<p>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. </p><p>The compound bromobenzisoxazolone barettin (cyclo[(6-bromo-8-(6-bromo-benzioxazol -3(1H)-one)-8-hydroxy)tryptophan)]arginine) was isolated from the sponge <i>Geodia barretti</i> and its ability to inhibit larval settlement of the barnacle <i>Balanus improvisus</i> was determined. With an EC<sub>50</sub> value of 15 nM, this compound’s antifouling effect was higher than those of the previously reported brominated dipeptides from <i>Geodia barretti</i>, i.e., barettin and 8,9-dihydrobarettin; moreover, this antifouling effect was demonstrated to be reversible. However, the compound lacked affinity for 5-HT<sub>1-7</sub> receptors, whereas barettin possessed specific affinity to 5-HT<sub>2A</sub>, 5-HT<sub>2C</sub> and 5-HT<sub>4</sub>, while 8,9-dihydrobarettin interacted with 5-HT<sub>4</sub>. 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 EC<sub>50</sub> value of 34 nM, displayed the highest settlement inhibition.</p><p>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 <i>Agelas</i>. 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.</p><p>In conclusion this work has produced new results regarding the potent bioactivity of compounds derived from the sponges <i>Geodia barretti</i> and <i>Agelas</i> spp. and increased SAR knowledge of the fouling inhibition, cytotoxicity and antimicrobial activity of these compounds.</p>
| Identifer | oai:union.ndltd.org:UPSALLA/oai:DiVA.org:uu-8218 |
| Date | January 2007 |
| Creators | Hedner, Erik |
| Publisher | Uppsala University, Division of Pharmacognosy, 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 ; 63 |
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