDK5. Docking studies using published X-ray crystal structures of CDK5 revealed both scaffolds target the ATP binding pocket.

Biology, ecology and trials of potential methods for control of the introduced ascidian Eudistoma elongatum (Herdman, 1886) in Northland, New Zealand

The Australian native colonial ascidian Eudistoma elongatum has spread throughout harbours and oyster farms in Northland, New Zealand. This paper summarizes results of a study on the biology, ecology and potential methods of control of this recently introduced species. Colonies were reproductive for nine months of the year and embryos were present in zooids at water temperatures above 14 o C. Low salinity was most likely the cause of variation in reproductive status observed. Larvae were able to swim for up to 6 hours, and remain viable at temperatures as low as 10°C at salinities above 20 psu. Only acetic acid was effective at killing colonies. Control using heat or other chemicals was not feasible for shallow subtidal populations identified in the study. E. elongatum has the potential to spread further within already occupied harbours, and to more southern harbours in New Zealand.

Kingamide A, a new indole alkaloid from the ascidian Leptoclinides kingi

Chemical investigation of the CH 2Cl 2/MeOH extract from the Australian ascidian Leptoclinides kingi led to the isolation of a new brominated indole alkaloid, kingamide A ( 1). The planar structure of kingamide A was elucidated following the interpretation of 1D/2D NMR and MS data, and the absolute configuration was determined using Marfey’s method. This is the first report of a natural product from L. kingi.

The Antibacterial ent-Eusynstyelamide B and Eusynstyelamides D, E, and F from the Arctic Bryozoan Tegella cf. spitzbergensis

The brominated tryptophan-derived ent-eusynstyelamide B (1) and three new derivatives, eusynstyelamides D, E, and F (2-4), were isolated from the Arctic bryozoan Tegella cf. spitzbergensis. The structures were elucidated by spectroscopic methods including 1D and 2D NMR and analysis of mass spectrometric data. The enantiomer of 1, eusynstyelamide B, has previously been isolated from the Australian ascidian Eusynstyela latericius. Antimicrobial activities are here reported for 1-4, with minimum inhibitory concentrations (MIC) as low as 6.25 μg/mL for 1 and 4 against Staphylococcus aureus. Eusynstyelamides 2 and 3 showed weak cytotoxic activity against the human melanoma A 2058 cell line.

ChemInform Abstract: Aplidiopsamine A, an Antiplasmodial Alkaloid from the Temperate Australian Ascidian, Aplidiopsis confluata.

A polyaromatic alkaloid, aplidiopsamine A was isolated from the temperate Australian ascidian, Aplidiopsis confluata, and its structure was determined from interpretation of mass, 1D and 2D NMR spectra. Aplidiopsamine A is the first alkaloid to possess the tricyclic aromatic substructure 3H-pyrrolo[2,3-c]quinoline conjugated to an adenine. Aplidiopsamine A exhibited significant inhibition of growth of chloroquine resistant and sensitive strains of the malaria parasite, Plasmodium falciparum, and minimal toxicity toward human cells.

Aplidiopsamine A, an Antiplasmodial Alkaloid from the Temperate Australian Ascidian, Aplidiopsis confluata

A polyaromatic alkaloid, aplidiopsamine A was isolated from the temperate Australian ascidian, Aplidiopsis confluata, and its structure was determined from interpretation of mass, 1D and 2D NMR spectra. Aplidiopsamine A is the first alkaloid to possess the tricyclic aromatic substructure 3H-pyrrolo[2,3-c]quinoline conjugated to an adenine. Aplidiopsamine A exhibited significant inhibition of growth of chloroquine resistant and sensitive strains of the malaria parasite, Plasmodium falciparum, and minimal toxicity toward human cells.

ChemInform Abstract: Botryllamides K and L, New Tyrosine Derivatives from the Australian Ascidian Aplidium altarium.

Chemical investigation of the Australian ascidian Aplidium altarium led to the isolation of two new tyrosine derivatives, botryllamides K (1) and L (2), together with six known metabolites, botryllamides A–C (3–5), botryllamide G (6) and perspicamides A (7) and B (8). The structures of these compounds were elucidated by spectroscopic analysis. This is the first reported chemistry from this species. Compounds 1–8 were evaluated for their cytotoxicity towards the tumour cell lines, MCF-7 (breast), H460 (lung) and SF268 (central nervous system).

Caelestines A−D, Brominated Quinolinecarboxylic Acids from the Australian Ascidian Aplidium caelestis

Four new brominated natural products, caelestines A-D (1-4), have been isolated from the Australian ascidian Aplidium caelestis. The structures of 1-4 were determined by analysis of their NMR and MS data. This is the first report of brominated quinolinecarboxylic acids from nature. Compound 1 has been previously synthesized but not spectroscopically characterized. Compounds 1-4 were tested against three mammalian cell lines (MCF-7, NFF, and MM96L) and a panel of microbial strains and showed only minor cytotoxicity.

Botryllamides K and L, new tyrosine derivatives from the Australian ascidian Aplidium altarium

Chemical investigation of the Australian ascidian Aplidium altarium led to the isolation of two new tyrosine derivatives, botryllamides K (1) and L (2), together with six known metabolites, botryllamides A–C (3–5), botryllamide G (6) and perspicamides A (7) and B (8). The structures of these compounds were elucidated by spectroscopic analysis. This is the first reported chemistry from this species. Compounds 1–8 were evaluated for their cytotoxicity towards the tumour cell lines, MCF-7 (breast), H460 (lung) and SF268 (central nervous system).

Antitrypanosomal pyridoacridine alkaloids from the Australian ascidian Polysyncraton echinatum

Abstract Bioassay-guided fractionation of the crude CH2Cl2/MeOH extract from the Australian ascidian Polysyncraton echinatum led to the isolation of a new pyridoacridine alkaloid, 12-deoxyascididemin (1), along with two known analogues, ascididemin (2) and eilatin (3). The structure of 1 was determined following extensive analysis of 1D/2D NMR and MS data. Biological evaluation showed that compounds 1–3 are potent antitrypanosomal agents with IC50 values of 0.077, 0.032, and 1.33 μM against Trypanosoma brucei brucei, respectively.

Leptoclinidamines A−C, Indole Alkaloids from the Australian Ascidian Leptoclinides durus

Three new indole alkaloids, leptoclinidamines A-C (1-3), were isolated from the Australian ascidian Leptoclinides durus. Their structures were determined by analysis of 2D NMR spectra. Leptoclinidamines A and B both contain an indoleglyoxylic acid attached to an L-arginine. The structure of leptoclinidamine A was confirmed by total synthesis. Leptoclinidamine C contains the naturally rare 1,3-dimethyl-5-(methylthio)histidine attached to a 6-bromoindole-3-carboxylic acid. Leptoclinidamine C (3) and both enantiomers of leptoclinidamine A (1) were tested for antimalarial, antitrypanosomal, and cytotoxic activity, but none of the compounds were bioactive.

Concise and Efficient Total Syntheses of Virenamides A and D

Concise total syntheses of linear thiazole-containing peptides virenamides A (1) and D (4), isolated from Australian ascidian Diplosoma virens have been accomplished from Boc-L-valine (6) in 7 steps. A cyclization between thioamide and bromoacetaldehyde was applied to form thiazole ring as a key step.

First record of the Australian ascidian Eudistoma elongatum in northern New Zealand

A colonial ascidian was first reported by marine farmers in Houhora Harbour, Northland, New Zealand in early 2005 and subsequently found on oyster racks in Parengarenga Harbour and the Bay of Islands. The Northland ascidian was identified with a combination of morphological characters and DNA cytochrome c oxidase I (COI) sequence data, as Eudistoma elongatum, a species native to Australia, where it is found from northern New South Wales to Northern Queensland, and distinguished from Eudistoma circumvallatum, the only reported species in this genus from New Zealand. Ascidian larvae are weak dispersers and long distance dispersal of E. elongatum is likely to be enhanced by vectors such as oyster barges and/or movement of cultured oysters. In its native range, E. elongatum is restricted to areas with a minimum winter sea temperature of 16°C. Assuming similar biological limitations apply in New Zealand, the spread of E. elongatum might be restricted to northern New Zealand (north of latitude 37°S).

Taxonomic affinities of three stalked colonial species of the Ascidiacea (Tunicata) from the central coast of New South Wales and indications of a trans‐Tasman connection

Three colonial aplousobranch ascidian species from the central coast of New South Wales were originally described from one of the earliest significant regional collections of Australian ascidians (Herdman, 1899). They have a similar habit, their colonies being long, oval to cylindrical gelatinous heads on relatively short, thick, fleshy stalks and they all respond in the same way to the multidirectional currents to which they are subjected in the habitats they occupy. Nevertheless, they are not closely related phylogenetically. One is the monotypic Euclavella claviformis (Herdman, 1899), known only from the central eastern Australian coast and the North Island (New Zealand). The second species is the indigenous Hypsistozoa distomoides (Herdman, 1899), known from the Great Australian Bight and the central eastern coast of Australia but related closely to the only other species known in this genus, its type species H. fasmeriana (Michaelsen, 1924), known only from New Zealand. The third species discussed, Sigillina cyanea (Herdman, 1899), an indigenous Australian species known from a wide range around the Australian continent, has no closely related species in the indigenous New Zealand fauna although a similar and partly sympatric species Sigillina australis (Savigny, 1816) does occur in New Zealand. A close relationship of Sigillina to the Pseudodistomidae (rather than the Holozoidae) is apparent. Larvae of H. distomoides are found to have characters formerly known only in larvae of the type species (see Brewin 1956, 1959).

Perspicamides A and B, Quinolinecarboxylic Acid Derivatives from the Australian Ascidian Botrylloides perspicuum

Two novel quinoline-2-carboxylic acid derivatives, perspicamides A (2) and B (3), were isolated from the Australian ascidian Botrylloides perspicuum. Extraction of the freeze-dried ascidian with methanol and purification of the extract by C18 MPLC followed by repeated C18 HPLC yielded the new compounds 2 and 3 as well as the known compounds botryllamides A-C (4-6). The structures of 2 and 3 were determined from analysis of 2D NMR spectra.

Novel amino acid derived natural products from the ascidian Atriolum robustum: identification and pharmacological characterization of a unique adenosine derivative.

Investigation of the methanolic extract of the Australian ascidian Atriolum robustum led to the isolation and characterization of five new amino acid derived structures (1-5). The structures were elucidated employing spectroscopic techniques (NMR, MS, UV, and IR). The absolute stereochemistry of 1 and 2 was established by chemical degradation, derivatization, and chiral GC-MS analysis. Structures 4 and 5 are complex nucleosides containing rare methylthioadenosine and methylsulfinyladenosine moieties, respectively. In radioligand binding studies the 5'-deoxy-5'-methylthioadenosine-2',3'-diester 4 exhibited affinity for A(1) and A(3) adenosine receptors with K(i) values below 10 microM. Its affinity was somewhat lower for A(2A) (K(i) = 17 microM) and much lower for A(2B) adenosine receptors. Analytical experiments using capillary electrophoresis showed that compound 4 was stable under the conditions of radioligand binding studies. Incubation with carboxylesterase resulted in slow hydrolysis of the adenosine derivative to 5'-deoxy-5'-methylthioadenosine (MTA), which was about 10-fold more potent at adenosine receptors than compound 4. Thus, the 2',3'-diester derivative 4 may act as a lipophilic prodrug of MTA in addition to its own adenosine receptor activity. GTP shift experiments indicated that the adenosine derivative was a partial agonist at A(1) adenosine receptors of rat brain cortical membranes. Compound 4 inhibited cAMP accumulation in Chinese hamster ovary (CHO) cell membranes recombinantly expressing the human A(3) adenosine receptor, thus indicating that the adenosine derivative also acted as a partial agonist at A(3)ARs. Homology models of the A(1) and the A(3) adenosine receptors in their putative active and inactive conformations were built and used for docking of the sterically demanding compound 4. It was found that this ligand fit well into the binding pockets of both receptor subtypes because of its highly flexible structure, although in somewhat different binding modes.

ChemInform Abstract: Prunolides A, B, and C: Novel Tetraphenolic Bis‐Spiroketals from the Australian Ascidian Synoicum prunum.

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