Indonesian J. Pharm. Vol. 25 No. 4 : 199 – 222 ISSN-p : 2338-9427 DOI: 10.14499/indonesianjpharm25iss4pp199 Review Article

NEW HOPE ON DRUG LEADS DEVELOPMENT FROM DEEP OCEAN: HALOGENATED ALKALOIDS OF AGELAS SPONGES

Triana Hertiani

Faculty of Pharmacy, ABSTRACT Universitas Gadjah Mada, Agelas sponge is found in abundancy from Indonesia’s Sekip Utara, Yogyakarta, ocean. This sponge produces an important chemotaxonomic group Indonesia 55281 of compounds, derived from pyrrole-imidazole alkaloids. This group of compounds is one of those exclusively found from marine Submitted: 04-05-2014 environment. Marine sponges are reported to be promising drug Revised: 05-07-2014 lead producers having unique chemical structures of which many Accepted: 08-09-2014 have no terrestrial counterparts. The objective of this report is to

give an overview of the reported attempts from up to down stream *Corresponding author to develop pyrrole-imidazole alkaloids as new drug lead. Literatures Triana Hertiani up to 2013 reporting this group of compounds from Agelas sponges

were studied. Discussion on the halogenated alkaloids covers the Email : [email protected] producers, description of high chemical diversity, identification, biosynthesis and ecological relevance as well as their role as a promising drug candidate. Alternatives to provide continous supplies for drug development are also discussed considering that wild harvesting of the sponge producers can lead to ecological damage in the future . Broad range of interesting pharmacological importance as well as several success in developing synthetic route for production supports its development as drug candidate.

Key words: Agelas, halogenated alkaloids, drug lead, sponge

INTRODUCTION also clinical trials which can be expected that A coverage of almost 75% of the Earth‟s the number will increase in the near future surface has positioned the ocean as the major (Amador et al., 2003). producer of natural products (Whitehead, According to Proksch and co-workers 1999). Unlike its terrestrial counterpart, unique (2002), the majority of marine natural products structures has been encountered and the currently in clinical trial or under clinical utilization has lack of ethno-medical history. evaluation are produced by invertebrates. The This issue together with technical difficulties in soft bodied, sessile or slow-moving marine collecting marine organisms held back the invertebrates having lack of morphological development of marine-derived natural products defense structure in form of spines or a as therapeutic agents. Nevertheless, synergism protective shell make them more vulnerable for collaboration involving pharmaceutical predation which justifies the ecological companies, academic institutions, governmental importance of utilizing chemical constituents and so non-governmental agencies, has made a for surveillance in the respective invertebrates significant progress in form of systemic (Proksch et al., 2002). investigations directed towards the collection Database provided by MarinLit (2002) and characterizations of marine natural shows that the source of new marine natural products, as well as the evaluation of their products is dominated by sponges (37%) biological activity (Christian et al., 1997; followed by coelenterates (21%). Blunt et al. in Amador et al., 2003). Large numbers of novel a review of marine natural products (2005) and marine-derived compounds reported in the Hu et al. (2011) supported the above mentioned literatures in the last decades exhibit the statement. This data somehow define the role positive development (Mayer and Gustafson, of marine invertebrates as a potential source of 2003; Amador et al., 2003). Some promising new drug candidates. Up to now more than agents which are naturally derived or the 17,000 marine products have been described synthetic derivates have entered preclinical and (MarinLit, 2006) of which sponges are

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responsible for more than 5300 different Murti, 2006; Eder et al., 1999), and A. products (Faulkner 2000, 2001, 2002). nemoecinata (Pedradab, 2005) were examples of Moreover, the chemical diversity of sponge secondary metabolite producers from the products is remarkable, in addition to the Agelas collected from Indonesia sea, of which unusual nucleosides, bioactive terpenes, sterols, A. nakamurai as the most reported sponge from cyclic peptides, alkaloids, fatty acids, peroxides, this genus (Hertiani et al., 2010; Murti, 2001, and amino acid derivatives (which are 2006; Sapar et al., 2013; Eder et al., 1999; frequently halogenated) (Sipkema et al., 2005). Trianto, 2005). Several other reports on this Pharmaceutical interest in sponges itself particular sponge are also derived from the was aroused in the early 1950s by the discovery neighbour sea, Papua New Guinea (Iwagawa et of the unusual nucleosides spongothymidine al., 1998). Many pharmacological-interesting and spongouridine in the marine sponge compounds found in these particular sponges Cryptotethia crypta (Bergmann and Feeney, 1950, including the marine specific halogenated 1951). These nucleosides were the basis for the alkaloids. synthesis of Ara-C, the first marine-derived anticancer agent, and the antiviral drug Ara-A Halogen containing metabolites (Prokch et al., 2002). Marine sponges are a rich source of As also found in terrestrial metabolites, highly halogenated compounds. They may many of marine natural products act as function to resist feeding by fish and fouling by regulators of specific biological functions. barnacles, bacteria, and fungi (Gribble, 2004). Some of them have pharmacological activity One of the widest group of halogenated due to their specific interactions with receptors alkaloids are bromine-containing alkaloids and enzymes which are not found in their (Dembitsky and Tolstikov, 2003). High halogen terestral counterpart. Marine metabolites face concentration in sea water has a consequence the problem that they become immediately of its contribution in the biosynthesis of some diluted by large volumes of seawater of which marine metabolites. Catalyzed by haloperoxi- requires a highly potency on a molecular basis dases, halogenide anions from sea-water are and retains a relatively low solubility oxidized (Hoffmann and Lindel, 2003) and (McConnel et al., 1994). It has been repeatedly then incorporated into organic compounds by shown that the accumulation of toxic or specific halogenases (Van Pee, 2001). distasteful natural product is an effective Enormous reactivity towards electrophilic strategy to repel potential predators (e.g. fishes) halogenation reactions is probably the cause or in a competition for living space (Proksch et why heteroatom containing secondary al., 2002; Proksch and Ebel, 1998; Proksch, metabolites such as pyrroles, indoles, phenols, 1999; McClintock and Baker, 2001). These and tyrosines are commonly found to be secondary metabolites, which are produced as a halogenated in sponges. Despite the relative result of evolutionary pressures to reserve or concentrations of chloride, bromide and iodide enhance an organisms ecological success ions exist in sea water (559mM, 0.86mM and (Proksch, 1999), have evolved into structurally 0.45M respectively); marine organisms oxidize diverse and usually stereo-chemically complex more bromide than chloride for incorporation compounds with specific biological activity into organic compounds (Faulkner, 1995). This (Edrada et al., 2000) many of which belong to may reflect the higher importance of novel chemical groups solely found in marine bromoperoxidase (BPO) relative to chloro- environment (Carte, 1993). peroxidase (CPO) in marine life, and underline The Agelas sponges classification falls the fact that chlorine cannot be oxidized to into phylum Porifera; class Demospongiae; active chlorine by BPO (Gribble, 1996b, 1998). order Agelasida; family Agelasidae and genus Therefore bromide ions have greater ease to be Agelas. This sponge found in abundance in oxidized and give bromonium species which Indonesia suggesting evolutionary fittness. react readily as electrophils with unsaturated Agelas linnaei, A. nakamurai (Hertiani et al., 2010; species (Whitehead, 1999).

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Brominated pyrroles have been isolated A distinct pseudomolecular ion pattern on several occasions as major constituents of of brominated compounds in LC/MS is very marine sponges. Many of the simpler members important for preliminary characterization. This of this class of compounds are structurally method can easily distinguish the presence of related as they comprise two heterocyclic rings different brominated metabolites from sponge linked by a linear chain (Whitehead, 1999). crude extracts. In LC/MS, after having the Over the last thirty years, numerous similar HPLC separation, the resulted peaks are alkaloids with various structures and interesting detected by the UV detector and mass biological activities have been isolated spectrometer. As more compounds can share essentially (but not exclusively) from various the same UV pattern, the possibility of sharing species of Agelasidae, Hymeniacidonidae and the same molecular weight is less. In the case of Axinellidae (Williams and Faulkner, 1996). brominated compounds, it is very rare to find different compounds having the same Characterization of halogenated molecular weight with the same degree of alkaloids by LC/MS bromination. The presence of bromine and chlorine in a molecule can be easily distinguished from the Structural diversity of pyrrole-imidazole molecular ion peak shown by their mass alkaloids in Agelas sponges spectra. The molecular ions of chlorine and Pyrrole-imidazole alkaloids are bromine-containing compounds will show exclusively found in marine sponges, mainly of multiple peaks due to the fact that each halogen the families Agelasidae, Axinellidae, and exists as two isotopes. While 79Br and 81Br exist Halichondridae. The underlying C11N5 building in relatively equal abundance, the natural block consists of a pyrrolyl-2-carbonyl unit chlorine isotopes consist of 75.77% of 35Cl and being connected via an amide linkage to a 2- of 24.23% 37Cl (Smith, 2005). Thus the amino-5-(3-amino) propylimidazole partial molecular ion of a chlorine-containing structure (Lindel et al., 2000a). The pyrrole-2- compound will have two peaks, separated by carbonyl unit can be non-, mono-, or two mass units, in an intensity ratio of 3:1, dibrominated in the 4- and 5- positions. while in a bromine-containing compounds Bromination of the pyrrole 3-position or of the these two peaks occur in approximately equal imidazole part has not been observed intensities. Therefore the presence of one (Hoffmann and Lindel, 2003). In some bromine in a molecule e.g. in mukanadin C will metabolites, the linear chain is cyclized to form be represented by two molecular ion peaks an AB core of a pyrrolopyrazinone bicyclic having a difference of two mass units in an system such as in dibromophakellin, agelastatin equal height. In the meantime, the presence of A, pala‟uamine, longamide A, and cyclooroidin two bromines as in midpacamide will appear as (Figure 1) (Jacquot et al., 2004). three molecular ion peaks having a difference A comparison of bromopyrrole of two mass units in an intensity ratio of 1:2:1. congeners reported from Agelas nakamurai Furthermore in a compound bearing three and Agelas linnaei reveals interesting finding bromines such as aplysamine-2, the molecular (Figure 2). In the A. nakamurai most ion will appear as multiple peaks having two reported congeners are monobrominated mass unit differences in a ratio of 1:2:2:1 (Hertiani et al., 2010; Murti, 2006; Uemoto et al., (Hertiani et al., 2009; Hertiani et al., 2010). 2009; Iwagawa et al., 1998) or dimers of The presence of fluorine and iodine, by monobrominated monomers (Eder et al., 1999), contrast, is mono isotopic, having masses of 19 with an exception in Ageladine A (Most of A. and 127 amu respectively (Smith, 2005). Thus linnaei metabolites, the pyrrole rings are neither fluorine nor iodine substitution will dibrominated with exception of agelanesin A, cause the above phenomenon as can be agelanesin B and agelongine which are observed in agelanesin B and agelanesin D monobrominated. Another difference observed (Hertiani et al., 2010). is that all metabolites of A. nakamurai found in

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O O O NH2 H H N N N H H Br A B C Br A B A B H N N H N HO N N D H C NH Br Br Cl N N N HN H N O NH2 HO palau'amine NH2 (-)-dibromophakellin agelastatin A CH3 NH2 O O

H H N N Br A B Br A B N N

Br Br OH N NH longamide A cyclooroidin 2 NH

Figure 1. Example of pyrrole-imidazole compounds having a pyrrolopyrazinone bicyclic system (Jacquot et al., 2004).

A. linnaei mebolites A. nakamurai metabolites A. nemoecinata metabolites 1H O Br N 1 O N 5 2 5 2 6 No reported congener 6 7 4 3 HN 4 7 Br 8 Br 3 HN 8 9 9 10 10 4-Bromopyrrole- 11 11 OH OH 2-carboxamido)-butanoic acid 4-(4,5-Dibromo-1-methyl-1H-pyrrole- (Murti, 2006) 2-carboxamido) butanoic acid O O H R 5 N O X 1 O 2 N No reported congener 4 6 5 2 8 3 HN 6 Br 7 4 7 10 3 HN Br 8 9 9 11 15 10 Hymenidin 12 R= H; X= Br; Oroidin 11 14 HN R= H, X = H, Keramidine N R= CH3; X = H: Sventrin HN 12 14 13 N

H2N NH2 H N O Br No reported congener N O 5 5 6 4-Bromo-1H-pyrrole- 6 4,5-Dibromo-1-methyl-1H-pyrrole- 2 4 2 2-carboxylic acid 4 2-carboxylic acid OH OH 3 Br 3 Br

NH2 O NH2

OCH3 8 + N HN 7 9NH HN 11 12 HO * * * 6 10 Br 13 N 14N N N 5 1 15 2 4 Br NH N Br 3 O Br O Dibromohydroxyphakellin Longamide C O Br Cyclooroidin

Figure 2. Selected pyrrole-imidazole compounds isolated from A. linnaei (Hertiani et al., 2010) and A. nakamurai (Hertiani et al., 2010; Murti, 2005) and from A. nemoecinata (Pedradab, 2005) showing the similarities and differences in the structure of related compound. * Only relative stereochemistry is shown

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this study have a free NH pyrrole while in most Brominated pyrroles: UV spectra of the A. linnaei metabolites, the NH pyrrole is characteristics methylated. A clear example is provided by the Databases of this group of compounds presence of 4-bromo-1H-pyrrole-2-carboxylic revealed their distinct UV spectra due to a acid in A. nakamurai, and its dibrominated N- shared chromophore, a pyrrole-2-carbonyl ring. methyl pyrrole congener in A. linnaei (Hertiani According to Jaffe and Orchin (1962), a et al., 2010). Furthermore, an analogue of the A. maximum absorption at around 270nm is linnaei metabolite, 4-(4,5-dibromo-1-methyl-1H- detected for this particular group. pyrrole-2-carboxamido) butanoic acid was Comparison of several pyrrole imidazole previously reported from A. nakamurai as 4- alkaloids showed different characteristics in bromo-2-carboxamido-butanoic acid (Murti, their UV spectra (Figure 3a). Pyrrole imidazoles 2006). Other finding reported by Pedradab having an additional tyramine in the molecules (2005) revealed the presence of di-brominated experience reduced intensity of the absorption brompyrroles i.e.: Slagenin D and E, Oroidin, band at around 270 nm and have an increase of Dehydrooroidin, Cyclooroidin, and the absorption band at around 210nm which monobrominated derivates, i.e. Slagenin A, represent the additional phenolic unit (Figure Sventrin and Keramadine from A. nemoecinata. 3b). A cyclization of the linear chain to form The pyrrole-imidazole compounds the pyrrolopyrazinone bicyclic system as can be isolated from A. linnaei were comprised of high observed in mukanadin C, longamide C, as well structural diversity, introducing some new as in the phakellins intensifies the absorption functionality. A new compound related to band at around 230nm (Figure 3d). Agelanin A, midpacamide, Agelanin B displays an unusual on the other hand, forms a cyclization between 3-hydroxyl-4-oxo-pentanoic acid instead of a N-7 and the imidazole ring which causes a hydantoin ring. Agelanin A introduces a unique major modification. A pronounced bathocromic functionality as the propylamide chain is cylized shift of the major band to  340nm is observed to form a dihydroimidazopyridinol ring. (Figure 3a) (Hertiani et al., 2010). This kind of Despite its very rare mode of cyclization, a bathocromic shift can also be observed in related structure was previously reported as hymenialdisins (Figure 3e) (Baker, 2004). dibromoagelaspongin, a phakellin related Stevensine which differs in the imidazoline ring compound isolated from Tanzanian sponge part, loses the second band and only shows a Agelas sp. (Fedoreyev et al., 1989). The major peak at around 240nm, while in 2- phakellins itself exhibit a unique array of bromoaldisin the second band is encountered functionality including a cyclic guanidine, a at around 315 nm (Pedradab, 2005). pyrrole carboxylic acid, a pyrrolidine, and a congener with potentially delicate vicinal Brominated pyrroles: biosynthesis aspect diaminal stereocenters (Poullennec et al., 2002). Despite the importance on pharma- More amino acid precursors may be cological activities and chemotaxonomic involved in the structure of agelanesins and the considerations (Braekman et al., 1992), mauritamides. In agelanesin, the imidazole ring knowledge on pyrrole-imidazole alkaloids is replaced with a halogenated tyramine. biosynthesis remains in question (Travert and Taurine related compounds are encountered in Al-Mourabit, 2004). Symbiotic microorganisms two mauritamide A congeners, mauritamide B were suggested to play a role in the biosynthesis and C, along with a quite simple compound 2- based on the fact that bromopyrole alkaloids is (4,5-dibromo-1-methyl-1H-pyrrole-2- reported from an assortment of sponge carboxamido) ethanesulfonic acid. Moreover, a genera. Moreover, populations of heterotrophic co-occurrence of the known serotonergic agent, bacteria were found in Carribean sponge Agelas agelongine with its pyridinium ring in the conifera,. Nevertheless, cellular localization structure to replace the imidazole nucleus and studies by differential centrifugation and an ester linkage to replace the amidic bond Ficoll density gradients demonstrated that (Cafieri et al., 1995) is also isolated from this A. oroidin and sceptrin were associated with linnaei sponge. sponge spherulous cells and not with the bacterial fraction (Richelle-Maurer et al., 2003).

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NH2 14 Br O N 13 5 N O N 6 N 12 2 1 2 6 15 A Br 5 N 11 4 7 OH Br 3 8 4 3 10 4,5-dibromo-1-methyl- OH Agelanin A 9 1H-pyrrole- carboxylic acid Br

H 20 X N O 5 1 18 N 2 Y 6 13 4 8 12 19 14 3 NH 10 17 B Br 7 11 9 O Agelanesin A (X = H; Y = Br) 15 Agelanesin B (X = H; Y = I) 16 Agelanesin C (X = Br; Y = Br) Agelanesin D (X = Br; Y = I)

Br N O 1 5 2 6 8 4 HN Br 3 7 O 10 3' H 9 N C 1' S O 2' O 11 HO 15 NR 14 12 HN 13 Mauritamide B ( R = H) Mauritamide C (R = CH CH ) NH 2 3

NH

HN Br OH R NH N N Br Br D N NH

O O Dibromophakellin ( R = H) Mukanadin C Dibromhydroxyphakellin (R= OH)

E

O O O H H HN N HN N H HN N Br Br Br

Br Br

NH O O N NH N NH2 H2N 3-bromohymenialdisin 2-bromoaldisin stevensine

Figure 3. UV absorption pattern of several pyrrole imidazole alkaloids. Note: a-d are from Agelas linnaei and Agelas nakamurai (Hertiani, 2007); e was modified from Baker, 2004; Pedradab, 2005)

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Several studies showed that spherulous cells, acid precursor and an amino propylimidazole when present, are producers of the bioactive moiety (Braekman et al., 1992). metabolites (Marin et al., 1998; Müller et al., 1986; Hoffmann and Lindel (2003) suggested a Salomon et al., 2001; Thompson et al., 1983; Turon different pathway of which ornithine is et al., 2000; Uriz et al., 1996; Richelle-Maurer et incorporated into proline, and being oxidized al., 2003). The production of an oroidin dimer, to form the pyrrole-2-carboxylic acid moiety. A stevensine, by adding amino acid precursors biosynthetic experiment performed by Andrade into a sponge cells culture performed by and collaborators (1999) in the sponge cell Andrade et al. (1999) supports that these cultures revealed that 14C-labeled proline, alkaloids are produced by sponge cell and not ornithine, and histidine were incorporated into by symbiont (Richelle-Maurer et al., 2003). stevensine. Natural compounds 3-amino-1-(2- A shared biosynthetic pathway is aminoimidazolyl)-prop-1-ene and 4,5-dibromo- proposed for pyrrole imidazole alkaloids based pyrrole carboxylic acid were proposed as on a common key metabolite, oroidin (Al intermediates (Andrade et al., 1999). Further- Mourabit and Potier, 2001; Hoffmann and more, Hoffman and Lindel (2003) proposed Lindel, 2003). Several alternatives have been that if histidine is a biogenetic precursor, the discussed with regard to their biosynthesis. natural product clathramide A could be a While the pyrrole part is generally expected to biogenetic intermediate in Agelas clathrodes be derived from proline/ornithine, different (Cafieri et al., 1998a; Cafieri et al., 1996). The proposals have been put forward for the 2- missing carbon atom would be incorporated amino-5-(3-amino) propylimidazole part (Lindel into the histidine-derived portion via et al., 2000a). Considering that the metabolism of methylation of the imidazole 5-portion, proline in some plants and microorganisms is followed by conversion of clathramide A to a known to be stress dependent (Hare and Cress, cyclopropane and subsequent ring opening 1997; Ballantyne and Storey, 1983), even (Figure 4) (Hoffman and Lindel, 2003). though the ecological role of proline in sponges NH2 CO2H N e NH2 is not known, its role under stress conditions is H N 2 d a H N NH 2 a d 2 N assumed crucial for surveillance. Thus, if proline HC2O H ornithine histidine lysine is involved in C11N5 formation under oxidative CO2H

conditions, this would be in accordance with the incorporation X ecological role of “oroidin-based” alkaloids N

Y used by sponges as a chemical arsenal for their H NH N 2 N N defense (Travert and Al-Mourabit, 2004). H H Braekman and collaborators (1992) O oroidin (X = Y = Br) proposed that proline, ornithine, and guanidine hymenidin (X = Br; Y = H) Br are probable precursors of both the bromopyrrole and 2-aminoimidazolinone Br N + NH2 HN moieties, based on the fact that proline and e H H N a d NH2 ornithine are two closely related amino acids of N N H O NH the glutamate group and the oxidation of + O CO2H N proline into pyrrole-2-carboxylic acid is a HO2C CH3 CH general catabolic pathway (Michal, 1972). d-hydroxyhomoarginine clathramide A 3 Saxitoxin which is an analogue of Figure 4. Plausible biosynthetic pathways aminopropylimidazole has been reported to be leading to the key pyrrole-imidazole alkaloid arouse from ornithine (Shimizu et al., 1984). (according to Hoffmann and Lindel, 2003). Other finding revealed the occurence of girolline with its linear or cyclized pyrrole Travert and Al-Mourabit (2004) derivatives in “Pseuodaxynissa” cantharella (Ahond postulated that a pseudo dipeptide pyrrole- et al., 1988), suggests the biosynthetic pathway proline-guanidine is the precursor which of these alkaloids proceeds by formation of an leads to the amide-connected C11N5 pyrrole amide bond between a pyrrole-2-carboxylic and 2-aminoimidazolinone sections (Figure 5).

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oxidative decarboxylation and isomerization of OH N H the resulting double bond, eventually forms

O NH oroidin (Figure 4) (Lindel et al., 2000a). proline NH Similar co occurence of homoarginine and OH N O N 2-amino-3-prop(en)ylimidazoles in the case H O N

O of the aplysinamisines I and II in Aplysina proline O O sp. (Rodriquez and Piña, 1993) and the NH H2N NH 2 2 HN HN NH similar biogenesis pathway of enduracididine, NH H2N NH an arginine-derived amino acid which has an guanidine imidazoline analogue of aminohistidine in its NH structure (Horii and Kameda, 1968; Hatano, et Br Br NH2 HN HN al., 1984; Garcia et al., 1996; Hemscheidt et al., NH NH NH N O O 1995) support the above hypothesis (Hoffman and Lindel, 2003). O N O N H H O O O O H H H H dispacamide A (E)-N-(3-(2-imino-5-oxoimidazolidin-4-ylidene)propyl)- N N N Br N 1H-pyrrole-2-carboxamide 1 Br OH OH OH OH Figure 5. Sequential pyrrole and 2-aminoimida- 3 Br Br zolinone sections formations (according to Travert and Al-Mourabit, 2004). Figure 6. Four building blocks and new nucleophilic positions (N-1 and C-3) (Al- First specific step in the pyrrole 2- Mourabit and Potier, 2001) aminoimidazole biosynthesis involves proline- based peptide synthesis, followed by an To explain the high structure diversity of oxidation of the proline to pyrrole section and this compound group members, Al Mourabit then by an oxidation rearrangement of proline- and Potier (2001) proposed different intra guanidine moiety to the 2-aminoimidazolinone. molecular cyclization mechanisms. Positions N- Bio mimetic spontaneous conversion study of 1 and C-3 of the pyrrole part participate in proline to 2-aminoimidazolinone derivatives intramolecular cyclizations (Figure 6) (Al suggested dispacamide A as the forerunner of Mourabit and Potier, 2001), while position C-2, oroidin. As a consequence of this proposed which is the most nucleophilic in a free pyrrole pathway, 4,5-dibromopyrrole-2-carboxylic acid has only rarely been quaternized (Hoffmann and 2-amino-5-(3-amino)propylimidazole are and Lindel, 2003). Among the simple probably exist as hydrolysis products and not heterocycles, free or N-methylated pyrrole precursors (Travert and Al-Mourabit, 2004). exhibits a relatively strong nucleophicity at C-2 Actually, either oroidin or dispacamide A which even rivals nucleophilic solvents are good candidates as a key metabolite linking (Richard et al., 1998; Mayr et al., 2003; the amino acid precursors to the pyrrole 2- Hoffmann and Lindel, 2003). aminoimidazole family. Moreover, both nucleophilic electrophilic compounds are frequently found in sponges position position 4 5 together with their closely related polycyclic 5 5 H N N H N N H N N derivatives (Travert and Al-Mourabit, 2004). 3 1 Moreover, homoarginine derivatives 2 NH NH NH2 2 eventually open the possibility of another alternative biosynthetic pathway of which Figure 7. The tautomerism and ambivalent indicates the existence of a biosynthetic reactivity of 2-amino-imidazole (as decribed by pathway via an open chain intermediate Al-Mourabit and Potier, 2001) (Assman et al., 1999). Hoffmann and Lindel (2003) proposed that hydroxylation of The 2-amino-imidazole building homoarginine at the -position, followed by block possesses tautomeric property which oxidation and cyclization generates 2- is important for the molecular diversity aminohomohistidine which then undergoes of pyrrole-imidazole alkaloids (Figure 7).

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OH

N COOH H Br NH2 X N proline O Br

H2N O N O Br H

OH NH Br N COOH N COOH agelanesin A (R = H; X = Br) H R1 agelanesin B (R = H; X = I) 4,5-dibromo-N-methylpyrrole- agelanesin C (R = Br; X = Br) 2-carboxylic acid + agelanesin D (R = Br; X = I)

COOH Br O NH H2N 2 O

HO S NH2 H ornithine Br N N O Taurine C OH

O Br 4-(4,5-dibromo-1-methyl-1H-pyrrole- 2-carboxamido) butanoic acid O Br H N N S NH2 OH O O H2N NH 2-(4,5-dibromo-1-methyl-1H-pyrrole- guanidine 2-carboxamido)ethanesulfonic acid

Br Br Br NH2 Br NH Br Br O Br Br HN HN H CN 3 NH N NH N N NH O NH O O HO H O N NH2 O N O N H N O N H H N

O midpacamide NH2

HO S Br O Taurine Br Br

O Br

N NH R Br N O N NH2 N O HN NR N O Br H2N N N N NH N O NH H OH HO S

O dibromophakellin (R = H) agelanin A mauritamide B (R = H) dibrmohydroxyphakellin (R = OH) mauritamide C (R = CH2CH3)

Figure 8. Proposed chemical pathway leading to several A. linnaei metabolites

Each tautomer engaged in this process may act In the case of Seribu Islands sample, A. as an initiator of controlled chain reactions linnaei, beside its possession of more diverse leading to various and complex compounds. pyrrole-imidazole alkaloids, there are no

The tautomerism which can exist simultaneously oroidin or dispacamide as well as homoarginine will give rise to polycyclic metabolites through alkaloids present, whereas some metabolite various combinations with pyrrolic building functionalities is unmatch with the available blocks and diverse modes of cyclization and/or theory. Midpacamide as the major metabolite dimerization (Al-Mourabit and Potier, 2001). together with the co-existence of mauritamides Based on the available theory about which exhibit relatively similar functional the pyrrole-imidazole alkaloids biosynthesis, it groups in the imidazole ring with a dehydro is more likely that hymenidin is the key building dispacamide A recommends a putative block in their biosynthesis in A. nakamurai biosynthetic pathway as described in figure 8. rather than oroidin. Intermolecular cyclization This pathway may explain the relation of involving the N-pyrrole and C-9 of this building almost all A. linnaei metabolites including, block leads to compounds like mukanadin C midpacamide, mauritamides, agelanin A as well and its new derivative longamide C. as the phakellins.

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An involvement of other amino acids the anti-predatory role of oroidin-based such as taurine and tyrosine may also be alkaloids could be their most important involved in the diversity of this group of biological function (Assmann et al., 2000; compounds. Mauritamides and N-methyl-4,5- Assmann et al., 2001). dibromopyrrole taurocarboxamide biosynthesis Lindel et al. (2000b) formulated the may require taurine as precursor. Meanwhile, structure-activity relationship of several oroidin tyrosine may involve in the agelanesins related compounds for feeding deterrent biosynthesis through a brominated tyramine activity. They reported that even though the related intermediate. Bioconversion pathway of pyrrole ring is required for the activity, this several bromopyrrole alkaloids remains in alone is not sufficient. A dibrominated pyrrole question. On the other hand, a co-existence of exhibited higher activity in comparison to less the agelongine alcoholic portion, brominated analogues. On the other hand, the pyridinebetaine A (Figure 9) in Agelas imidazole moiety is not feeding deterrent on its longissima by Cafieri et al. (1998b) may own, but enhances the activity of the pyrrole somehow correlate to the agelongine unusual ring. A methylation of the N-pyrrole, the structure. oxidation state of the imidazole ring at the 4-

O position and the functionalization of the O

OH imidazole 2-position were found to give no OH influence on activity. Removal of the imidazole N+ N+ moiety with retention of the chain resulted in HN Br O loss of activity, except for the acid. Among the OH similar, active compounds, increasing polarity O appeared to enhance feeding deterrence. This agelongine pyridinebetaine A anti feeding assay also revealed an additive Figure 9. Agelongine and pyridinebetaine A effect of the active compounds but no synergy (Cafieri et al., 1998b). was observed (Lindel et al., 2000b). Field assays performed by Richele-

Halogenated pyrroles: Ecology approach Maurer et al. (2003) showed that concentration towards pharmacology prospects of pyrrole imidazole alkaloids, oroidin and Biosynthesis of alkaloids consumes sceptrin in A. conifera were unaffected by valuable amino acids while efficiency should prolonged protection from fish predators. It is become a basis consideration for compounds suggested that these compounds were production. It should be an evolutionary produced possibly at the limit of effectiveness. advantage for a living organism to generate a Wounding induced a three- to four-fold maximum degree of molecular diversity and increase production of both compounds and function, on the basis of a common building higher amount of these bromopyrroles exuded block. It would be even better, if the building into the surrounding seawater than normal. block itself can be part of life saving efforts. This action may prevent further predation as Oroidin is a perfect example. This compound well as protection against invading micro- has been reported as the chemical weapon of organisms and from fouling (Richele-Maurer et Agelas sponges against predation by reef fishes al., 2003). This argument is in accordance with and in the same time takes part as a key the activity of oroidin and several other building block of the pyrrole imidazole bromopyrrole alkaloids against fouling and alkaloids. (Hoffmann and Lindel, 2003). The bacterial infection (Tsukamoto et al., 1998). The conservation of brominated pyrrole-imidazole strategy to enhance production of bioactive alkaloids as natural products in the tissue of compounds in response to environmental sponges within the genus Agelas suggests that changes would optimize fitness. Defence are these compounds have been elaborated and known to be costly, while energy is needed for retained as part of chemical defenses (Lindel et other functions such as growth and al., 2000b). From an ecological point of view, reproduction (Schupp et al., 1999; Richele- Maurer et al., 2003).

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An attempt to translate the result of the alkaloids in A. linnaei may be due to their ecological function of the halogenated pyrroles function as chemical defense for the host reveals possible development of this compound sponge in order to provide broader spectrum of group as drug lead. Based on the assumption protection. Midpacamide, as a main feeding that effect of calcium influx and calcium levels deterrent (Lindel et al., 2000b) displays moderate in neurons, secretory cells may be related to the cytotoxicity against mouse lymphoma cell feeding deterrence through smell and taste, L5178Y (46.7% inhibition in 10μg/mL sample

Bickmeyer et al. (2004; 2005) performed an concentration) and only low antibacterial activity experiment to observe the effect of several against B. subtilis. The role of cytotoxic activity bromopyrrole alkaloids on calcium levels in as well as antimicrobial and antifouling activity PC12 cells (rat phaeochromocytoma cell line). is presumably taken by other metabolites. It was reported that unpalatable 4,5- A different finding was observed in A. dibromopyrrole-2-carboxylic acid against nakamurai which relies more on their diterpene predatory reef fish is not (only) transduced by alkaloids but not pyrrole-imidazole compounds specific membrane receptors present on for chemical defences. Considering that these sensory nerve cells but (additionally) has a more diterpenoids play a major role in sponge general pharmacological effect on the cellular defense may answer to the less diverse calcium homeostasis (Bickmeyer et al., 2004). production of pyrrole-imidazole alkaloids in Basically, chemo-receptive cells are this sponge. Among the pyrrole-imidazole exposed to the environment, and cellular metabolites, 4-bromo-1H-pyrrole-2-carboxylic signalling may be modulated by substances acid and hymenidin are discovered to be interacting with the basic physiology of the cell, predominating. From their structure one can but not necessarily by binding to specific taste predict that these compounds contribute in the receptors (Bickmeyer et al., 2004, 2005). As the feeding deterrent mechanism of the sponge same mechanism may work in sensory cells of producer, together with the other congener, 4- predatory fishes and other animals like snails bromo-1H-pyrrole-2-carboxamide. the inhibition of Ca2+ influx into receptor cells More literatures on the oroidin derivates may be one reason for chemoreceptive detection bioactivity were reports on biofilm inhibition (Bickmeyer et al., 2004, 2005). In harmony with effects (Richards et al., 2008a, 2008b, 2008c, the ecological point of view, blockade on calcium 2008d, 2008e; Ballard et al., 200; Huigens et al., entry may be pharmacologically important since 2007) This effect has been proposed to be in it can induce vasorelaxation as obseved in many correlation with the sponge‟s antifouling defense hypertension drugs (Bickmeyer et al., 2004). mechanism (Hertiani, 2008). Sponges as filter- Midpacamide is the major constituent of feeder organisms need to be free of fouling in the A. linnaei (1.01% of sponge dried weight) order to pump water and nutrition. Therefore, a (Hertiani et al., 2010). It is a dibrominated chemical defense in form of antifouling pyrrole having a N-methylated hydantoin ring compounds can be one powerful strategy. connected through a propylamide chain. Never-theless a research done on several According to Lindel and collaborators (2000b), oroidin related from A. linnaei showed no this compound is the most potent as feeding inhibition on biofilm formation of S. epidermidis deterrent in comparison to the other six pyrrole by in vitro method (Hertiani, 2008). This activity imidazole alkaloids tested, 4,5-dibrompyrole was reported from other type of compounds carboxamide, 4,5-dibromopyrrole-2-carboxylic isolated from A. nakamurai, the (-)-Ageloxime acid, oroidin, keramadine dispacamide and (Hertiani et al., 2010; Hertiani, 2008). Considering racemic longamide A. Based on this finding that biofilm associated micobes have great accompanied with its predominance in the significance for public health, since they may sponge, it is likely to assume that midpacamide cause a dramatical decrease in susceptibility functions as the main chemical weapon of A. towards antimicrobial agents (Donlan, 2001). linnaei against its predators. Finding a potential biofilm inhibitor is Relatively high structure diversity and therefore of interest in combating infection predominance of the pyrrole-imidazole especially in immunesuppressed condition.

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NH

12 HN NH+ Br HO Br N 15 H N 10 1' HN Br H NH2 2 6 N 1 N N R - N SO3 H H H Tauroacidin A, R = Br 3' Oroidin O Tauroacidin B, R = H O

R2 R2 R1 R1

H H N HN N N R2 NH 2 NH2 OH H OH N H OH O 1 N N O N H O N 5 H H Br NH H H NH HN 12 H 1 8 N N H R NH2 N H NH2 HN Cl 10 Cl 15 NH2 NH2 O 1 2 1 2 Agelastatin A, R1 = H, R2 = CH Palau'amine, R = R = H Styloguanidine, R = R = H 3 1 2 Agelastatin C, R1 = OH, R2 = CH 4-Bromopalau'amine, R = H, R = Br 3-Bromostyloguanidine, R1 = H, R2 = Br 3 1 2 Agelastatin D, R1 = H, R2 = H 4,5-dibromopalau'amine, R = R = Br 2,3-Dibromostyloguanidine, R1 = R2 = Br

Figure 10. Some bioactive halogenated-pyrrole derivatives from sponges.

Agelastatins (Figure 10) is probably the repression of OPN and inhibition of OPN- most important pyrrole-imidazole alkaloids mediated malignant cell invasion, adhesion, and isolated from Agelas sponges. These colony formation in vitro (Mason et al., 2008). compounds have a unique fused tetracyclic Longley also highlighted the ability of this skeleton which may formally be derived from compound in inhibiting β-catenin, which an open chain pyrroloaminopropylimidazole controls transcription of multidrug resistance precursor similar in structure to oroidin (Longley and Johnston, 2005). Therefore, it (Whitehead, 1999). In 1998, Hong et al. could be helpful in reducing drug resistance reported the isolation of the known Agelastatin issues, possibly both as single agent as well as in A together with two new alkaloids, Agelastatins combination therapy (Forte et al., 2009). Hale C and D from a West Australian sponge and collaborators reported that agelastatin A Cymbastela sp. (Axinellidae). Agelastatin A was was also exhibited inhibition activity towards highly toxic to brine shrimp with LC50 of 1.7 glycogen synthase kinase-3 β (GSK-3β), an ppm (5.0μM) whereas Agelastatin C was much enzyme responsible for the neurofibrillary less toxic with LC50 of ~ 220ppm. Insecticidal tangles typically found in Alzheimer‟s disease, activity of Agelastatin A was reported to be and as a mimetic of insulin (Hale et al., 2003). comparable to a commercial preparation of the The Palau„amines (Figure 10) is another biopesticide Bacillus thuringiensis (Hong et al., series of complex, halogen containing alkaloids 1998; Whitehead, 1999). belonging to oroidin family. These compounds Agelastatin A was reported to exhibit exhibit six contiguous rings and an unbroken significant cytotoxicity towards many types of chain having eight chiral centers (Whitehead, cancer cell lines (D‟Ambrosio et al., 1993; 1996; 1999). Palau‟amine and its 4-bromo and 4,5- Meijer et al., 2000; Pettit et al., 2005). This dibromo derivatives were isolated in 1998 compound inhibited tumor cell growth from Kinnel et al. together with three previously 1.5 to 16 times more potently than cisplatin, reported ring A regioisomers (styloguanidines), particularly, against human bladder, skin, colon, from the sponge Stylotella aurantium. and breast carcinomas (Hale et al., 2005). Palau‟amine itself was reported to display a Moreover, Agelastatin A was demonstrated to remarkable range of biological activities having be very effective in down-regulating the an IC50 value of less than 18 ngml-1 in the expression of β-catenin and in up-regulating mixed lymphocyte reaction, and values of IC50 Tcf-4, an inhibitor of osteopontin (OPN) at the of 0.1 and 0.2μg/mL-1 against P-3888 and cellular level. These two effects result in A-549 cel lines, respectively (Whitehead, 1999).

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Br Br H3CO O

OH OH Br Br Br Br O O O O N N

H N H N N O N OCH3

HO HO Br O Br Br O Br O NH OH O NH OH

O O Agelorin A, (2S,2'S) OH Br 11-Epifistularin-3 Agelorin B, (2R,2'R) OH Br

O

OH HO OH HO NH N O

H N N S Br Br S N H NH O N NP-LAQ824 Psammaplin A HO OH

HO OH O N

H Br S N N S Br H

N O HO OH

HO OH N O

H N S Br Br S N H

O N Bisaprasin HO OH

Figure 11. Some bioactive bromotyrosine-derived metabolites found in sponges

The preclinical studies of this compound are agents, with narrow therapeutic windows. currently in progress for anti-fungal, anti-tumor Number of bromine substitution on the pyrrole and immunosuppressive agent (Kinnel et al., carbon was reported to be important for the 1998; Whitehead, 1999). antiplasmodial activity (Tasdemir et al., 2007), Tauroacidins A and B (Figure 10), two which was also observed in the activity towards novel taurine-residue-containing bromopyrrole T. brucei rhodiense and Leishmania (Scala et al., alkaloids which were isolated from an 2010). The imidazol type ring was suggested to Okinawan sponge Hymeniacidon sp. (Figure 12) be of important for antimalarial activity (Scala et (Kobayashi et al., 1997). Both alkaloids were al., 2010). reported to show inhibitory activity against EGF receptor kinase and c-erb B-2 kinase (IC50, Tyrosine derived brominated compounds 20μg/mL-1 each) (Kobayashi et al., 1997). Three from A. linnaei other novel taurine derived brompyrrole Other important halogen containing alkaloids isolated from A. linnaei, Mauritamide secondary metabolites from sponges are the B, C and 2-(4,5-dibromo-1-methyl-1H-pyrrole- brominated compounds biogenetically related 2-carboxamido)ethanesulfonic acid (Figure 9), to tyrosine (Figure 11). Although this group of exhibited no inhibition on the protein kinases compounds is more likely to be found in (Hertiani, 2007). Verongid sponges (Hamman et al., 1993; Other report from Scala et al. (2010) Tabudravu and Jaspars, 2002), nevertheless, exhibit the potency of bromopyrrole alkaloids König and Wright (1993) have reported the as a potential drug lead for anti protozoa. isolation of bromotyrosine-derived alkaloids Dispacamide B and spongiacidin B were (Agelorins A and B, and 11-Epifistularin-3) reported as a potential antimalarial and can be from Agelas oroides. developed as drug lead based on the result that Psammaplin A, a symmetrical bromo- these compounds showing significant activity tyrosine disulfide possessing oxime moieties with low or no toxicity towards mammalian isolated from Verongid sponges, was found to cells (L6). Moreover, Scala et al. (2010) also have potent cytotoxicity to P 388 cells (IC50 of described dibromopalau‟amine and longamide 0.3μg/mL-1). Its dimeric metabolite, bisaprasin B potency as trypanocidal and antileishmanial was also occured in the sponge producer

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Br 20 O X H N O 1 18 OH 5 N Br 2 Y Br 6 13 O 4 8 12 19 O N 14 3 NH 10 17 H Br 7 11 N N O 9 O 15 HO 16 Br O Br Agelanesin A (X = H; Y = Br) O NH OH Agelanesin B (X = H; Y = I) Agelanesin C (X = Br; Y = Br) Agelanesin D (X = Br; Y = I) O Agelorin A, (2S,2'S) OH Br Agelorin B, (2R,2'R) (König and Wright, 2003) Br H3CO

OH Br Br O O N

N H N OCH3

HO Br O Br O NH OH

O 11-Epifistularin-3 (König and Wright, 2003) OH Br

Figure 12. Chemical structures of tyrosine-derived brominated compounds from Agelas oroides (König and Wright, 1993) and from A. linnaei (agelanesin A-D) (Hertiani et al., 2010)

(Arabshahi and Schmitz, 1987; Quiñoà and 11-epi-fistularin-3 are other known tyrosine- Crews, 1987; Rodriquez et al., 1987). The fact related representatives from the marine sponge that the psammaplins have been isolated from a genus Agelas (König and Wright, 1993). diversity of sponge “sources” and that The presence of a halogenated tyramine brominated aromatic amino acid derivatives are moiety linked to a brominated pyrrole unit has common in marine bacteria suggest that these never been reported before from natural metabolites may actually be produced as a products. Replacement of the brominated collaborative work between the sponge host tyramine moiety in agelanesin A and agelanesin and the associated microorganisms (Simmons et C with iodinated tyramine in agelanesin B and al., 2005). agelanesin D attract attention to this group of Both psammaplin A and bisaprasin were compounds. reported as DNA methyl transferase and It is very challenging to find out why this histone deacetylase inhibitors (Pina et al., 2003). Agelas sponge incorporated iodine into the This is an interesting finding considering the agelanesins to substitute the bromine. Iodo- potential relationship between DNA methyl alkaloids are known to be very rare natural transferase and histone deacetylase as epigenetic products which are until now only isolated modifiers of tumor suppressor gene activity from marine organisms, (Gribble, 1996a, (Pina et al., 2003). Furthermore, psammaplin A 1996b, 1998, 2000; Faulkner, 1995) more has also been reported to inhibit topoisomerase specifically from very few algae and sponges II (Kim et al., 1999) and aminopeptidase N with (Niedleman and Geigert, 1986; Constantino et in vitro angiogenesis suppression (Shim et al., al., 1994). Iodide availability in sea water is far 2004). below other halogens such as bromide and Four new brominated pyrrole derivatives chloride. connected to a halogenated tyramine unit were Despite its low concentration, unlike obtained from A. linnaei (Hertiani et al., 2010). chloride, all known haloperoxidases are Halogenated tyrosine-derived metabolites are effective in oxidizing iodide (Niedleman and actually more likely to be found in Verongid Geigert, 1986). According to Constantino et al. sponges, although they were also reported from (1994), biosynthesis of iodinated metabolites several others (Constantino et al., 1994; König seems to be related to the capability of and Wright, 1993). Agelorin A and B as well as organisms to concentrate iodine from sea

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water, rather than to the presence of a specific agelanesin A-D is important for the activity peroxidase. This argument was based on the (Hertiani et al., 2010). fact that most iodo-metabolites have been Based on the IC50 values of the isolated from red algae, which are known to agelanesines against mouse lymphoma cell line contain iodine concentrations as high as 0.5% (L5178Y), a possible structure activity of weight wt (Constantino et al., 1994). An relationship is suggested. Since the highest iodotyrosine alkaloids sponge producer, activity was shown by agelanesin A followed by Iotrochota birotulata was reported to contain agelanesin B, D and C, respectively, less significant amounts of iodine (0.12-1.21%), bromination on the pyrrole ring seems to be together with comparable quantities of bromine important for the activity (Hertiani et al., 2010). (0.16-2.66%) (Kaestner, 1967). Hence this This is somehow in contrast to the result of supports the relationship between the presence feeding deterrent activity reported by Lindel et of iodo- metabolites and high concentration of al., 2000b, since higher degree of the iodine in the sponge tissue (Constantino et al., bromination in the pyrrole ring will increase the 1994). activity (Lindel et al., 2000b). Meanwhile, Another question arising from the different halogen atom attached to the tyramine agelanesins unique structure is their unit (C-12) causes only slight difference on the biosynthesis. As described earlier, pyrrole cytotoxicity (Hertiani et al., 2010). imidazole family of compounds such as oroidin and sceptrin are predicted to be produced by Synthesis approach: an alternative for sponge cells and not by the associated bacteria continuous supply (Richele-Maurer, 2003). Meanwhile Simmons One of the most important requirement and collaborators (2005) proposed that the of a natural product being developed as brominated tyrosine metabolites may actually medicine or drug lead, it should be obtained by be derived from the biosynthetic pathway of a continuous supply. Despite being a promising microorganisms living in association with lead for many medicinal purposes, halogenated sponges. It is therefore more likely that in case alkaloids in Agelas sponges have been of the agelanesins, the brominated pyrrole 2- postulated to be originated from sponge cell carboxylic acids are produced by the sponge itself and not from its symbiont (Richelle- cell at first, and further converted by associated Maurer et al., 2003). This fact has closed the bacteria to afford agelanesins. posibility of obtaining these alkaloids through In addition to its unique chemical cultivation of the endophytes/symbionts as one structure, this group of compounds also possible alternative in obtaining marine showed interesting bioactivity. Agelanesin A - metabolites with more eco-friendly approach. D showed cytotoxicity against the mouse Mariculture is one approach in effort to lymphoma cell line (L1578Y) with IC50 value provide continuous supply by cultivating 4.5μg/mL; 4.8μg/mL; 9.2μg/mL; and sponge in its environment. This approach has 7.8μg/mL respectively. In comparison to other advantages as cultivation can be managed in its brominated pyrroles isolated from A. linnaei, natural condition and may be expected to only this group of compounds shows produce compound of interest. Nevertheless A. pronounced cytotoxicity (Hertiani et al., 2010). nakamurai collected from Menjangan Island in At the same time, aplysamine-2 and different collection time, resulted different aeroplysinin-1, obtained from Pseudoceratina chemical constituents as reported by Hertiani purpurea exhibits the same activity as well. Some and collaborators (2010) and Murti (2006). other brominated tyrosine compounds have Another report by Eder and collaborators also been previously reported to be cytotoxic (1999) reported dimers, i.e., Sceptrin, such as psammaplin A and bisaprasin Debromosceptrin, Ageliferin, Nakamuric acid (Arabshahi and Schmitz, 1987; Quiñoà and and its methyl ester derivate. A. nakamurai Crews, 1987; Rodriquez et al., 1987). Hence it is from Okinawa has been reported to produce suggestive that the halotyramine moiety of other constituents as well as the sponge

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collected from Papua New Guinea (Iwagawa et in Papeo‟s approach was also useful in the first al., 1998). Eventhough the above finding can be total synthesis of (Z)-axinohydantoin. Different due to different isolation procedures applied series of analogues were synthesized (He et al., for each research groups, further evaluation 2007; Chacun-Lefevre et al., 2000; Wan et al., should be done in order to define the best 2004). Those derivatives left the main features cultivation as well as isolation procedure of the of (Z)-HMD binding site in the kinase ATP target compounds. unchanged. Efforts have been made to improve Several of promising halogenated its selectivity and permeability (Kaiser et al., alkaloids from Agelas have been successfully 2007; Mangu et al., 2008; Parmentier et al., synthesized in laboratory. One interesting 2009). example is the Agelastatins. These natural Psammaplin A, is a promising anti products share a complicated tetracyclic core cancer candidate isolated from Verongid having four stereocenters, which is a sponges. This compound has close structure synthetically challenging structure. The relationship with the halogenated tyrosine impressive biological activity, following its derived alkaloids from Agelas sponges. This scarce availability have triggered the total compounds has been developed as a drug lead synthesis attempts for these contriguing of which its analogue substance, NP-LAQ824 substance. Fifteen total syntheses have been (Remiszewski, 2003), has recently entered phase achieved for this compound, each presenting I clinical trials in patients with solid tumors or different strategies (Kitagawa et al., 1983; Stien leukemia (Simmons et al., 2005). et al., 1999; Feldman et al., 2002; Feldman et al., The susccess of producing oroidin 2002; Domostoj et al., 2004; Davis and Deng, derivatives by several approach (Fresneda et al., 2005; Nicolaou et al., 2000). 2001; Lindel and Hoffmann, 1997; Olofson et Ageladine A which is 4-(4,5-dibromo- al., 1998; Sun and Chen, 2007; Ando et al., 1H-pyrrol-2-yl)]-1H-imidazo[4,5-c]pyridin-2- 2006) have offer more possibility of producing amine has been reported to be successfully antiprotozoal compounds which are closely synthesized through a 12-step total synthesis related to this compounds as described by Scala by using a 6π-azaelectrocyclization and a et al. (2010) by a synthetic route. The synthesis Suzuki−Miyaura coupling of N-Boc-pyrrole-2- of the oroidin itself has been reported in many boronic acid of which a chloropyridine roles as literatures (as reviewed in Forte et al., 2009). key step (Meketa and Weinreb, 2006). Ageladin The method by Richards et al. (2008e) offers a A has been reported as a potential antiangiogenic possibility of producing the synthetic derivates matrixmetalloproteinase inhibitor isolated from related to this groups of compound for A. nakamurai (Fujita et al., 2003) antibiofilm activity against P. aeruginosa. Eventhough (Z)-hymenialdisine [(Z)- A synthetic approach opens many doors HMD s not derived form Agelas sponge, its for these compounds to be developed as drug worth to be discussed here considering its lead. Their presence as a highly diverse group properties as the only pyrrole imidazole of compounds has offered new possibilities for alkaloids being potential kinase inhibitor. As it utilization as medicinal purposes. As we know showed nanomolar kinase inhibitory activity that marine sponge metabolites face difficulties against pan-kinases (Meijer et al., 2000), it is to be developed as drug as it needs tremendous potentially useful not only for the treatment of amount and a continuous supply, a possiblity of cancer, but also for neurodegenerative disorders having these compounds syntheized in the as Alzheimer‟s, inflammatory pathologies, type- laboratory is relieving. 2 diabetes and cancer. Synthetic approaches (Annoura et al., CONCLUSION 1995; Xu et al., 1997, Sosa et al., 2000, Portevin Halogenated alkaloids are marine sponge et al., 2003; Papeo et al., 2005) towards specific which offers a tremendous and unique

(Z)-HMD have beenreported to produce structure diversity. These metabolites play multrigrams of yield. 1-Benzoyl-2-methyl- significant role for their sponge producers and sulfanyl-1,5-dihydroimidazol-4-one employed at the same time take part in the ecological aspects. Many halogenated alkaloids including

214 Volume 25 Issue 4 (2014) Triana Hertiani

those found in Agelas sponges exhibit debromohymenialdisine: Stereospecific promising activity to be developed for construction of the 2-amino-4-oxo-2- medicinal purposes. Despite being sponge- imidazolin-5(Z)-disubstituted ylidene originated-metabolites, which put big question ring system. Tetrahedron Lett. 36, 413– mark on their continuous supply has not stop 416. its development. Many efforts have resulted Arabshahi L., Schmitz FJ., Brominated tyrosine succesful production of selective metabolites metabolites from an unidentified sponge, through chemical synthesis, and many more J. Org. Chem., 1987, 52, 3584-3586 analogues were created for better activity or Assmann M., Van Soest RWM., Köck M., bioavailability to fulfill the needs for new drug 2001, New antifeedant bromopyrrole from the deep. alkaloid from the Caribbean sponge Stylissa caribica, J. Nat. Prod., 64, 1345- ACKNOWLEDGEMENT 1347 Author thank Prof. Peter Proksch Assmann M., Lichte E., Pawlik JR., Köck M., (Heinrich-Heine Universiteit, Duesseldorf, 2000, Chemical defenses of the Germany) and to Dr. RuAngelie Edrada-Ebel Caribbean sponges Agelas wiedenmayeri for valuable support on the manuscript and Agelas conifera, Mar. Ecol. Prog. Ser., preparation. 207, 255 – 262 Baker Z., 2004, Isolation and Structure REFERENCES Elucidation of Bioactive Secondary Ahond A., Zurita MB., Colin M., Fizames C., Metabolites from Marine Sponges and Laboute F., Laurent D., Poupat C., Tunicates, Dissertation, Heinrich-Heine Pusset J., Thoison M., Potier P., 1998, La Universität, Düsseldorf girolline, nouvelle substance Ballantyne JS., Storey KB., 1983. Mitochondria antitumoraJe extraite de I'eponge from the ventricle of the marine clam, Pseudaxlnyssa cantharella n.Sp., C.R. Acad. Mercenaria mercenaria: substrate Paris, 307, 145-148 preferences and effect of pH and salt Al Mourabit A., Potier P., 2001, Sponge's concentration on proline oxidation, Molecular Diversity Through the Comp. Biochem. Physiol., 76B, 133-138 Ambivalent Reactivity of 2- Ballard TE., Richards JJ., Wolfe AL., Melander Aminoimidazole: A Universal Chemical C. 2008, Synthesis and antibiofilm Pathway to the Oroidin-Based Pyrrole- activity of asecond-generation reverse- Imidazole Alkaloids and Their amide oroidin library: A structure- Palau'amine Congeners, Eur. J. Org. activity relationship study. Chem. Eur. J. Chem., 237 – 243 14, 10745–10761. Amador ML., Jimeno J., Paz-Ares L., Cortes- Bergmann W., Feeney RJ., 1951, Contributions Funes H., Hidalgo M., 2003, Progress in to the study of marine products. XXXII. the development and acquisition of The nucleosides of sponges. J.O.C.,16, anticancer agents from marine sources, 981 – 987 Ann. Oncol., 14, 1607-1615 Bergmann W., Feeney RJ., 1950, The isolation Ando N., Terashima S. 2006, A novel synthesis of a new thymine pentoside from of the 2-aminoimidazol-4-carbaldehyde sponges J. Am. Chem. Soc., 72, 2809 derivatives, versatile synthetic Bickmeyer U., Drechsler C., Köck M., intermediates for 2-aminoimidazole Assmann M., 2004, Brominated pyrrole alkaloids. Synlett 2836–2840. alkaloids from marine Agelas sponges Andrade P., Willoughby R., Pomponi SA., Kerr reduce depolarization-induced cellular RG., 1999, Biosynthetic Studies of the calcium elevation, Toxicon, 44, 45 – 51 Alkaloid, Stevensine, in a Cell Culture of Bickmeyer U., Assmann M., Köck M., Schütt the Marine Sponge Teichaxinella C., 2005, Bromoageliferin and morchella Tetrahedron Lett., 40, 4775-4778 dibromoageliferin, secondary metabolites Annoura H., Tatsuoka T. 1995, Total syntheses from the marine sponge Agelas conifera, of hymenialdisine and

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