<p>The marine sponge <i>Geodia barretti</i> produces a range of secondary metabolites. Two of these compounds were isolated and elucidated guided by their ability to inhibit settlement of cypris larvae of the barnacle <i>Balanus improvisus</i>. The compounds barettin (cyclo-[(6-bromo-8-en-tryptophan)-arginine]) as E/Z mixture and 8,9-dihydrobarettin (cyclo-[6-bromo-tryptophan)-arginine]) were determined by using mass spectrometry, nuclear magnetic resonance and quantitative amino acid analysis.The bioactivity of these brominated dipeptides is in the range of antifouling substances used today: EC<sub>50</sub> values of 0.9 µM (barettin) and 7.9 µM (8,9-dihydrobarettin). The compounds were successfully synthesised and then tested in a field experiment to evaluate their antifouling properties. The compounds were incorporated in four different commerical, non-toxic marine coatings. The concentrations of the compounds were 0.1 and 0.01% (w/w) and coated panels were exposed to field conditions for eight weeks. The experiment evaluated the effect of barettin and 8,9-dihydrobarettin on recruitment of the barnacle <i>B. improvisus</i> and the blue mussel <i>Mytilus edulis</i> (major Swedish foulers). The most efficient paint was a SPC polymer, for which the reduction of recruitment of <i>B. improvisus</i> was 89% with barettin (0.1%) and 61% with 8,9-dihydrobarettin (0.1%). For <i>M. edulis</i> the reduction of recruitment was 81% with barettin (0.1%) and 72% with 8,9-dihydrobarettin (0.1%) with the same SPC paint. Furthermore, 14 analogs of barettin and dipodazine were synthesised and tested for their ability to inhibit larval settlement. Two of the analogs have a barettin scaffold and twelve have a dipodazine scaffold. Six of the analogs displayed significant settlement inhibition with the most potent inhibitor being benzo[g]dipodazine (EC<sub>50</sub> value 0.034 µM). The effect of benzo[g]dipodazine was also shown to be reversible. Finally, an investigation of the mode of action was performed on 5-HT receptors. Barettin demonstrated a specific affinity to 5-HT<sub>2A</sub>, 5-HT<sub>2C</sub> and 5-HT<sub>4</sub>, while 8,9-dihydrobarettin interacted only with 5-HT<sub>2C</sub> of the receptor subtypes tested (5-HT<sub>1</sub>-5-HT<sub>7</sub>).</p>
| Identifer | oai:union.ndltd.org:UPSALLA/oai:DiVA.org:uu-6797 |
| Date | January 2006 |
| Creators | Sjögren, Martin |
| Publisher | Uppsala University, Department of Medicinal Chemistry, Uppsala : Acta Universitatis Upsaliensis |
| Source Sets | DiVA Archive at Upsalla University |
| Language | English |
| Detected Language | English |
| Type | Doctoral thesis, comprehensive summary, text |
| Relation | Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, 1651-6192 ; 32 |
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