A sponge allelochemical induces ascidian settlement but inhibits metamorphosis

Secondary metabolites synthesised by sessile invertebrates appear to play a role in creating and maintaining space on hard substrata by repelling competitors. In this study, we investigated the responses of the larvae of the ascidian Herdmania curvata to haliclonacyclamine A (HA), the major component of a suite of cytotoxic alkaloids extracted from the sponge Haliclona sp. 628. Both Haliclona sp. 628 and Herdmania curvata inhabit the crest and slope of Heron Island Reef. High rates of settlement were induced in competent H. curvata larvae by a range of concentrations of HA, all lower than that naturally occurring in the sponge. HA did not induce precompetent larvae to settle. Although early metamorphosis of HA-induced larvae was normal, larvae exposed to all but the lowest concentration of HA were developmentally arrested after completion of tail resorption, at about 4 h after the initiation of metamorphosis. These postlarvae underwent extensive cellular necrosis within 24 h. We also demonstrate that the addition of a transcriptional inhibitor, actinomycin D, to larvae also causes inhibition of metamorphosis after tail resorption is completed. Analyses of incorporation of radiolabelled nucleotides to measure levels of transcription during normal development and after the addition of the transcriptional inhibitor indicate that there is a significant burst of transcriptional activity just after tail resorption is completed. Despite inhibiting metamorphosis at the same stage as actinomycin D, HA increases initial rates of RNA synthesis after induction of metamorphosis in a manner similar to that observed in normal postlarvae until the onset of cellular necrosis. We conclude that HA initially induces H. curvata larvae to settle and progress through early metamorphosis possibly by engaging the same pathway as other artificial and environmental cues but subsequently inhibits completion of metamorphosis, resulting in death of the postlarvae. Since HA does not affect overall transcription rates, it appears to disrupt another important developmental process during early metamorphosis.

9,10-Dihydroxy-1,8-cineole (1,3,3-Trimethyl-2-oxabicyclo[2.2.2]octane-10,11-diol)

The title compound (3) has been synthesized and its presence sought in the urinary metabolites of the brushtail possum. © CSIRO 2001

Regioselective synthesis of antiparallel loops on a macrocyclic scaffold constrained by oxazoles and thiazoles

[GRAPHICS] The regioselective syntheses and structures are reported for two tris-macrocylic compounds, each possessing two antiparallel loops on a macrocyclic scaffold constrained by two oxazoles and two thiazoles. NMR solution structures show the loops projecting from the same face of the macrocycle. Such molecules are shown to be prototypes for mimicking multiple loops of proteins.

Difficult macrocyclizations: New strategies for synthesizing highly strained cyclic tetrapeptides

Cyclic tetrapeptides are an intriguing class of natural products. To synthesize highly strained cyclic tetrapeptides; we developed a macrocyclization strategy that involves the inclusion of 2-hydroxy-6-nitrobenzyl (HnB) group at the N-terminus and in the middle of the sequence. The N-terminal auxiliary performs a ring closure/ring contraction role, and the backbone auxiliary promotes cis amide bonds to facilitate the otherwise difficult ring contraction. Following this route, the all-L cyclic tetrapeptide cyclo-[Tyr-Arg-Phe-Ala] was successfully prepared.

Designing supramolecular structures from models of cyclic peptide scaffolds with heterocyclic constraints

Cyclic peptides containing oxazole and thiazole heterocycles have been examined for their capacity to be used as scaffolds in larger, more complex, protein-like structures. Both the macrocyclic scaffolds and the supramolecular structures derived therefrom have been visualised by molecular modelling techniques. These molecules are too symmetrical to examine structurally by NMR spectroscopy. The cyclic hexapeptide ([Aaa-Thz](3), [Aaa-Oxz](3)) and cyclic octapeptide ([Aaa-Thz](4), [Aaa-Oxz](4)) analogues are composed of dipeptide surrogates (Aaa: amino acid, Thz: thiazole, Oxz: oxazole) derived from intramolecular condensation of cysteine or serine/threonine side chains in dipeptides like Aaa-Cys, Aaa-Ser and Aaa-Thr. The five-membered heterocyclic rings, like thiazole, oxazole and reduced analogues like thiazoline, thiazolidine and oxazoline have profound influences on the structures and bioactivities of cyclic peptides derived therefrom. This work suggests that such constrained cyclic peptides can be used as scaffolds to create a range of novel protein-like supramolecular structures (e.g. cylinders, troughs, cones, multi-loop structures, helix bundles) that are comparable in size, shape and composition to bioactive surfaces of proteins. They may therefore represent interesting starting points for the design of novel artificial proteins and artificial enzymes. (C) 2002 Elsevier Science Inc. All rights reserved.

The occurrence of hopanoids in planctomycetes: implications for the sedimentary biomarker record

Hopanoids have generally been found in aerobic bacteria (i.e. methanotrophs, heterotrophs and cyanobacteria). Here we show that a variety of hopanoids (i.e. bacteriohopanetetrol, diplopterol, diploptene and a C-27 hopanoid ketone) occur in planctomycetes, including strictly anaerobic bacteria capable of anaerobic ammonium oxidation. Since planctomycetes have a widespread occurrence in Nature, this indicates that they may be an additional source for sedimentary hopanoids. (C) 2004 Elsevier Ltd. All rights reserved.

Nematocidal thiocyanatins from a southern Australian marine sponge Oceanapia sp.

Investigations of a southern Australian marine sponge, Oceanapia sp., have yielded two new methyl branched bisthiocyanates, thiocyanatins D-1 (3a) and D-2 (3b), along with two new thiocarbamate thiocyanates, thiocyanatins E-l (4a) and E-2 (4b). The new thiocyanatins belong to a rare class of bioactive marine metabolite previously only represented by thiocyanatins A-C (1, 2a/b). Structures were assigned on the basis of detailed spectroscopic analysis, with comparisons to the known bisthiocyanate thiocyanatin A (1) and synthetic model compounds (5-7). The thiocyanatins exhibit potent nematocidal activity, and preliminary structure-activity relationship investigations have confirmed key characteristics of the thiocyanatin pharmacophore.

Rugulotrosins A and B: Two new antibacterial metabolites from an Australian isolate of a penicillium sp.

Two new antibacterial agents, rugulotrosin A (1) and B (2), were obtained from cultures of a Penicillium sp. isolated from soil samples acquired near Sussex Inlet, New South Wales, Australia. Rugulotrosin A (1) is a chiral symmetric dimer, and its relative stereostructure was determined by spectroscopic and X-ray crystallographic analysis. Rugulotrosin B (2) is a chiral asymmetric dimer isomeric with 1. Its structure was determined by spectroscopic analysis with comparison to the co-metabolite 1 and previously reported fungal metabolites. Both rugulotrosins A and B displayed significant antibacterial activity against Bacillus subtilis, while rugulotrosin A was also strongly active against Enterococcus faecalis and B. cereus.

Tetra- and tribromopbenoxyanisoles in Marine Samples from Oceania

Some methoxylated polybrominated diphenyl ethers (MeO-BDEs) are known halogenated natural products (HNPs) and are frequently detected in higher organisms of the marine environment. In this study we demonstrate that a prominent MeO-BDE, previously detected in marine mammals from Australia, is identical to 3,5-dibromo-2-(2',4'-dibromo)phenoxyanisole(BC-3,6-MeO-BDE47). Up to 1.9mg/ kg of 6-MeO-BDE 47 was present in cetaceans from Australia, 0.2-0.3 mg/kg in two crocodile eggs from Australia, but concentrations of 1 or 2 orders of magnitude lower were found in shark liver oil from New Zealand and in marine mammals from Africa and the Antarctic. Concentrations of 6-MeO-BDE47 in samples from Australia were in the same range as anthropogenic pollutants such as PCB 153 and p,p'-DDE. Along with 6-MeO-BDE 47 and the known HNP 4,6-dibromo-2-(2',4'-dibromo)phenoxyanisole (BC-2,2'-MeO-BDE 68), several tribromophenoxyanisoles (MeO-triBDE) were present in tissue of Australian cetaceans. To determine their structure, abiotic debromination experiments were performed using 6-MeO-BDE 47 and 2'-MeO-BDE 68 and superreduced di cyanocobalamine. These experiments resulted in formation of eight MeO-triBDEs, all of which were detected in the cetacean samples. Five of these eight MeO-triBDEs could be identified based on two standard compounds as well as gas chromatographic and mass spectrometric features. It was also shown that the first eluting isomer (compound 1), 6-MeO-BDE 17 (compound 2), and 2-MeO-BDE 39 (compound 5) were the most prominent MeO-triBDEs in the Australian cetacean samples. The concentrations of the MeO-triBDEs in two cetacean samples were 0.20 and 0.36 mg/kg, respectively. Although the reductive debromination with dicyanocobalamine resulted in a different congener pattern than was found in the marine mammals, it could not be excluded that the tribromo congeners of 6-MeO-BDE 47 and 2'-MeO-BDE 68 in the samples were metabolites of the latter.

Gymnoascolides A-C: Aromatic butenolides from an Australian isolate of the soil ascomycete Gymnoascus reessii

Three new aromatic butenolides, gymnoascolides A-C (1-3), have been isolated from the Australian soil ascomycete Gymnoascus reessii and assigned structures on the basis of detailed spectroscopic analysis. The absolute configurations of gymnoascolides B (2) and C (3) at C-5 were solved using a combination of chemical derivatization and quantum chemical simulations.

Calbistrin E and two other new metabolites from an Australian isolate of Penicillium striatisporum

An Australian isolate of Penicillium striatisporum collected near Shalvey, New South Wales, exhibited selective antifungal activity against Candida albicans versus Saccharomyces cerevisiae. Bioassay-directed fractionation yielded members of the rare class of fungal metabolites known as the calbistrins. These included a new example of this structure class, calbistrin E (1), as well as the known polyenes calbistrin C (2) and deformylcalbistrin A (3). Also recovered from P. striatisporum were new triene and butenolide acids, striatisporin A (4) and striatisporolide A (5), together with the known fungal metabolites versiol (6) and (+)-hexylitaconic acid (7). Structures for all metabolites were determined by detailed spectroscopic analysis.

Spongosoritin A: A new polyketide from a Fijian marine sponge, Spongosorites sp.

A new polyketide, spongosoritin A, with a rare vinylagous alpha,beta-unsaturated gamma-lactone moiety was isolated from a Fijian marine sponge, Spongosorites sp., and the structure assigned by detailed spectroscopic analysis.

Aspergillazines A-E: novel heterocyclic dipeptides from an Australian strain of Aspergillus unilateralis

Biological and chemical pro ling of an Australian strain of the fungus Aspergillus unilateralis (MST-F8675), isolated from a soil sample collected near Mount Isa, Queensland, revealed a complex array of metabolites displaying broad chemotherapeutic properties. Noteworthy among these metabolites were a unique series of highly modified dipeptides aspergillazines A-E, incorporating a selection of unprecedented and yet biosynthetically related heterocyclic systems. Co-occurring with the aspergillazines was the recently described marine-derived fungal metabolite trichodermamide A (cf. penicillazine), whereas re-fermentation of A. unilateralis in NaCl (1%) enriched media resulted in co-production of the only other known example of this structure class, the marine-derived fungal metabolite trichodermamide B. Further investigation of A. unilateralis returned the known terrestrial fungal metabolite viridicatumtoxin as the cytotoxic and antibacterial principle, together with E-2-decenedioic acid, ferulic acid, (7E,7'E)-5,5'-diferulic acid and (7E,7'E)-8,5'-diferulic acid. The aromatic diacids have previously been reported from the chemical and enzymatic (esterase) treatment of plant cell wall material, with their isolation from A. unilateralis being their first apparent reported occurrence as natural products. Structures for all metabolites were determined by detailed spectroscopic analysis and, where appropriate, comparison to literature data and/or authentic samples.

The fate of Lyngbya majuscula toxins in three potential consumers

Blooms of Lyngbya majuscula have been reported with increasing frequency and severity in the last decade in Moreton Bay, Australia. A number of grazers have been observed feeding upon this toxic cyanobacterium. Differences in sequestration of toxic compounds from L. majuscula were investigated in two anaspideans, Stylocheilus striatus, Bursatella leachii, and the cephalaspidean Diniatys dentifer. Species fed a monospecific diet of L. majuscula had different toxin distribution in their tissues and excretions. A high concentration of lyngbyatoxin-a was observed in the body of S. striatus (3.94 mg/kg(-1)) compared to bodily secretions (ink 0.12 mg/kg- 1; fecal matter 0.56 mg/kg(-1); eggs 0.05 mg/kg(-1)). In contrast, B. leachii secreted greater concentrations of lyngbyatoxin-a (ink 5.41 mg/kg(-1); fecal matter 6.71 mg/kg(-1)) than that stored in the body (2.24 mg/kg(-1)). The major internal repository of lyngbyatoxin-a and debromoaplysiatoxin was the digestive gland for both S. striatus (6.31 +/- 0.31 mg/kg(-1)) and B. leachii (156.39 +/- 46.92 mg/kg(-1)). D. dentifer showed high variability in the distribution of sequestered compounds. Lyngbyatoxin-a was detected in the digestive gland (3.56 +/- 3.56 mg/kg(-1)) but not in the head and foot, while debromoaplysiatoxin was detected in the head and foot (133.73 +/- 129.82 mg/kg(-1)) but not in the digestive gland. The concentrations of sequestered secondary metabolites in these animals did not correspond to the concentrations found in L. majuscula used as food for these experiments, suggesting it may have been from previous dietary exposure. Trophic transfer of debromoaplysiatoxin from L. majuscula into S. striatus is well established; however, a lack of knowledge exists for other grazers. The high levels of secondary metabolites observed in both the anaspidean and the cephalapsidean species suggest that these toxins may bioaccumulate through marine food chains.