8-9-dihydrobarettin and barettin

Barettin, 8,9-dihydrobarettin, bromoconicamin and a novel brominated marine indole were isolated from the boreal sponge Geodia barretti collected off the Norwegian coast. The compounds were evaluated as inhibitors of electric eel acetylcholinesterase. Barettin and 8,9-dihydrobarettin displayed significant inhibition of the enzyme, with inhibition constants (Ki) of 29 and 19 μM respectively towards acetylcholinesterase via a reversible noncompetitive mechanism. These activities are comparable to those of several other natural acetylcholinesterase inhibitors of marine origin. Bromoconicamin was less potent against acetylcholinesterase, and the novel compound was inactive. Based on the inhibitory activity, a library of 22 simplified synthetic analogs was designed and prepared to probe the role of the brominated indole, common to all the isolated compounds. From the structure-activity investigation it was shown that the brominated indole motif is not sufficient to generate a high acetylcholinesterase inhibitory activity, even when combined with natural cationic ligands for the acetylcholinesterase active site. The four natural compounds were also analysed for their butyrylcholinesterase inhibitory activity in addition and shown to display comparable activities. The study illustrates how both barettin and 8,9-dihydrobarettin display additional bioactivities which may help to explain their biological role in the producing organism. The findings also provide new insights into the structure-activity relationship of both natural and synthetic acetylcholinesterase inhibitors.

Topics: Acetylcholinesterase; Animals; Biological Products; Cholinesterase Inhibitors; Geodia; Humans; Indole Alkaloids; Indoles; Peptides, Cyclic; Structure-Activity Relationship

A metabolomic approach was used to identify known and new natural products from the marine sponges Geodia baretti and G. macandrewii. G. baretti is known to produce bioactive natural products such as barettin (1), 8,9-dihydrobarettin (2), and bromobenzisoxazolone barettin (3), while secondary metabolites from G. macandrewii are not reported in the literature. Specimens of the two sponges were collected from different sites along the coast of Norway, and their extracts were analyzed using UHPLC-HR-MS. Metabolomic analyses revealed that extracts from both species contained barettin (1) and 8,9-dihydrobarettin (2), and all samples of G. baretti contained higher amounts of both compounds compared to G. macandrewii. The analysis of the MS data also revealed that samples of G. macandrewii contained a compound that was not present in any of the G. baretti samples. This new compound was isolated and identified as the N-acyl-taurine geodiataurine (4), and it was tested for antioxidant, anticancer, and antibacterial properties.

Topics: Animals; Biological Products; Geodia; Marine Biology; Metabolomics; Microbial Sensitivity Tests; Molecular Structure; Norway; Nuclear Magnetic Resonance, Biomolecular; Peptides, Cyclic; Taurine

The current work shows that two structurally similar cyclodipeptides, barettin (1) and 8,9-dihydrobarettin (2), produced by the coldwater marine sponge Geodia barretti Bowerbank act in synergy to deter larvae of surface settlers and may also be involved in defense against grazers. Previously, 1 and 2 were demonstrated to bind specifically to serotonergic 5-HT receptors. It may be suggested that chemical defense in G. barretti involves a synergistic action where one of the molecular targets is a 5-HT receptor. A mixture of 1 and 2 lowered the EC(50) of larval settlement as compared to the calculated theoretical additive effect of the two compounds. Moreover, an in situ sampling at 120 m depth using a remotely operated vehicle revealed that the sponge releases these two compounds to the ambient water. Thus, it is suggested that the synergistic action of 1 and 2 may benefit the sponge by reducing the expenditure of continuous production and release of its chemical defense substances. Furthermore, a synergistic action between structurally closely related compounds produced by the same bioenzymatic machinery ought to be the most energy effective for the organism and, thus, is more common than synergy between structurally indistinct compounds.

Topics: Animals; Anomura; Cold Temperature; Depsipeptides; Geodia; Hydrocarbons, Brominated; Larva; Marine Biology; Molecular Structure; Peptides, Cyclic; Receptors, Serotonin; Thoracica; Water

Many sessile suspension-feeding marine organisms rely on chemical defense to keep their surfaces free from fouling organisms. The brominated cyclopeptides barettin (cyclo[(6-bromo-8-entryptophan)arginine]) ( 1) and 8,9-dihydrobarettin (cyclo[(6-bromotryptophan)arginine]) ( 2) from the cold-water sponge Geodia barretti have previously displayed settlement inhibition of barnacle larvae in a dose-dependent manner. In this paper, we describe a novel dibrominated cyclopeptide, bromobenzisoxazolone barettin (cyclo[(6-bromo-8-(6-bromobenzioxazol-3(1 H)-one)-8-hydroxy)tryptophan)]arginine) ( 3), which we have isolated from G. barretti and which displays settlement inhibition of barnacle larvae ( Balanus improvisus) with an EC 50 value of 15 nM. The chemical structure was determined using MS and 2D-NMR.

Topics: Animals; Geodia; Hydrocarbons, Brominated; Larva; Marine Biology; Molecular Structure; Oceans and Seas; Peptides, Cyclic; Sweden; Thoracica

In this field investigation the two cyclopeptides, isolated from the marine sponge Geodia barretti Bowerbank (Geodiidae, Astrophorida), are shown to be very efficient in preventing recruitment of the barnacle Balanus improvisus (Cirripedia, Crustacea) and the blue mussel Mytilis edulis (Protobranchia, Lamellibranchia) when included in different marine paints. These brominated cyclopeptides, named barettin and 8,9-dihydrobarettin were incorporated in different non-toxic coatings. The substances were used in the concentrations 0.1 and 0.01% in all treatments. The most efficient paint was a SPC polymer. This paint, in combination with barettin and 8,9-dihydrobarettin, reduced the recruitment of B. improvisus by 89% (barettin, 0.1%) and by 67% (8,9-dihydrobarettin, 0.1%) as compared to control panels. For M. edulis, the reduction of recruitment was 81% with barettin (0.1%) and 72% with 8,9-dihydrobarettin (0.1%) included in the SPC paint. This indicates that the two compounds from G. barretti could provide non-toxic alternatives as additives in antifouling paints, since the heavy metal-based marine paints are to be replaced.

Topics: Animals; Aquaculture; Bivalvia; Paint; Peptides, Cyclic; Pest Control; Population Dynamics; Porifera; Ships; Thoracica

In this work, we show the potent antifouling effects of two compounds, barettin (cyclo[(6-bromo-8-entryptophan)arginine]) (1), isolated as a Z/E mixture (87/13), and 8,9-dihydrobarettin (cyclo[(6-bromotryptophan)arginine]) (2), isolated from the marine sponge Geodia barretti. The compounds were isolated guided by their ability to inhibit the settlement of cyprid larvae of the barnacle Balanusimprovisus, and their structures were determined by means of mass spectrometry, NMR, and quantitative amino acid analysis. The activities of these brominated diketopiperazine-like cyclic dipeptides are in the range of antifouling agents in use today, as shown by their EC(50) values of 0.9 and 7.9 microM, respectively. However, contrary to today's antifouling agents, the effects of barettin and 8,9-dihydrobarettin are nontoxic and reversible. A small set of synthetic analogues, including l-arginine, l-tryptophan, 5-bromo-d,l-tryptophan, 6-bromo-d,l-tryptophan, and 6-fluoro-d,l-tryptophan, were tested for possible structure-activity relationships. None of these compounds showed any effect at a concentration of 10 microM. We hypothesize that the isolated compounds are part of the sponge's chemical defense to deter fouling organisms. This theory is supported by the fact that barettin is found in water exposed to living specimens of G. barretti in concentrations that completely inhibit barnacles from settling.

Topics: Animals; Dose-Response Relationship, Drug; Larva; Marine Biology; Molecular Structure; Oceans and Seas; Peptides, Cyclic; Porifera; Stereoisomerism; Thoracica