A total of 35 compounds comprising diverse structural groups of compounds including both alkaloids and terpenes were isolated; fourteen of which are new derivatives. The structures of the new compounds were unambiguously established on the basis of NMR spectroscopic (1H, 13C, COSY, 1H-detected direct and long range 13C-1H correlations) and mass spectrometric (EI, and ESI) data. The identities of the known compounds were established by comparison with published data. Sponge samples originated from several collection sites in Indonesia. A combination of a chemically-and biologically driven approach for drug discovery was employed. Extracts were screened for antibacterial, antifungal, and cytotoxic activities as well as protein kinase inhibition parallel to the usage of TLC, and HPLC coupled to UV and MS in the isolation of the chemically most interesting substances. Enumerated below are the compounds which have been isolated and structurally elucidated and whose bioactivities have been further characterized. 1. Agelas n.sp. secondary metabolites Extract of the unidentified Agelas sponge from Peniki East Island (Seribu Islands), Jakarta, yielded sixteen structurally related brominated pyrroles, including eleven new congeners. Diverse structures of the brominated pyrroles are elucidated wherein several new functionalities are shown to be introduced in the molecule such as in agelanin A (2), agelanin B (3), and agelanesins (4 to 7). Pronounced cytotoxicity against mouse lymphoma cell (L5178Y) was shown by all agelanesins. The tyramine moiety must be responsible for the cytotoxic activity since other congeners without the tyramine unit displayed no cell-growth inhibition. Less degree of bromination on the pyrrole ring may also play a role in its cytotoxicity, considering that the monobrominated pyrrole-agelanesins, agelanesin A (4) and B (5) display lower IC50 in comparison to their dibrominated congeners, agelanesin C (6) and D (7). The iodine substituent presumably is not important for the cytotoxicity. 2. Agelas nakamurai secondary metabolites Extract of the sponge Agelas nakamurai collected in Menjangan Island, yielded five monobrominated pyrrole derivatives, one of which is found to be a new congener, longamide C (20). A hypotaurocyamine diterpenoid, (+)-agelasidine C (19) was isolated together along with adenine related compounds, adenosine and 9-methyladenine as well as the new diterpenoids derivatves, (-)-agelasine-D (18) and its congener (-)-ageloxime-D (17). (-)-Agelasine D, (-)-ageloxime D and (+)-agelasidine-C exhibit prominent cytotoxicity towards the mouse lymphoma cell line L5178Y. Biofilm inhibition assay done on (-)-agelasine D, (-)-ageloxime D, (+)-agelasidine C as well as on (-)-agelasine I suggests that the diterpene part is important for the activity together with the adeninium part. Between the (-)-agelasine D and (-)-ageloxime D, the amine unit on C-6’ is important for the antibacterial activity. A replacement of the amine unit with an oxime group as in the ageloxime D will displace the antibacterial activity but on the other hand will inhibit biofilm-formation of S. epidermidis. Both (-)-agelasine-D and (-)-ageloxime D were toxic to the cyprids larva of Balanus improvisus Darwin, where (-)-ageloxime D was approximately 10 times more toxic than (-)-agelasine D. 3. Pseudoceratina purpurea secondary metabolites Extract of the sponge Pseudoceratina purpurea collected in Watudodol, Banyuwangi, yielded five brominated tyrosine derivatives. The presence of the antifouling substance, aplysamine-2 (27) as well as isofistularin-3-bioconversion products, (+)-aeroplysinin-1 (28), bisoxazolidinone derivatives (29), together with the dienone ketal congeners 30 and 31 were identified. 4. Axynissa sp. secondary metabolites Search on bioactive compounds as protein kinase inhibitors has lead to the isolation of two bisabolene phenol derivatives, (+)-curcuphenol (33) and (+)-curcudiol (34) in the active fractions of Axynissa sp. collected from Ambon, Maluku. 5. Mycale phyllophyla secondary metabolites Study on the sponge extract Mycale phyllophyla collected from Menjangan Island, Bali, revealed the presence of 5-pentadecyl-1H-pyrrole-2-carbaldehyde derivatives (32a) together with (E)-5-pentadec-6-enyl-1H-pyrrole-2-carbaldehyde (32b) in a cytotoxic active fraction. 6. Rhabdastrella rowi secondary metabolite The quinolin-4-ol (35) was obtained from the Balinese marine sponge Rhabdastrella rowi extract in minute quantity. Up to now this compound has only been obtained synthetically and has never been reported from natural sources.

The main focus of this book entitled is to provide an up-to-date coverage of marine sponges and their significance in the current era. This book is an attempt to compile an outline of marine sponge research to date, with specific detail on these bioactive compounds, and their pharmacological and biomedical applications. The book encompasses twenty chapters covering various topics related to Marine Sponges. Initial couple of chapters deal about the worldwide status of marine sponge research, the recent findings regarding dynamics of sponges, and several interesting research areas, that are believed to be deserving of increased attention. Variety of sponges, their toxicology, metagenomics, pharmaceutical significance and their possible applications in biomedicine has been discussed in detail. The second half of this part includes chapters on chemical ecology of marine sponges followed by the discussion on importance of bioeroding sponges in aquaculture systems. The following four chapters of the book deal majorly with the chemical molecules of marine sponges. In the fifth chapter, marine sponge-associated actinobacteria and their pysicochemical properties have been discussed followed by their bioactive potential. The biological application of marine sponges has been presented in later chapters with the classification of biologically active compounds being explored in detail. The second half of the book presents the vast repertoire of secondary metabolites from marine sponges, which include terpenoids, heterocycles, acetylenic compounds, steroids and nucleosides. Further, the bioactive potential of these compounds has also been discussed. One of the constituent chapter elaborates the bioactive alkaloids from marine sponges namely, pyridoacridine, indole, isoquinolene, piperidene, quinolizidine, steroidal and bromotyrosine alkaloids isolated from them. In the next couple of chapters, important sponge polymers and the anticancer effects of marine sponge compounds have been presented. The most interesting aspect of sponge biology is their use in biomedical arena. An effort has been made in this book, to cover the major constituents of sponges and their biomedical potentials. The major portion of sponge body is composed of collagen and silica and used in tissue engineering as scaffold material. This part of the book compiles chapters delineating the isolation of sponge biomaterials including collagen and their use in medical diagnostics. Overall, this book would be an important read for novice and experts in the field of sponge biology.

"Handbook of Marine Natural Products" takes a fresh approach to describing the major themes of research in this rapidly developing field. This two volume reference work begins with a section that provides a taxonomic survey of the secondary metabolites of diverse marine life including microbes, algae, and invertebrates. This is followed by a demonstration of the techniques and strategies employed in modern structure elucidation of complex natural products. The natural roles of marine natural products are then explored in a series of focused chapters which include the topics of symbiosis, anti-predation and antifouling, chemical interactions, and defence against UV stress. Various routes which facilitate the understanding of marine natural product biosynthesis are subsequently explained and these are followed by an extensive set of chapters on the biomedical potential of marine natural products. The latter portion of this section considers the technologies and scientific disciplines necessary for advancing bioactive marine natural product lead compounds into actual pharmaceuticals. The reference work finishes with a selection of chapters describing marine toxins and their impact on public health and seafood resources. Final thoughts presented at the end of the second volume focus on the future of this field of investigation and discovery research. This publication is presented as a reference handbook and general concepts are emphasized and illustrated with numerous interesting examples, graphical information, and a comprehensive index. "Handbook of Marine Natural Products" introduces students who are at advanced undergraduate and entry graduate student levels to this fascinating multidisciplinary field. It is an ideal desk companion for courses focusing on this contemporary area.

Sponges are soft bodied and sessile animals, which lack spine and shell (Armstrong & Quigley 1999). For their defence against fouling organisms, predators, and neighbours competing for space, sponges rely on bioactive natural products instead (Proksch et al. 2002). In this project the marine sponge Ianthella basta Oken, 1815, belonging to the order Verongida Bergquist, 1978, was investigated. Species of the order Verongida are biochemically characterised by the production of brominated tyrosine derivatives. (Bergquist & Cook 2002) Several bastadins and a brominated phenyl acetic acid were isolated. One other sponge was investigated too, Callyspongia “blue”, which yielded a brominated diphenyl ether (compound 5). Bastadins are characteristic secondary metabolites of the sponge I. basta. They are tyrosine-derived, brominated, oxime-bearing macro bis-diaryl ether tetrapeptides, which can be either cyclic or linear. 36 bastadin and hemibastadin derivatives are known; additional to these one new congener named bastadin-24 was isolated during this work. The bastadins do not only inhibit barnacle larval settlement, thrombocyte aggregation, display cytotxicity, inhibit bacterial growth as well as protein kinases, as described in this thesis, but do also show for example antagonistic effects on the ryanodin receptor and calcium channels in the endoplasmatic reticulum (Mack et al. 1994, Chen et al. 1999) In this project ten bastadins (bastadin-2, -3, -4, -6, -7, -9, -10, -11, -16, -24), one hemibastadin (hemibastadin-1), one phenyl acetic acid and one brominated diphenyl ether were isolated and elucidated. In addition to these three hemibastadin-1 congeners, were synthesized (L-tyrosine-tyramide, norbromohemibastadin-1 and 6,6’- dibromohemibastadin-1) for SAR studies. All compounds (isolated and synthesized) were tested in following assays: i) barnacle antifouling assay, ii) human thrombocyte aggregation, iii) cytotoxicity, iv) antibiotic activity, and v) inhibition of different protein kinases. Biofouling causes significant economical and environmental losses worldwide through reducing boat speeds and increasing fuel consumption (Wahl 1989). Until today organotin, copper oxide, and herbicide coatings have been commercially used for preventing on-growth. These coatings were, however recently banned IMO with a complete prohibition by 2008 (IMO 2001). Barnacles are severe macro-fouling organisms. Attempts are now being made to understand the physiology of barnacle larvae, their settlement behaviour, and their ability to metamorphose (Fusetani 2004, Sjögren et al. 2004a, Dahlström et al. 2005). This is important not only for understanding ecological processes, but also for finding environmentally sound non-toxic antifouling agents. As sponges are filter feeders, over-growth by fouling organisms would be devastating for their survival as inhaling pores would likely be clogged. A reliable chemical defence is therefore decisive for these organisms. And they therefore have become prime candidates in the search for antifouling entities. The bastadins isolated here were screened in the barnacle assay together with the synthesized hemibastadin analogues as well as other previously isolated brominated compounds of sponge origin. All bastadins, hemibastadin-1, norbromohemibastadin-1, 2,2’-dibromo-hemibastandin-1, and psammaplin A, turned out to be active against barnacle cyprid settlement. Bastadin-16, psammaplin A, hemibastadin-1, and norbromohemibastadin-1 also showed to be toxic against the larvae. The conclusion was drawn that an oxime group is decisive for the antifouling activity in these compounds. In contrast to the lipophilic psammaplin A, the hydrophilic sulphated psammaplin A derivative showed no antifouling activity. It was therefore hypothesized that the compound needed to cross membranes and that the target for psammaplin A lied intracellularly. The brominated diphenyl ether (also called compound 5) was active without any toxicity in the barnacle antifouling assay. This compound was taken into screening studies together with other diphenyl ethers against bacterial growth, diatom activity, and mollusc settlement. Compound 5 turned out to be the most active substance in all of the three assays. The other active brominated diphenyl ethers did all carry four bromines, just like compound 5. The non-brominated diphenyl ether did not display any activity at all. The knowledge that oxime bearing compounds possess thrombocyte anti-aggreagtion properties took the bastadins to be tested against human thrombocyte aggreagation with various results. Bastadin-9 and -16 showed the most pronounced activites followed by norbromohemibastadin-1 as well as bastadin-6 and -7. Neither of these inhibited the thromboxane formation to an effeicient extent. L-tyrosine-tyramide did not show any activity and the activity of the other hemibastadin-1 analogues decreased with increasing amounts of bromines. Bastadin-16 and norbromohemibastadin-1 were taken further to studies of the mechanism of action and tested against thrombocyte aggregation stimulated with collagen, ADP, collagen+SC 560 (COX-1 antagonist), and the thromboxane receptor (TP) agonist U 46619. The results pointed in the direction of a TP antagonistic effect. Bastadin-16 and norbromohemibastadin-1 as well as the inactive bastadins 3 and 11 were tested in a TP displacement assay. Interestingly all the tested compounds turned out to be active against TP. Further tests remain to be done to evaluate why some bastadin-3 and -11 do not inhibit the aggregation but indeed TP. Binding to the plasma proteins may be a reason for this observation. All compounds were tested for their cytotoxicity against the mouse lymphoma, L5178Y. Active bastadins were bastadin-2, -4, -6, -11, and -16. Compound 5 was the most active substance and interestingly the hemibastadin-1 analogue L-tyrosinetyramide, was the only synthezised derivative displaying activity. This compound was not active in any other assays. It is difficult to draw any SAR conclusions to the cytotoxicity data, but obviously the bromination does not play a major role. The compounds tested for their protein kinase inhibition were bastadin-3, -6, -7, -11, -16, and -24 as well as the full set of synthesized hemibastadin-1 analogues. Bastadin-3 exhibited the strongest inhibition against most protein kinases followed by bastadin-24. The least active bastadins turned out to be bastadin-6 and -16, which only inhibited a few protein kinases. Bastadin-7 showed a broader inhibitory effect than these, but not as strong as bastadin-3 and bastadin-24. None of the successfully synthesized hemibastadin-1 analogues were active. A linear structure seems to advocate a protein kinase inhibition. None of the compounds isolated or synthesized in this project showed any activity against S.epidermidis biofilm formation. However, activity against several bacterial stains including S. epidermidis, S. aureus, and E. faecium was shown by bastadin-3 and -4 as well as hemibastadin-1 and compound 5. Activity against L. major and T. brucei was observed for compound 5. Bastadin-4 was also active against T. brucei. As stated in the beginning of this thesis, sponge-derived metabolites possess a great vary of biological activities. This is probably because of their defensive function in their original environment. This defence mechanism can also be seen by the antifouling activity displayed by the bastadins. The novel bastadin activities found here may contribute to the understanding of the mode of action of these entities as well as increase the comprehension of the biological and pharmacological systems as such.