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Antifouling activity of synthesized peptide analogs of the sponge metabolite barettin
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
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2006 (English)In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 27, no 9, 2058-2064 p.Article in journal (Refereed) Published
Abstract [en]

Barettin (cyclo [(6-bromo-8-en-tryptophan) arginine]), a diketopiperazine isolated from the marine sponge Geodia barretti, is a potent inhibitor of barnacle larvae settlement with an EC50-value of 0.9 mu M. In the present study, 14 analogs of barettin and its structural congener dipodazine were synthezised and tested for their ability to inhibit larval settlement. Two of the analogs have an intact barettin skeleton. The remaining analogs have a dipodazine skeleton (a diketopiperazine where arginine is replaced with glycine). Six of the tested synthetic analogs displayed significant settlement inhibition with the most potent inhibitor being benzo[g]dipodazine, which displayed even stronger activity than barettin (EC50-value 0.034 mu M). The effect of benzo[g]dipodazine was also shown to be readily reversible, when cyprids were transferred to filtered seawater (FSW).

Place, publisher, year, edition, pages
2006. Vol. 27, no 9, 2058-2064 p.
Keyword [en]
barettin, dipodazine, marine sponges, Geodia barretti, synthesis, cyprid settlement
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-94327DOI: 10.1016/j.peptides.2006.03.027ISI: 000240379800002PubMedID: 16781016OAI: oai:DiVA.org:uu-94327DiVA: diva2:168141
Available from: 2006-04-19 Created: 2006-04-19 Last updated: 2011-06-16Bibliographically approved
In thesis
1. Bioactive Compounds from the Marine Sponge Geodia barretti: Characterization, Antifouling Activity and Molecular Targets
Open this publication in new window or tab >>Bioactive Compounds from the Marine Sponge Geodia barretti: Characterization, Antifouling Activity and Molecular Targets
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The marine sponge Geodia barretti 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 Balanus improvisus. 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: EC50 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 B. improvisus and the blue mussel Mytilus edulis (major Swedish foulers). The most efficient paint was a SPC polymer, for which the reduction of recruitment of B. improvisus was 89% with barettin (0.1%) and 61% with 8,9-dihydrobarettin (0.1%). For M. edulis 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 (EC50 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-HT2A, 5-HT2C and 5-HT4, while 8,9-dihydrobarettin interacted only with 5-HT2C of the receptor subtypes tested (5-HT1-5-HT7).

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 57 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 32
Keyword
Pharmacognosy, Geodia barretti, barettin, secondary metabolites, settling inhibition, Balanus improvisus, analogs, 5-HT, Farmakognosi
Identifiers
urn:nbn:se:uu:diva-6797 (URN)91-554-6534-X (ISBN)
Public defence
2006-05-11, C10:305, BMC, Box 574, 75123, Uppsala, 09:30
Opponent
Supervisors
Available from: 2006-04-19 Created: 2006-04-19Bibliographically approved
2. Bioactive Compounds in the Chemical Defence of Marine Sponges: Structure-Activity Relationships and Pharmacological Targets
Open this publication in new window or tab >>Bioactive Compounds in the Chemical Defence of Marine Sponges: Structure-Activity Relationships and Pharmacological Targets
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Marine invertebrates, in particular sponges, represent a source of a wide range of secondary metabolites, many of which have been attributed various defensive capabilities against environmental stress factors. In this thesis sponge-derived low-molecular peptide-like compounds and associated analogs are investigated for bioactivity and pharmacological targets.

The compound bromobenzisoxazolone barettin (cyclo[(6-bromo-8-(6-bromo-benzioxazol -3(1H)-one)-8-hydroxy)tryptophan)]arginine) was isolated from the sponge Geodia barretti and its ability to inhibit larval settlement of the barnacle Balanus improvisus was determined. With an EC50 value of 15 nM, this compound’s antifouling effect was higher than those of the previously reported brominated dipeptides from Geodia barretti, i.e., barettin and 8,9-dihydrobarettin; moreover, this antifouling effect was demonstrated to be reversible. However, the compound lacked affinity for 5-HT1-7 receptors, whereas barettin possessed specific affinity to 5-HT2A, 5-HT2C and 5-HT4, while 8,9-dihydrobarettin interacted with 5-HT4. In an attempt to evaluate structure-activity relationships synthesized analogs with barettin and dipodazine scaffolds were investigated for antifouling activity. The analog benso[g]dipodazine, with an EC50 value of 34 nM, displayed the highest settlement inhibition.

The studies of the structure-activity relationships of sponge-derived compounds were extended to cover analogs of agelasines and agelasimines originally isolated from sponges of the genus Agelas. Synthesized (+)-agelasine D and two structurally close analogs were investigated for cytotoxic and antibacterial activity. The profound cytotoxicity and broad spectrum antibacterial activity found prompted a further investigation of structure-activity relationships in 42 agelasine and agelasimine analogs and several characteristics that increased bioactivity were identified.

In conclusion this work has produced new results regarding the potent bioactivity of compounds derived from the sponges Geodia barretti and Agelas spp. and increased SAR knowledge of the fouling inhibition, cytotoxicity and antimicrobial activity of these compounds.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 54 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 63
Keyword
Pharmacognosy, 5-hydroxytryptamine, agelasine, agelasimine, antibacterial, antifouling, barettin, bromobenzisoxazolone barettin, cytotoxic, marine, secondary metabolite, sponge, Farmakognosi, Agelas, Geodia barretti
Identifiers
urn:nbn:se:uu:diva-8218 (URN)978-91-554-6971-9 (ISBN)
Public defence
2007-10-19, B7:113a, BMC, BMC, Uppsala, 13:15
Opponent
Supervisors
Available from: 2007-09-27 Created: 2007-09-27 Last updated: 2011-06-16Bibliographically approved

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