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Sniðmát Meistaraverkefnis HÍ Exploring marine sponges and their associated microorganisms as a source of natural compounds Margarida Costa Thesis for the degree of Philosophiae Doctor December 2018 Leit að sjávarnáttúruefnum úr svömpum og samlífsörverum þeirra Margarida Costa Ritgerð til doktorsgráðu Háskóli Íslands Heilbrigðisvísindasvið Lyfjafræðideild Desember 2018 Thesis for a doctoral degree at the University of Iceland. All right reserved. No part of this publication may be reproduced in any form without the prior permission of the copyright holder. © Margarida Costa 2018 ISBN 978-9935-9445-1-1 Printing by Háskolaprent Reykjavik, Iceland 2018 Author´s address Ana Margarida Pinto e Costa Faculty of Pharmaceutical Sciences School of Health Sciences University of Iceland Supervisor Professor Margrét Thorsteinsdóttir Faculty of Pharmaceutical Sciences School of Health Sciences University of Iceland Co-supervisor Professor Sesselja Ómarsdóttir Faculty of Pharmaceutical Sciences School of Health Sciences University of Iceland Doctoral committee Professor Elín Soffia Ólafsdóttir (other than Faculty of Pharmaceutical Sciences supervisors) School of Health Sciences University of Iceland Dr. Marta Pérez Natural Products Department PharmaMar, Spain Opponents Professor Olivier Thomas School of Chemistry, Marine Biodiscovery National University of Ireland Assistant Professor Benjamín Sveinbjörnsson Faculty of Physical Sciences School of Engineering and Natural Sciences University of Iceland Ágrip Hafið hefur að geyma mikinn líffræðilegan fjölbreytileika er gríðarleg uppspretta lífvirkra efnasambanda með mikla möguleika á þróun nýrra lyfjasprota. Sjávarsvampar og samlífsörverur þeirra framleiða fjölbreytileg og einstök annarstigs efnasambönd. Markmið þessa verkefnis var að rannsaka efnainnihald og lífvirkni náttúruefna úr mismunandi sjávarasvömpum og samlífsörverum þeirra. Í því skyni var fimm svömpum safnað í hafinu í kringum Ísland, þremur svömpum úr Indó-Kyrrahafinu og tvær tegundir geislagerla (e.actinomycetes) safnað af svömpum, þeir ræktaðir upp og einangraðir. Hemjandi áhrif náttúruefnanna voru könnuð á krabbameinsfrumur, bakteríudrepandi áhrif í rækt og offituvirkni í sebrafiskalíkani. Lífrænir úrdrættir úr fimm íslenskum sjávarsvömpum voru rannsakaðir. Óskautuðu úrdrættirnir innhéldu mikið af fituefnum. Efnagreiningaraðferð með háhraðavökvagreini tengdum massagreini (UPLC-QTOF-MS) var hámörkuð til að skima fyrir og fjarlægja (dereplication) þekkt náttúruefni til að auka skilvirkni við greiningu á skautuðum úrdráttum. Sjö þekktir núkleósíðar og núkleóbasar voru greindir í útdrættinum (e. dereplication) þegar leitað var eftir nýjum efnasamböndum. Þekktu efnasamböndin voru einangruð og efnabygging þeirra staðfest með 1H-kjarnsegulgreiningu (NMR). Frekari rannsóknum á lífvirknileiddri einangrun og efnainnihaldi íslenskra sjávarsvampa var hins vegar hætt vegna þess að úrdrættirnir sem unnið var með sýndu enga lífvirkni í þeim prófunum sem framkvæmd voru. Þrjár svamptegundir: Acanthostrongylophora sp., Acanthodendrilla sp. og Acanthostrongylophora ingens sem safnað var í Indó-Kyrrahafinu voru rannsakaðar. Nýtt haploscleridamín efni og köfnunarefnis- hliðstæðuefnasamband voru einangruð úr metanólúrdrætti Acanthostrongylophora. Tvö ný díterpen efnasambönd voru einangruð úr svampinum Acanthodendrilla og leiddi þessi uppgvötum í ljós að Acanthodendrilla var eina Dendroceratida ættkvíslin þar sem þessi efnasambönd höfðu ekki áður fundist. Fimm ný efnasambönd úr bisabólan- efnaflokknum voru einangruð og skilgreind úr svampnum Acanthostrongylophora ingens, ásamt eftirfarandi þekktum efnasamböndunum. Niðurstöður úr lífvirknimælingum sýndu að efnasambandið, 6-(1,5-dímetýl-1,4-hexadíenýl)-3-metýlbenzen-1,4-díól hafði iii frumuhemjandi áhrif krabbameinsfrumur í rækt. Auk þess höfðu þessi bisabólan efnasambönd hamlandi áhrif í offituvirknilíkani í sebrafiskum. Efnasambönd með tveimur flúorvirinín C hópum voru auðkennd í úrdráttum frá samlífsörverum svampa af geislagerlastofninum (e. Actinomycete) (DIL- 12-02-135). Þessi efnasambönd voru auðkennd með massagreiningu og er þetta í fyrsta sinn sem þessi efnasambönd eru einagruð úr sjávarlífverum. Jafnframt voru tvö þekkt efni, mangrolide A og naphthoquinone, einangruð með aðstoð massagreiningaraðferðar úr öðrum geislagerlastofni (CP9-13-01- 036). Niðurstöður sýndu að naphthoquinone hefur bæði krabbameinsfrumuhemjandi áhrif og sýklahemjandi áhrifa gegn Staphylococcus aureus. Niðurstöður verkefnisins sýna að svampar og samlífsörverur þeirra eru rík uppspretta áhugaverðra og fjölbreyttra náttúruefna með mismunandi lífvirkni og því mikilvægt að halda áfram leitinni að nýjum og spennandi efnum úr lífverum í hafinu. Lykilorð: Sjávarnáttúruefni, sjávarsvampar, geislagerlar, annarstigs efnasambönd, lífvirkni iv Abstract The ocean represents a tremendous source of biologically active metabolites with great potential for the development of new pharmaceuticals. Marine sponges and their microbial associates are known as the most prolific source of structurally diverse and unique secondary metabolites. The present work aimed to explore the potential of different sponge and sponge-associated microorganisms as a source of natural compounds with possible pharmacological applications. Five sponge individuals collected in the Icelandic waters, three in the Indo-Pacific Ocean and two sponge-associated actinomycete strains were used for that purpose. Cytotoxic, anti-bacterial and anti-obesity activities were tested. Organic extracts were prepared from the five sponges collected in Iceland. The apolar extracts were found to be rich in fatty acids. The UPLC-QTOF-MS method used for dereplication of the present natural compounds was successfully optimized in order to increase efficiency when analyzing polar extracts. Seven known nucleosides and a nucleobase were dereplicated. The compounds were isolated and their structure confirmed by 1H-NMR. The Icelandic sponge's study was, however, discontinued due to the absence of promising extracts. Three sponge specimens collected in the Indo-Pacific Ocean were studied: Acanthostrongylophora sp., Acanthodendrilla sp. and Acanthostrongylophora ingens. Acanthostrongylophora sp. methanolic extract resulted in the isolation of haploscleridamine and a new nitrogenated analog. Acanthodendrilla sp. was found to be the producer of two spongian diterpenes with novel structures. This discovery withdrew Acanthodendrilla of being the only Dendroceratida genus that had not been reported as a producer of this class of compounds. Acanthostrongylophora ingens revealed to be the producer of five new bisabolane related compounds, the previously reported 6-(1,5- dimethyl-1,4-hexadienyl)-3-methylbenzene-1,4-diol and 1-(2,4-dihydroxy-5- methylphenyl)ethan-1-one. The bioactivity studies showed that 6-(1,5- dimethyl-1,4-hexadienyl)-3-methylbenzene-1,4-diol have moderate cytotoxic activity against the tested cancer cell lines. Bisabolane-related compounds also demonstrated to have anti-obesity potential based on the zebrafish Red Nile assay. The actinomycete strain DIL-12-02-135 mycelial cake was found to contain two group C fluvirucinins. Those compounds were obtained through mass spectrometry-guided isolation and represent the first isolation of this class of v compounds from marine sources. Another mass spectrometry-guided isolation carried out in the actinomycete strain CP9-13-01-036 yielded two known compounds: mangrolide A and a naphthoquinone. Naphtoquinone was shown to have both strong cytotoxic activity against the tested cell lines and anti-bacterial activity against Staphylococcus aureus. The studied marine sponges and actinomycete strains resulted in several known and new compounds with valuable bioactivities. Marine sponges demonstrated, once again, to be a tremendous source of bioactive natural compounds. Keywords: Marine natural products, marine sponges, actinomycetes, secondary metabolites, bioactivity vi Acknowledgments The experimental work reported in this thesis was mainly developed in the Faculty of Pharmaceutical Sciences - University of Iceland and at ArcticMass ehf. Reykjavik, Iceland. A secondment of eight months was also done at PharmaMar S.A. facilities in Madrid, Spain. This Ph.D. project was financially supported by Marie Curie Actions of the European Union's Seventh Framework Program FP7/2007-2013/ under REA grant agreement number 607786, BluePharmTrain, and Bergthora and Thorsteinn Scheving Thorsteinsson Fund. To all foundations, institutions and private companies involved, thank you very much for making it possible. I am very grateful for all the experience and knowledge acquired during this journey. I would like to thank, particularly, to my mentor Professor Margrét Thorsteinsdóttir for all the guidance, encouragement and advices during the past years. To my co-supervisor, Professor Sesselja Ómarsdóttir thanks for her continuous support and scientific input. Besides them, I would also like to thank my committee member Professor Elín Soffía Ólafsdóttir for her reviews, corrections and motivation. A special acknowledgment goes to Marta Pérez, in PharmaMar. Thank you so much for the opportunity to be involved with that great company where marine natural products are the only focus, but more than that, thank you for all the scientific support. Your help was crucial for this work! Still in PharmaMar, I would like to thank specially to Dr. Librada Cañedo for all the guidance during the work with microorganisms and to Dr. Rogélio Férnandez for all the NMR help. I would also like to thank everyone
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