uu.seUppsala universitets publikasjoner
Endre søk
RefereraExporteraLink to record
Permanent link

Direct link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Brominated cyclodipeptides from the marine sponge Geodia barretti as selective 5-HT ligands
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för biologisk beroendeforskning.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för biologisk beroendeforskning.
Vise andre og tillknytning
2006 (engelsk)Inngår i: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 69, nr 10, s. 1421-1424Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The brominated cyclodipeptides barettin(cyclo[(6-bromo-8-entryptophan) arginine]) and 8,9-dihydrobarettin ( cyclo[(6-bromotryptophan) arginine]) isolated from the marine sponge Geodia barretti have previously been shown to inhibit settlement of barnacle larvae in a dose-dependent manner in concentrations ranging from 0.5 to 25 mu M. To further establish the molecular target and mode of action of these compounds, we investigated their affinity to human serotonin receptors. The tryptophan residue in the barettins resembles that of endogenous serotonin [5-hydroxytryptamine]. A selection of human serotonin receptors, including representatives from all subfamilies (1-7), were transfected into HEK-293 cells. Barettin selectively interacted with the serotonin receptors 5-HT2A, 5-HT2C, and 5-HT4 at concentrations close to that of endogenous serotonin, with the corresponding K-i values being 1.93, 0.34, and 1.91 mu M, respectively. 8,9-Dihydrobarettin interacted exclusively with the 5-HT2C receptor with a K-i value of 4.63 mu M; it failed to show affinity to 5-HT2A and 5-HT4, indicating that the double bond between the tryptophan and arginine residue plays an important role in the interaction with the receptor proteins.

sted, utgiver, år, opplag, sider
2006. Vol. 69, nr 10, s. 1421-1424
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-94328DOI: 10.1021/np0601760ISI: 000241562700009PubMedID: 17067154OAI: oai:DiVA.org:uu-94328DiVA, id: diva2:168142
Tilgjengelig fra: 2006-04-19 Laget: 2006-04-19 Sist oppdatert: 2018-01-13bibliografisk kontrollert
Inngår i avhandling
1. Bioactive Compounds from the Marine Sponge Geodia barretti: Characterization, Antifouling Activity and Molecular Targets
Åpne denne publikasjonen i ny fane eller vindu >>Bioactive Compounds from the Marine Sponge Geodia barretti: Characterization, Antifouling Activity and Molecular Targets
2006 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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).

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2006. s. 57
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 32
Emneord
Pharmacognosy, Geodia barretti, barettin, secondary metabolites, settling inhibition, Balanus improvisus, analogs, 5-HT, Farmakognosi
Identifikatorer
urn:nbn:se:uu:diva-6797 (URN)91-554-6534-X (ISBN)
Disputas
2006-05-11, C10:305, BMC, Box 574, 75123, Uppsala, 09:30
Opponent
Veileder
Tilgjengelig fra: 2006-04-19 Laget: 2006-04-19bibliografisk kontrollert
2. Bioactive Compounds in the Chemical Defence of Marine Sponges: Structure-Activity Relationships and Pharmacological Targets
Åpne denne publikasjonen i ny fane eller vindu >>Bioactive Compounds in the Chemical Defence of Marine Sponges: Structure-Activity Relationships and Pharmacological Targets
2007 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2007. s. 54
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 63
Emneord
Pharmacognosy, 5-hydroxytryptamine, agelasine, agelasimine, antibacterial, antifouling, barettin, bromobenzisoxazolone barettin, cytotoxic, marine, secondary metabolite, sponge, Farmakognosi, Agelas, Geodia barretti
Identifikatorer
urn:nbn:se:uu:diva-8218 (URN)978-91-554-6971-9 (ISBN)
Disputas
2007-10-19, B7:113a, BMC, BMC, Uppsala, 13:15
Opponent
Veileder
Tilgjengelig fra: 2007-09-27 Laget: 2007-09-27 Sist oppdatert: 2011-06-16bibliografisk kontrollert

Open Access i DiVA

Fulltekst mangler i DiVA

Andre lenker

Forlagets fulltekstPubMed

Personposter BETA

Göransson, Ulf

Søk i DiVA

Av forfatter/redaktør
Göransson, Ulf
Av organisasjonen
I samme tidsskrift
Journal of natural products (Print)

Søk utenfor DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric

doi
pubmed
urn-nbn
Totalt: 617 treff
RefereraExporteraLink to record
Permanent link

Direct link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf