REVIEW www.rsc.org/npr | Natural Product Reports

Cold-water marine natural products

Matthew D. Lebar, Jaime L. Heimbegner and Bill J. Baker*

Received (in Cambridge, UK) 28th November 2006First published as an Advance Article on the web 29th March 2007DOI: 10.1039/b516240h

Covering: up to the end of 2005

Marine natural products isolated from organisms collected from cold-water habitats are described.Emphasis is on bioactive compounds from tunicates, sponges, microbes, bryozoans, corals, algae,molluscs and echinoderms. Synthetic studies of several important classes of cold-water compounds arehighlighted.

1 Introduction2 Reviews3 Microbes3.1 Bacteria3.2 Fungi3.3 Microalgae4 Macroalgae5 Sponges6 Corals7 Bryozoans8 Molluscs

Department of Chemistry, University of South Florida, 4202 E. Fowler Ave,CHE205, Tampa, FL, USA. E-mail: bjbaker@cas.usf.edu; Fax: +1 813 9741733; Tel: +1 813 974 4145

Matt Lebar received his BS degree in chemistry at the University of Hawaii, Manoa, in 2004. He is now working on his PhD in Bill Baker’slab at the University of South Florida in Tampa.

Jaime Heimbegner studied chemistry at Sweet Briar College in Lynchburg, Virginia, and received her BS degree in 2004 after completing anHonors Thesis focused on natural products chemistry. She then joined the University of South Florida where she is currently working on herPhD under the direction of Bill Baker.

Bill Baker obtained his BS in chemistry from California Polytechnic State University in San Luis Obispo, CA, and studied under PaulScheuer at the University of Hawaii where he earned his PhD. He held postdoctoral appointments with Ron Parry at Rice University andCarl Djerassi at Stanford University before taking an Assistant Professorship at Florida Institute of Technology. He moved to the Universityof South Florida in 2001 where he is now Professor. His research interests in marine natural products chemistry have taken him all over theglobe, including nine field seasons of research in Antarctica.

Matt Lebar Jaime Heimbegner Bill Baker

9 Tunicates10 Echinoderms10.1 Steroids10.2 Triterpene glycosides11 Miscellaneous12 Conclusion13 Acknowledgements14 References

1 Introduction

Marine natural products have been the subject of chemical andpharmacological interest for several decades now and have estab-lished themselves as a diverse group of biomedically important

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compounds.1 To date, more than 17 000 compounds have beenreported from marine sources,2 and interest in a number of marine-derived drug candidates remains intense.3 For reasons as diverseas accessibility, climate and prevailing theory, the vast majorityof marine organisms studied have originated from tropical andtemperate waters. As a consequence, fewer than 3% of reportedmarine natural products originate from organisms collected inpolar habitats, despite the fact that one entire continent and asignificant portion of global shallow-water habitat are found atpolar latitudes

Cold-water habitats are defined for the purposes of this reviewto capture the chemistry of psychrophiles, those organisms ex-periencing temperatures near the extreme low end of the liquidphase of water. Besides the polar deep-sea, this includes thetemperate and tropical deep-sea, which, below the thermocline,is a nearly constant 4 ◦C.4 In shallow-water (less than 1000 m),our definition encompasses those organisms experiencing ice atsome point in their annual cycle. This latter habitat is easy tocharacterize in the Southern Hemisphere since it constitutes thecontinent of Antarctica. Northern shallow-water habitats experi-encing seasonal ice are harder to identify due to variability in theextent of winter sea ice. Thus, we have based our selection criteriafor this review on mean sea-surface temperatures reported by theU. S. National Oceanographic and Atmospheric Administration(NOAA), as reflected in a typical sea-surface temperature (SST)plot such as that shown in Fig. 1.5 These coldest habitats include,for example, the Canadian Maritimes, the Northern Sea of Japanand the Kuril Islands, but exclude the Northeast Pacific belowthe Aleutian Islands and the North Sea below 60 ◦N latitude.Since scientific reports often describe only broad geographiccollection sites, there is no doubt that this review has erredin both directions in characterizing cold-water natural productsfrom shallow-water northern latitudes, including some reports onorganisms that do not experience seasonal ice while excludingsome that do. Nonetheless, we believe that this review has capturedthe significant cold-water natural product literature as well as thegeneral trends of cold-water marine natural product chemistry.

Fig. 1 Mean global sea-surface temperature (SST) reflecting a NorthernHemisphere winter. Habitats in the three lowest color zones are includedin this review (−2 to +4 ◦C).

Arguments of low biodiversity, with implications of low chem-ical diversity,6 are among the multitude of reasons why the cold

regions have been overlooked as sources of chemical diversity. Suchspeculation has been premature and both aspects, low chemicaland biological diversity, have proven to be oversimplifications.Sponges, for example, are as abundant in high latitudes as theyare in temperate waters, and in fact approach the lower limits oftropical sponge biodiversity.7 Among photosynthetic organisms,which have extended periods of darkness to contend with, whatis lacking in biodiversity8 is made up in biomass.9 Cold-watermicrobial biodiversity is largely unexplored but recent effortsto characterize Antarctic marine microbial communities havedemonstrated them to be rich and often uncharacterized.10–12

Physiological adaptations have enabled psychrophilic organismsto thrive in the extreme cold.13 While a thorough review of suchadaptations is beyond the scope of this review, it is useful to notesome of the trends of polar marine organisms in their adaptationto freezing temperatures. Besides maintaining a cytosol that isisosmotic with sea water, the presence in some organisms ofcryoprotective solutes,14 antifreeze proteins15,16 and exopolymers17

can buffer these organisms against the damaging effects ofintracellular ice formation. Enzymatic structural adaptations,18,19

including a reduction in protein residues displaying ion-pairing,hydrogen bonding and even p-stacking aromatic interactions,20,21

have enabled these organisms to maintain metabolic rates com-mensurate with their mesophilic congeners.22,23 Protected againstice formation and enzymatically adapted to function most ef-ficiently at low temperature, psychrophiles are as apt to divertmetabolic energy and other secondary metabolic resources tochemical defense as are mesophiles.

2 Reviews

Cold-water marine natural products have not been previouslyreviewed. Various aspects of the chemistry of Antarctic organismshave been reviewed,24–29 including a comprehensive account ofAntarctic marine natural products24 that appeared in 2001, detailsof which will not be reproduced here except to highlight recentadvances.

3 Microbes

Chemistry from psychrophilic microorganisms has appeared inthe chemical literature only recently, yet the group represents thelargest contributor, seventy-three compounds, to this review. Thisstatistic reflects the significant contribution that psychrophilesstand to make to chemodiversity discovery programs, whilethe associated bioactivity, described below, argues for furtherinvestigation by drug-discovery programs.

3.1 Bacteria

Among the first studies of deep-sea microbiota, the macrolactinsA–F (1–6), macrolactinic acid (7), and isomacrolactinic acid (8)represent a family of unusual antiviral and cytotoxic macrocycliclactones produced by an undescribed Gram-positive marinebacterium.30 The bacterium was originally isolated from a slurryof sterile seawater and sediment from a 980 m sediment corefrom the North Pacific, and was unable to be classified usingnormal taxonomic methods. Further bioassay of the compoundsrevealed that the parent aglycone macrolactin A was the most

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bioactive, exhibiting selective antibacterial activity, inhibition ofB16–F20 murine melanoma cancer cells in vitro assays, significantinhibition of mammalian Herpes simplex viruses (types I andII), as well as protection of T-lymphoblast cells against humanHIV viral replication30 and of neuronal cells.31 The stereochemicalconfigurations of macrolactins B and F were later determinedto be the same by a combination of 13C-acetonide analysis usingisotopically enriched acetone, oxidative degradation, and chemicalcorrelation.32 Since macrolactin A is the aglycone of macrolactinB, it was suggested that the stereochemistry of macrolactin A wasthe same as that of macrolactins B and F. Final stereochemicaldetermination for the series was established by synthesis.33

Macrolactin A has been the subject of several synthetic effortsresulting in conformation of the stereochemical assignment.33–36

Synthetic efforts supplanted fermentation as a source for phar-macological studies due to problems with the original culture,34

although the discovery of additional (mesophilic) macrolactinproducers may obviate the problem.31,37–39

A new pluramycin metabolite, c-indomycinone (9), has beenisolated from the culture broth of a Streptomyces sp. obtainedfrom a deep-sea (4680 m) sediment core,40 along with two knownrubiflavinones. Members of this pluramycin class of antibiotics

contain an anthraquinone-c-pyrone nuclei but have different sidechains at position 2.

Guaymasol (10) and epiguaymasol (11) are two new aromatictriols isolated from the culture of a Bacillus sp. taken from a 1834 msediment core from the Guaymas Basin in the Gulf of California.41

Small, simple aromatic compounds such as the guaymasols arereported to be frequently produced by deep-sea bacilli.

An actinomycete of the genus Nocardiopsis, found in deep-seaPacific sediments (3000 m), contained a new cyclic tetrapeptide(12),42 which was devoid of cytotoxicity.

Several bis- and tris-indole derivatives (13–20) from the NorthSea bacterium Vibrio parahaemolyticus have been isolated.43 Tris-indole 18 was described for the first time from this sourcewhile the others were known from natural and synthetic sources;stereochemical analysis of 18 was not reported. Bioassays wereused to test the alkaloids against a range of bacteria and fungithough none of the isolates displayed significant antibiotic activity.

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Three new pyrrolosesquiterpenes, glaciapyrroles A–C (21–23),were isolated from a culture of Streptomyces sp. obtained from anAlaskan marine sediment.44 Only 21 was subject to stereochemicalanalysis. Although there are many natural products that containpyrroles, there are very few among terpenes; only one otherexample has been observed in nature. Glaciapyrrole A (21)exhibited an IC50 of 180 lM toward the colorectal adenocarcinomaHT-29 and melanoma B16–F10 human cancer cell lines.

A Western Pacific deep-sea actinomycete, Streptomyces sp.strain KORDI-3238, isolated from sediment collected at 3000 m inthe Ayu Trough, has been found to produce streptokordin (24), acytotoxic methylpyridine, along with four known compounds.45

Streptokordin displays modest cytotoxicity toward a humanleukemia cell line (K-562) and broad spectrum antibiotic activity.

An actinobacterium isolated from sediment collected from theNorth Atlantic Ocean near Holyrood, Newfoundland, elaboratedtwo new indolocarbazoles, holyrines A and B (25, 26).46 Theconfiguration of the hemiketal in 26 has not been established.The holyrines may be intermediates in the biosynthesis of stau-rosporine.

Istamycins A (27) and B (28) are antibiotics found in theculture filtrate of Streptomyces tenjimariensis.47 The istamycinsexhibit strong inhibitory activity against both Gram-positiveand Gram-negative bacteria, especially aminoglycoside-resistantstrains with the exception of an AAC(3)-producing organism(MICs: Escherichia coli K-12 C600 R135: 27, >50 lg mL−1,28, 25 lg mL−1, and Pseudomonas sp.: 27, 50 lg mL−1, 28,>25 lg mL−1).

The bacterium Bacillus sp., isolated from sea mud near theNorth Pole, contains three new iturin-class acylpeptides namedmixirins A–C (29–31).48 Iturins are cyclic lipopeptides that containseven amino acids and one long-chain a-amino fatty acid. MixirinsA, B, and C were all found to inhibit human colon tumor cells(HCT-116 IC50 0.68, 1.6, and 1.3 lg mL−1, respectively).

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A culture of the rare Gram-positive bacterium Janibacterlimosus isolated from the North Sea was found to contain twonew compounds, a tetrahydroquinoline derivative, helquinoline(32), and N-acetylkynuramine (33).49 Helquinoline was mod-erately antibacterial toward Bacillus subtilis, Streptomyces viri-dochromogenes, and Staphylococcus aureus. N-acetylkynuramine,reported here from an Arctic sea-ice bacterium, is reminiscent oferebusinone, isolated from a number of Antarctic invertebrates,such as the sponge Isodictya erinacea.50

Pseudoalteromonas haloplanktis, isolated from seawater in thevicinity of the Dumont d’Urville Antarctic station, was found tocontain one new (34) and six known (35–40) diketopiperazines,51

a class of compounds previously reported from an Antarcticbacterium.52 Stereochemical assignment of the pipecolinic acidcomponent of 38–40 was not assigned. Several other compoundsreported, including two polypeptides, were obtained from thesterile media.

A strain of Streptomyces collected from a shallow-sea sedimentnear Livingston Island, Antarctica was found to elaborate 2-amino-9,13-dimethyl heptadecanoic acid (41), as well as other,previously described, lipids.53 This compound was subjected tobioassay and showed inhibition of Bacillus subtilis and Micro-coccus leutus (MIC 50 and 15 lg mL−1, respectively) but did notinhibit Candida albicans nor Escherichia coli.

A marine isolate of the actinobacterium Nocardia sp. collectedfrom an expedition in the Kuril and Simushir Islands producesubiquinone Q9 (42).54 This is the first ubiquinone to be isolatedfrom actinobacteria. Ubiquinone Q9’s cytotoxic activity wasdetermined using mouse erythrocytes (MIC 30–50 lg mL−1) andfertilized eggs of the sea urchin Strongylocentrotus intermedius(MIC 40 lg mL−1).

An unidentified Gram-positive bacterium cultured from a deep-water (5000 m) sediment sample elaborates two new caprolactams,caprolactin A and B (43, 44).55 Caprolactins A and B were found tobe mildly cytotoxic towards KB cells (MIC 10 lg mL−1) and LoVocells (MIC 5 lg mL−1). Both compounds also exhibit antiviralactivity towards Herpes simplex type II virus (MIC 100 lg mL−1).The structures of caprolactins A and B were deduced usingspectroscopic methods and confirmed by synthesis.

3.2 Fungi

The deep-water (4380 m) filamentous fungus Penicillium cory-lophilum has been found to produce five new polyketides:(+)-formylanserinone B (45); (-)-epoxyserinone A (46); (+)-epo-xyserinone B (47); hydroxymethylanserinone B (48); anddeoxyanserinone B (49).56,57 Pentaketide 45 exhibited leukemiaselectivity as well as modest activity against the MDA-MB-435 breast cancer cell line, the latter displaying an IC50 of2.9 lg mL−1. These anserinones represent the first isolation ofcompounds from a deep-water, marine-derived saltwater fungalculture. Stereochemical evaluation of 48 and 49, which wereisolated as mixtures with known anserinones, was not completed.

A North Sea jellyfish-derived fungus Epicoccum purpurascenswas found to produce the secondary metabolite epicoccamide(50).58 This natural product is an unusual tetramic acid derivativethat is composed of glycosidic, fatty acid, and tetramic acid (aminoacid) subunits. These three subunits arise from three biosyntheti-cally distinct pathways. There are many tetramic acid derivatives

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that have exhibited cytotoxicity, but surprizingly epicoccamide didnot exhibit bioactivity in a number of assay systems.

Diterpene myrocin A (51), polyketide apiosporic acid (52), themonomethyl ester of 9-hydroxyhexylitaconic acid (53), and the(−)-enantiomer (54) of the known (+)-hexylitaconic acid wereisolated from the marine fungus Apiospora montagnei found inthe inner tissue of the North Sea alga Polysiphonia violacea.59 Allcompounds were tested for antibacterial, antifungal, and antialgalactivity and were found to be inactive at the 50 lg per disk level.

The marine fungus Chaetomium olivaceum was isolated fromsediments near Paramushir Island, among the Kuril islands, andwas found to produce antibacterial and cytotoxic compounds.60

The triterpenoid 3b-methoxyolean-18-ene, also known as miliacin(55), was the major component of the chloroform–ethanolicextract of the fungus. This compound was initially isolatedfrom the seeds of switch-grass Panicum miliaceum, and was laterfrequently found in higher plants. Miliacin has been found toinduce hemolysis of erythrocytes at pH 7 (HC50 2 × 10−4 M).

3.3 Microalgae

The cold waters of the Canadian Maritime provinces and thecoasts of the North Sea have been troubled in recent years by toxicblooms of microalgae, so called harmful algal blooms (HABs).61,62

While HABs are not limited to cold-water habitats,63 the followingexamples of microalgal toxins serve to illustrate the chemicaldiversity of the cold-adapted congeners.

The Canadian Maritime provinces were introduced to thephenomenon when shellfish in the province of Prince Edward

Island were found to contain domoic acid (56). A member of thekainoid family of neuroexcitatory amino acids related to kainicacid, domoic acid, was traced to a bloom of the diatom Nitzschiapungens f. multiseries and found since in related diatoms along thePacific Coast of North and Central America, in New Zealand, andin Europe. Due to loss of memory in those who have consumeddomoic acid-contaminated shellfish, the associated malady, whichis sometimes deadly, is known as amnesic shellfish poisoning(ASP).

Paralytic shellfish poisoning (PSP) is a term first applied tosaxitoxin (57) and subsequently to the family of related toxins.Found in dinoflagellates from both mesophilic and psychrophilichabitats, PSPs cause cramps, blockage of respiration and othersigns of paralysis.62 Among the Northeastern Canadian Provinces,cultured isolates of the dinoflagellate Alexandrium tamarense werefound to contain a variety of PSP toxins responsible for themortality of caged salmon including C2, GTX4, NEO, GTX5(B1), GTX3, GTX1, STX, C1, and GTX2 (57–62).64

The pectenotoxins are a family of mild toxins originating fromspecies of Dinophsis throughout the world.65 They appear to be oflow toxicity even at doses as high as 5000 lg kg−1. Pectenotoxins63 and 64 have been isolated as the minor constituents from abloom of Dinophsis acuta collected from net hauls in Norway.

The spirolides (65–75) constitute another family of potentmicroalgal toxins. They are extremely toxic compounds (LD50

for spirolide A being 250 lg kg−1) that were first isolated fromNova Scotian mussels (Mytilus edulis) and scallops (Placopecten

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magellanicus), and ultimately shown to originate from the di-noflagellate Alexandrium ostenfeldii.66,67 Isolation of the toxinswas driven by a mouse-toxicity bioassay. Symptoms observed intreated mice included cramps and jumping, and survival timeswere as low as four minutes. Spirolides B (66) and D (68), themajor metabolites in shellfish digestive gland extracts, were the firstto be characterized. Two ring-A hydrolysis products, biologicallyinactive spirolides E (74) and F (75),68 were subsequently reported.However, upon successful culture of the producing dinoflagellate,A. ostenfeldii, spirolides E and F were not observed as cultureproducts, suggesting that they are mollusc-hydrolized detoxifica-tion products.67 Cultured dinoflagellates also provided spirolidesA (65), C (67) and 13-desmethyl-spirolide C (69) in sufficientquantity for characterization.67 A Norwegian mussel bed sufferinga bloom of A. ostenfeldii was found to elaborate, besides spirolidesA–D, 13,19-didesmethylspirolide C (70), spirolide G (71) and 20-methylspirolide G (72).69,70 The G-series of spirolides differ fromspirolides A–F in that they have a six-membered ring C. Recentevidence suggests that shellfish can also detoxify spirolides byesterification of the macrocycle, as demonstrated by the isolationof 17-O-palmitoyl-20-methylspirolide G (73), a nontoxic spirolidefound in shellfish but not found in cultured A. ostenfeldii.71 Thestereochemistry of 13-desmethylspirolide C has been the subject

of modeling studies, establishing the relative stereochemistry asbeing the same as that found in pinnatoxins A and D, which aretemperate-water-derived toxins that share rings A–C and E withthe spirolides.72 The expectation73 is that spirolides A–F share the

same stereochemistry, as depicted. The bis-spiroacetal ring system(rings B, C and D) has been the subject of synthetic efforts in boththe spirolides73,74 and pinnatoxins,75 the latter as part of a totalsynthesis.

Recent biosynthetic studies of the spirolides have shown themto originate via the polyketide pathway.76 Beginning with a glycinestarter unit, resulting in the imine nitrogen observed in thespirolides, intact acetate accounts for 28 of the carbon atoms of 13-desmethylspirolide C (69), while all the methyl groups are observedto originate from C-2 of acetate. Interestingly, five carbons of thecontiguous chain derive from isolated acetate methyl groups.

Other HAB toxins, first described from mesophilic climates,have been detected in cold-water isolates of the producing organ-isms. Azaspiracid (76), for example, and several of its congeners,have been isolated from as far north as Songnefjord, Norway.77

In the south of Norway, Flodevigen mussel beds were found to

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be contaminated by Protoceratium reticulatum, and both musselsand shellfish yielded yessotoxin (77) and several derivatives.78

4 Macroalgae

For reasons discussed above, algal biodiversity is low in polarhabitats, and excluded from deep-water habitats due to the lackof light. This is reflected in their contribution to cold-waterchemodiversity, where they represent a small proportion of thereported compounds. Despite their low abundance, at least oneimportant group of compounds (antifouling fembrolides79) hasbeen reported.80

The red Antarctic alga Delisea pulchra has been found toelaborate three new dimeric halogenated furanones, pulchralidesA–C (78–80),80 as well as several known fembrolides.79 In contrastto the fembrolides, pulchralides showed no antimicrobial activitytoward Staphylococcus aureus, Escherichia coli, and Candidaalbicans.

Another Antarctic red alga, Plocamium cartilagineum, hasbeen studied extensively.25 A recent collection was investigatedand found to produce a new halogenated monoterpene, an-verene (81).80 Anverene has shown moderate bioactivity againstvancomycin-resistant Enterococci faecium (VREF) with a zoneof inhibition of 8 mm, but does not show bioactivity againstmethicillin-resistant Staphylococcus aureus (MRSA), methicillin-sensitive Staphylococcus aureus (MSSA), Escherichia coli, orCandida albicans.

The red alga Myriogramme smithii, also from Antarc-tica, has been reported to produce p-methoxyphenol and p-hydroxybenzaldehyde.80 These simple aromatic compounds havebeen determined to be responsible for the feeding deterrence ofthe sympatric sea star Perknaster fuscus.

The Antarctic brown alga Desmarestia menziesii elaborates anew quinone derivative, menzoquinone (82),80 as well as twominor metabolites, the chromenol derivatives 83 and 84.81 It washypothesized that 83 and 84 were derived from benzoquinoneprecursors, however, no such precursors were found in theorganism, suggesting that they may be formed in living algathrough non-enzymatic cyclization.81 Menzoquinone displayedgrowth inhibition of MRSA (8 mm), MSSA (6 mm), and VREF(7 mm), along with significant feeding deterrence against the seastar Odontaster validus.80

The Antarctic brown alga Cystosphaera jaquinotii produces thesteroid cystosphaerol 85.80 Bioassay data were not reported.

The chemical compositions of three collections of the red algaLaurencia nipponica from the western part of the Sea of Japan,south of Vladivostok, Russia, were investigated. Each samplewas found to elaborate chemically distinct compounds but allwere morphologically similar. One collection produces a series ofpreviously isolated sesquiterpenoids, the other predominantly C15

bromoallene ethers, and the last collection afforded the new halo-genated diterpenes 15-bromoparguer-9(11)-ene-16-ol (86) and 15-bromoparguer-7-ene-16-ol (87).82

5 Sponges

Not unlike mesophilic sponges, psychrophilic sponges are aprolific source of cold-water chemodiversity. Taken with previ-ously reviewed Antarctic sponge metabolites,24 seventy-one cold-water sponge metabolites have been described. In terms ofsignificant contributions to the biomedical sciences, compoundsfrom sponges (variolins) are the most advanced cold-water drugcandidate (see below).

Discorhabdin alkaloids have featured prominently in the spongechemistry of the Southern Ocean.25,29 Recently, discorhabdin R(88) has been isolated from two different sponges from the familyLatrunculiidae, (Southern Negombata sp. and Antarctic Latrun-culia sp.).83 As is the case with previously isolated discorhabdins,discorhabdin R bears significant antibacterial properties, specifi-cally against Gram-positive (Staphylococcus aureus, Micrococcus

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luteus) and Gram-negative (Serratia marcescens, Escherichia coli)bacteria. The relative stereochemistry of the epoxide remains unre-solved. In the Antarctic sponge Latrunculia apicalis, discorhabdinsC (89) and G (90)84 are distributed in a linear gradient, decreasingtoward the center of the spherically symmetrical sponge.85 Thisdistribution provides an optimal chemical defense against the seastar Perknaster fuscus, a discorhabdin-sensitive84 generalist spongepredator.86 Discorhabdin and related pigments have been isolatedfrom temperate and tropical sponges of the genera Latrunculia,Prianos, Zyzzya, and Batzella, and they continue to generatebiomedical interest.87

Dendrilla membranosa is a bright yellow circumpolar Antarcticsponge. The sponge does not possess spicules or other form ofphysical defense and uses its chemical defenses to protect againstpredation by nudibranchs or the aforementioned spongivoroussea star Perknaster fuscus.86 A collection of D. membranosa fromAnvers Island was found to elaborate membranolides B–D (91–93).88 Specimens from King George Island were found to elaboratea series of degraded and rearranged membranolides (94–97).89

The absolute stereochemistry of terpene 94 was determined bychiroptical methods. The stereochemistry of 95–97 was determinedusing conformational analysis and comparison to structurallysimilar spongian-metabolites. Membranolides C and D are activeagainst Gram-negative bacteria and fungi.

An unknown species of Suberites collected from both KingGeorge Island and McMurdo Sound elaborates a family of

terpenes known as the suberitenones.90,91 The defining structuralcharacteristics of these compounds are that they are sesterterpeneswith a cyclohexenone substituent on a phenanthrene tricyclicskeleton. Suberitenones A (98) and B (99) have been identifiedas the sponges major metabolites, and suberitenones C (100), D(101), and suberiphenol (102) as its minor metabolites. Bioactivitystudies have shown that suberitenone B inhibits the cholesterylester transfer protein (CETP), which is used to mediate the transferof cholesteryl ester and triglyceride between high and low-densitylipoproteins. Suberitenone B along with the other sesterterpeneshave defensive properties toward a major Antarctic spongivore,the sea star Perknaster fuscus.24

The related Antarctic sponge Suberites caminatus collectedfrom King George Island produces the aldehyde sesterterpenecaminatal (103), which possesses a novel carbon skeleton thathas been named caminatane.92 Caminatal consists of a bicyclicmoiety with an unusual aldehyde attached to the C-8 position thatleads to an isoprenoid aromatic ring. A subsequent collection ofthis sponge from King George Island led to the isolation of twonew suberitane-related sesterterpenes, oxaspirosuberitenone (104)and 19-episuberitenone (105).93 Oxaspirosuberitenone contains athree-ring carbocycle fused in a perhydrophenanthrene fashion.The oxaspiro carbon that holds together the cyclohexanone andoxane rings makes this compound a new structural type ofsuberitane framework. No bioactivity was described for thesecompounds.

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Two new 3-alkyltetrahydropyridine alkaloids, haliclamine Cand D (106, 107), were isolated from the arctic sponge Haliclonaviscosa.94 This sponge was also found to elaborate the 3-alkylpyridinium alkaloid, viscosamine95 (108) as well as the acyclic1,3-dialkylpyridinium alkaloid, viscosaline96 (109). Viscosalinepossesses a b-alanine that is covalently bonded to one alkylchain, which is an unprecedented structural motif. Although 3-alkyl pyridines are commonly found in sponges of the genusHaliclona and related genera, viscosaline is the first acyclicdimeric 3-alkyl pyridine alkaloid from natural sources.94–96 Thehaliclamines C and D showed a strong inhibition of two sympatricbacterial strains.97 These alkaloids are likely candidates for feedingdeterrence observed in extracts of H. viscosa toward sympatricpredators.98

The Norwegian sponge Polymastia boletiformis elaborates aseries of novel steroid–amino acid conjugates, the polymasti-amides (110–115).99,100 Polymastiamide A (110) represents the

first example of a naturally occurring steroid with a side chaincontaining an amide of an amino acid. Further investigation of thesponge extracts led to the isolation of polymastiamides B–F (111–115). Polymastiamide A exhibited in vitro antimicrobial activityagainst various pathogens (MICs in a 1/4-inch disk diffusionassay: Staphylococcus aureus (100 lg per disk); Candida albicans(75 lg per disk) and Pythium ultimum (25 lg per disk)).

Geodia barretti (G. baretti) is a sponge found commonlyalong the North Sea coast of Sweden and Norway. Specimenscollected from Kosterfjord, on the Northern Swedish West coast,and the Sula Ridge of Norway, have yielded two antifoulingbrominated diketopiperazines, barettin and its 8,9-dihydro analog(116, 117).101,102 Barettin, an 87 : 13 Z/E mixture, and 8,9-dihydrobarettin were found to inhibit the settlement of barnaclelarvae with EC50 values of 0.9 and 7.9 lM;103,104 the effects arenontoxic and reversible. Further study has shown both barettinand 8,9-dihydrobarettin, when mixed with paint, significantlyreduced the recruitment of barnacle Balanus improvisus and musselMytilus edulis.105 Just 0.1% barettin in paint reduced recruitmentof B. improvisus by 89% and M. edulis by 81%. The sameconcentration of 8,9-dihydrobarettin reduced recruitment of B.improvisus (67%) and M. edulis (72%). These two compoundshave potential as a non-toxic alternative to heavy-metal-basedantifouling paints. They also serve as selective serotonin-receptorligands and the striking selectivity differences between the two,barettin targeting 5-HT2A, 5-HT2C, and 5-HT4 receptors, while117 interacts exclusively with the 5-HT2C receptor, may pro-vide insight into serotonergic-associated diseases.106 Barettin and8,9-dihydrobarettin were synthesized via a Horner–Wadsworth–Emmons reaction of 6-bromoindole-3-carboxaldehyde.104,107

Besides diketopiperazines, Geodia barretti produces three N-methylated nucleosides (118–120).108 3-Methylcytidine (118) and3-methyl-2′-deoxycytidine (119) exhibit strong contractile activityin a guinea-pig ileum assay.

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Kirkpatrickia variolosa is a bright red sponge that inhabitsthe Antarctic benthos. This colorful sponge produces a series ofpigments, variolins (viz. 121–123), which have the very unusualpyridopyrrolopyrimidine ring system.109,110 This unique structurehas no precedence in either terrestrial or marine natural products;variolin A (121) is zwitterionic. All of the variolins are potentcytotoxins toward the P388 cell line. Their mechanism of actionhas been established as inhibition of cyclin-dependent kinase(CDK).111 The unique structure and potent bioactivity of thisfamily of compounds have made them a desired synthetic target.Variolin B (122) has been the main focus of synthetic interestbecause it is the most active analog in the variolin family.112 Thefirst total synthesis of variolin B113 was reported in 2001 andsince then several other synthetic routes to both variolin B andits deoxy derivative have appeared.113–119 Different strategies havebeen developed to synthesize the variolin core.120–123 Eight syntheticderivatives of variolin B with different substituents at positions C-5and C-7 were tested against sixteen human tumor cell lines.119 Noneof the eight synthetic compounds were significantly more activethan the natural product, although a few derivatives performedcomparably. Another synthetic variolin B analog, designatedPM01218 (124), has shown potent growth inhibitory activityagainst several human cancer cell lines.124 To further explore theactivity of PM01218, a highly sensitive method for quantitativeanalysis of the drug in mouse and rat plasma has been developedutilizing HPLC–ESI-MS tandem mass spectrometry.

The North Atlantic sponge Pseudosuberites hyalinus elaboratesfour new bromoindole alkaloids (125–128).125 The indoles wereprepared synthetically by a variant of the Leimgruber–Batchoindole synthesis and used to confirm the identity of the naturalproducts.

The Norwegian sponge Plaktortis simplex elaborates twonovel cyclic peroxides (129, 130) with a dodec-4-enoic acid unitbackbone.126 When tested for bioactivity, 130 exhibited moderatein vitro activity against six solid human tumor cell lines with IC50

values in the range 7–15 lg mL−1.

Bretonin A (131) and isobretonin A (132) are glycerides isolatedfrom an unidentified demosponge collected from the NorthBrittany Sea.127 Bretonin A consists of glycerol esterified by4-hydroxybenzoic acid, and isobretonin A consists of glyceroletherified by a C12 trienic linear alcohol. Bretonin B (133) wasalso isolated from the same sponge but due to insufficient massit was unable to be thoroughly studied. The stereochemistry ofthese compounds was determined by synthesis.128 No bioactivitywas reported for the bretonins.

6 Corals

Cold waters are largely devoid of the reef-building scleractiniancorals but are abundant in the soft-bodied octocorals that arewell known for their chemical diversity. Cold-water Cnidaria were,historically, among the first marine animals to be chemically stud-ied. Ackermann’s studies of North Sea anemones129 in the early1950’s were contemporary with Bergman’s studies of Caribbeansponges.130 Cold-water species of soft corals have been the sourceof forty-eight described compounds, two-thirds of which are fromAntarctic species.

More than a dozen new steroids have recently been reportedfrom two Antarctic octocorals. Anthomastus bathyproctus elabo-rates seven steroids (134–140)131 while Dasystenella acanthine wasshown to produce seven polyoxygenated steroids (141–147), thelatter of which displayed micromolar activity as growth inhibitorsof several human tumor cell lines.132

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The Antarctic gorgonian octocoral Dasystenella acanthine hasalso been reported to produce three nonpolar sesquiterpenes (148–150), two of which (148, 149) were previously known.133 In a Gam-busia affinis (mosquito fish) ichthyotoxicity assay, 149 and 150 werefound to be toxic at 10 ppm suggesting that the compounds serveas defensive metabolites. They exhibited no feeding deterrencetoward the goldfish Carassius auratus. The use of fish species thatdo not co-occur with the coral makes an ecological role hard toassign. However, mosquitofish are considered a nuisance invasivespecies, despite continued intentional release as mosquito-controlagents.

The soft coral Alcyonium paessleri collected near the SouthGeorgia Islands elaborates a series of fifteen illudalane sesquiter-penoids, the alcyopterosins (151–165).134 These are the firstilludalane sesquiterpenoids to be isolated from the marine en-vironment. Eight of these compounds contain nitrate esters,never before found in a natural product, and the other four arechlorinated. Alcyopterosins 151, 156, 159 and 162 showed mildcytotoxicity toward Hep-2 (human larynx carcinoma) cell linewith an IC50 of 13.5 lM, while alcyopterosins 151, 156, and 162exhibited cytotoxicity toward HT-29 (human colon carcinoma) atan IC50 of 10 lg mL−1. The alcyopterosin ring system has beenconstructed via a highly efficient arene annulation of a lineartriyne precursor catalyzed by rhodium(I), ultimately leading toalcyopterosin E.135

Two new sesquiterpenoids, paesslerins A and B (166, 167),containing an unprecedented tricyclic skeleton were isolated fromanother collection of Alcyonium paessleri near the South GeorgiaIslands.136 The paesslerins displayed moderate cytotoxicity againsthuman tumor cell lines.

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Among the rare cold-water scleractinian corals, Madrepora oc-ulata collected from the Norwegian North Sea was found to elab-orate two 10-hydroxydocosapolyenoic acids (168, 169) that wereisolated as methyl esters.137 The coral also produces other known10-hydroxydocosapolyenoic acids and 8-hydroxyeicosapolyenicacid, implying the intervention of a rare lipoxygenase with highx13 specificity.

The circumpolar Arctic soft coral Gersemia fruticosa, knowncommonly as a sea raspberry due to its physical appearance,elaborates a number of steroids and eicosanoids. Collectionsfrom the White Sea of Northwestern Russia have been sub-ject to considerable attention with regard to their eicosanoidbiosynthetic pathway.138–140 These coral-derived mammalian-typeprostaglandins139 are not biosynthesized by the expected allene-oxide pathway, but rather by a cyclooxygenase (COX)141 that isevolutionarily divergent from the mammalian enzyme.142 WhiteSea and Canadian collections of G. rubiformis also elaborate anumber of steroids. Specimens collected in Newfoundland werefound to have oxidized steroids 170 and 171143 while those fromNorthern Russia contain polyoxygenated sterols (172–175) andthe 9,11-secosterols (176–178), which display cytotoxicity towardhuman erythroleukemia K-562 cells.144,145 Sterols 172–177 havebeen found to inhibit the growth of human leukemia K562 cellsin vitro, with IC50 values of 16, 21, 21, 14, >60, and 29 lM,respectively.145,146 The compounds were also tested against HL-60 and P388.DI leukemia cell lines and sterols 172, 173 and 175exhibited a similar antiproliferative activity: against HL-60 theactivity (IC50) was 18, 14, and 29 lM; against P388.DI cells, IC50

values of 21, 18, and 21 were obtained. Synthetic efforts toward the9,11-seco skeleton in this series has been reported,147,148 includingthe key ring-C cleavage, starting from desoxycholic acid.

A collection of Plumarella sp. from near the Kuril Islandregion of the Northwestern Pacific Ocean elaborates two newcytotoxic diterpenoids, plumarellide (179) and the ethyl ester ofplumarellic acid (180).149 Both compounds exhibited moderatehemolytic activity against mouse-blood erythrocytes, inducing50% hemolysis at concentrations of 140 and 250 lM, respectively.

Ainigmaptilone A (181) and B (182), sesquiterpenes basedon the eudesmane carbon skeleton, were isolated from the softcoral Ainigmaptilon antarcticus collected from the Eastern WeddellSea of Western Antarctica.150 Ainigmaptilone A is a defensivemetabolite that is not only an antibiotic but also significantlyinhibits predation by a local predatory sea star, Odontaster validus.

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7 Bryozoans

Bryozoans are well known producers of bioactive metabolitesand the cold-water representatives are no exception. Cold-waterbryozoans have been the source of thirty-five published naturalproducts. Although none of the published reports of cold-waterbryozoan chemistry have originated from Southern Hemisphereorganisms, Antarctic bryozoan diversity is rich and bioactive.151

One alkaloid, tambjamine A (183), previously reported from atropical bryozoan, has been found in the Antarctic bryozoanBugula longissima.152

The circumpolar bryozoan Flustra foliacea has been extensivelystudied, resulting in a plethora of brominated tryptophan-derivedalkaloids. The bryozoan occurs from the decidedly temperateBrittany coast, north to the cold waters of the Swedish, Norwegianand German North Sea, as well as in the Canadian Maritimes.Among the very first studies of bryozoans, flustramines A andB (184, 185), from the physostigmine class of alkaloids, weredescribed in 1979.153,154

Flustramine C (186), flustraminol A (187) and flustraminolB (188) were subsequently reported, without stereochemicalassignment, from the same bryozoan,155 followed by reports offlustramide A (189)156 and B (190),157 flustrabromine (191)158 6-bromo-Nb-methyl-Nb-formyltryptamine (192),156 and flustrarineB (193).159 Interestingly, it was found that flustrarine B couldbe reversibly converted to flustramine B N-1-oxide (194) upontreatment with acid.159 Flustramine E (195), which displays activityagainst Botrytis cinerea and Rhizotonia (= Rhizoctonia?) solani,160

and debromoflustramine B derivative 196, were obtained froma Danish collection of the bryozoan. A recent collection of F.foliacea, from Steingrund on Germany’s North Sea coast, yieldedfour indole alkaloids, 197–200 and the physostigmine alkaloid201.161,162

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From the Western Hemisphere, a collection of Flustra foliaceafrom the Minas Basin, Nova Scotia, elaborates flustramines A–C(184–186), originally found in North Sea collections of F. foliacea,and the related dihydroflustramine C (202).163 Five additionalphysostigmine-related brominated alkaloids were subsequentlyfound in the North American F. foliacea (203–207) and reportedwithout stereochemical assignment.164

Along with the many tryptophan-derived indoles, Flustra foli-acea has also yielded a bromo-substituted quinoline (208).165

Alkaloids from Flustra foliacea have displayed a variety ofbioactivities. Physostigmine alkaloids are of current interest fortheir potential role in the treatment of Alzheimer’s disease.166 Flus-tramine A has muscle relaxant properties,167 potassium-channelblocking activity,161 and is modestly cytotoxic toward HCT-116.168

Deformylflustrabromine (199) was found to selectively increasethe current obtained in a4b2 receptors when co-applied withacetylcholine,168 while its N-prenyl derivative 200 has an affinityfor neuronal nicotinic acetylcholine receptors using radioligandbinding assays.162

Many syntheses of physostigmine-containing natural pro-ducts169 have been completed, including: flustraminol B;170 flus-tramines A and B, flustramides A and B;171–173 flustramineC;174–176 dihydroflustramine C and flustramine E.177 Many ofthe debromoflustramines and debromoflustramides have beensynthesized.175,178–181

The alkaloid and terpene variation in different collections ofF. foliacea were analyzed via GC-MS.182,183 Different bryozoancollections yielded unequal amounts of alkaloids and terpenes.For example, the flustramine content of F. foliacea collectionsfrom Danish and Swedish waters have been compared.167 It wasfound that more northern, Swedish, specimens of these containedabout twice the amount of alkaloids as the Danish collection ofthe same species.167

Illustrative of the terpene content of the Flustra genus, diterpene209, from the bryozoan F. foliacea, was isolated as a racemicmixture.161,184 As a racemate, 209 could arise from the self-

condensation of citral during the work-up of the extract or couldbe one of the rare examples of a racemic natural product. In vitrobase-catalyzed dimerization of citral afforded 209, suggesting thatit is an artifact. No bioactivity is reported for 209.

Four halogenated indole–imidazole alkaloids designated secu-ramines A–D (210–213) have been reported in the North Seabryozoan Securiflustra securifrons.185 Securamines E–G (214–216)were later found in the same bryozoan.186 Securamines A and B,when dissolved in DMSO, equilibrate to macrocyclic alkaloidsgiven the names securines A and B (217, 218), respectively.

Dendrobeania murrayana from Nova Scotia elaborates the C21

tetracyclic terpenoid lactone murrayanolide (219), which appearsto be the first of its kind to be isolated from a bryozoan.187

Norsesterterpenes are rarely found in marine organisms, and evenmore rarely in bryozoans, which generally produce alkaloids andsimpler diterpenes. Murrayanolide exhibited inhibitory activityagainst metalloprotease collagenase IV at an MIC of 25 lg mL−1

with a 54% inhibition.

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8 Molluscs

Extensive research has been conducted on the Antarctic molluscAustrodoris kerguelenensis, a dorid nudibranch which produces ahost of diterpene glyceryl esters, a group of compounds character-istic of being produced by the mollusc rather than acquired fromthe mollusc diet, a common defensive strategy of nudibranchs.188,189

Other than A. kerguelenensis, there are few reports of cold-watermollusc chemistry; only thirty-five cold-water mollusc-derivednatural products have been reported, primarily from Antarctica.

The external body parts of Austrodoris kerguelenensis containnumerous terpenoid glyceryl esters, 220–228.24,190,191 Stereochem-ical analysis of previously described192 225 and 228 led to theirrevision as 223 and 224.190 These compounds deter sympatricpredators such as the sea star Odontaster validus,191,193 and arehypothesized to be made by de novo biosynthesis as opposedto sequestration from its sponge diet.191 Further, A. kergue-lenensis elaborates two novel nor-sesquiterpenes, austrodoral(229) and austrodoric acid (230),194 both of which have beensynthesized.195,196

The pteropod Clione antarctica, a shell-less, pelagic mollusc, wasfound to contain a defensive polyketide metabolite, pteroenone(231).197 A new synthesis of all four stereoisomers has con-firmed the structural assignment.198,199 Pteroenone is a defensivecompound that deters fish predation.24,200 In a very unusualrelationship,26 the small mollusc C. antarctica is abducted byan amphipod (Hyperiella dilatata) which attaches the captured

mollusc to its back, utilizing the anti-feeding properties of thepteropod for its own defense.201 The stereochemical integrity ofpteroenone was established via synthesis that produced all fourdiastereomers,202 a sample set which lends itself to an investigationof the role of stereochemistry in an ecological context.

The 3,4-seco triterpenoid lovenone (232) was isolated fromthe skin extract of the nudibranch Adalaria loveni.203 Lovenoneis the first report of a degraded triterpenoid from a doridnudibranch. The most structurally similar compound to lovenoneis limatulone,204 which is the only other triterpenoid reported froma marine mollusc. Lovenone exhibits moderate in vitro cytotoxicityagainst human ovarian carcinoma HEY (ED50 11 lg mL−1) andhuman glioblastoma/astrocytoma U-373 (ED50 11 g mL−1) celllines.

The skin extracts of the North Sea dorid nudibranch Limaciaclavigera were found to contain a new symmetrical diacylguani-dine, designated limaciamine (233).205

9 Tunicates

Despite the small number of metabolites, twenty, reported todate from cold-water tunicates, the potent cytotoxicity of themeridianins and palmerolides (see below) make this one ofthe most interesting groups of cold-water invertebrates from abiomedical perspective.

The meridianins (234–240), a series of brominated 3-(2-aminopyrimidine)indoles isolated from the South Atlantic (SouthGeorgia Islands, 100 m) ascidian Aplidium meridianum, have beenfound to prevent cell proliferation and induce cell apoptosis.206

The meridianins with the exception of meridianin G (240) and therelated isomeridianins C and G (241, 242), were found to inhibitCDKs, GSK-3, PKA and other kinases in the low micromolarrange.206 Of the active meridianins, meridianins B and E were themost potent inhibitors.206 Due to the potent bioactivity displayedby the meridianins, attention has turned to their synthesis.207–210

Several synthetic approaches to meridianins and the structurallyrelated variolins have been developed.210–213 Along with naturallyoccurring meridianins, potent cytotoxic synthetic meridianinderivatives have also been reported.214 The meridianin series hasalso been found in Palmer Station, Antarctica, collections of therelated tunicate Synoicum sp.152

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Synoicum adareanum is a circumpolar colonial tunicate foundcommonly in the waters of Antarctica near Anvers Island. S.adareanum elaborates the unusual enamide-bearing macrolide,palmerolide A (243).215 This polyketide targets melanoma (e.g.UACC-62 LC50, 18 nM) in the National Cancer Institute’s 60cell line panel with three orders of magnitude greater sensitivityrelative to other cell lines tested. Palmerolide A appears to act onmelanoma by inhibition of vacuolar ATPase (IC50 2 nM).

The flatworm Prostheceraeus villatus, collected in the waters offBergen, Norway, was found to contain five alkaloids (244–248),all of which are sequestered from its diet of tunicates, Clavelinalepadiformis.216 This is the first reported example of a flatworm-sequestering bioactive secondary metabolites from its prey. Lep-adin A (244) and the pentachlorooctatriene 249 were originallyisolated from the tunicate,217 while 245–248, first discovered inthe flatworm, have since been found in the tunicate as well.

Pyrrolidines 247 and 248 have not been assigned stereochemistry.Alkaloids 244, 245 and 248 display significant in vitro cytotoxicityagainst human cancer cell lines. Lepadin A, for example, displayedin vitro activity toward murine leukemia P388 (ED50 1.2 lg mL−1),breast cancer (MCF7, 2.3 lg mL−1), glioblastoma/astrocytoma(U373, 3.7 lg mL−1), ovarian (HEY, 2.6 lg mL−1), colon (LoVo,1.1 lg mL−1) and lung (A549, 0.84 lg mL−1). This significantbioactivity has prompted the development of several lepadinsyntheses.218–221

Ascidians belonging to the genus Eudistoma collected in theNorthern Sea of Japan were found to contain two ergolinealkaloids, pibocin A and B (250, 251).222,223 The indole nitrogenin pibocin A is unsubstituted, whereas pibocin B incorporatesan unusual N-O-methylindole group previously found only interrestrial plants. Pibocin B is also moderately cytotoxic againstmouse Ehrlich carcinoma cells.

Glabruquinone A (252), also known as desmethylubiquinoneQ2, and its minor isomer glabruquinone B (253) are two newdiprenylquinones found in the ascidian Aplidium glabrum.224

Glabruquinone A is of special interest not only because it ismore structurally related to ubiquinone than any other linearpolyprenyl quinones from sponges and ascidians, but also becauseit exhibits cancer-preventive activity. This activity has been shownin the anchorage-independent transformation assay against mouseJB6 P+ Cl 41 cells that had been transformed with an epidermalgrowth factor. The IC50 of glabruquinone A against the colonieswas 7.3 lM. It was also found to increase the UVB-induced p53-dependent transcriptional activity against these cells by 2.5 timeswhen used at 10 lM concentration. Anticancer activity was alsoexhibited against HCT-116, MEL-28, and HT-460 human tumorcells with IC50 of 12.7, 17.5 and 50.5 lM, respectively.

The first oxadiazinone alkaloid found in nature, alboinon (254),was discovered in the North Sea ascidian Dendrodoa grossularia.225

Alboinon was prepared from its imidazole analog by treatmentwith m-CPBA, inducing a Baeyer–Villiger rearrangement.

10 Echinoderms

Taken with the eighty compounds reviewed from Antarcticechinoderms through 2000,24 the additional metabolites reported

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herein constitute the largest single source of cold-water naturalproduct chemistry.

10.1 Steroids

The deep-water sea star Styracaster caroli, collected at a depthof 2000 m off the coast of New Caledonia, was found tocontain three polyhydroxycholanic acid derivatives, designatedcarolisterol A–C (255–257).226 These polyhydroxysteroids (PHSs)are unique because they contain a polyhydroxycholanic acidmoiety connected to D-cysteinolic acid via an amide linkage.

Two new asterosaponins, sanguinoside A and B (258, 259), wereisolated from two species of Pacific Far Eastern starfish collectedin the Sea of Okhotsk, Henricia sanguinolenta and H. leviusculaleviuscula.227

A steroidal glycoside, phrygioside A (260), and its aglycone (261)have been isolated from a Sea of Okhotsk starfish Hippasteriaphrygiana.228 H. phrygiana also yielded the new cyclopropane-containing steroid phrygiasterol (262) and steroid glycoside phry-gioside B (263).229 Phrygiasterol displayed an IC50 of 50 lg mL−1

against Ehrlich carcinoma cells. Phrygioside B induced apoptosisof the Ehrlich cell with an EC50 of 70 lg mL−1, and also inhibitedCa2+ influx into mouse splenocytes. The starfish Asterias rathbuni,collected in the Bering Sea yielded two new polyhydroxysteroidalglycosides, rathbuniosides A and B (264, 265).230 RathbuniosideA inhibits cell division of fertilized sea urchin eggs at 7.0 ×10−5 M. The new glycoside aphelasteroside (266) along with threeknown compounds (267–269) were isolated from Aphelasteriasjaponica, a starfish found in the Sea of Okhotsk near the KurilIslands.231

Five new polar steroids, polyhydroxysterols 270–273 and theglycoside leviusculoside J (274), were isolated from Henricialeviuscula dredged from the Sea of Okhotsk.232 Compounds271 and 274 displayed moderate hemolytic activity in mouse-erythrocytes assays (HC50 210 lM and 80 lM, respectively).Polyhydroxy steroids dominate the extracts of Luidiaster dawsonicollected in the Sea of Okhotsk,233 while Henricia aspera elab-orates polyhydroxy steroid glycosides.234 The stereochemistry of

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H. derjugini-polyhydroxylated steroids has been established byMosher’s method.235

Two new compounds, a steroidal glycoside (275) and a steroidalketone (276), were isolated from extracts of Henricia sanguino-lenta and H. leviuscula leviuscula.236 These two compounds aremoderately cytostatic toward fertilized sea urchin eggs.

A new polyhydroxylated steroid (277) and a previously de-scribed glycoside, laeviuscoloside G (278), were isolated from thesea star Henricia sanguinolenta, collected in the Sea of Okhotsk.237

Sulfated PHSs from the sea star Diplopteraster multipes havestructural similarities to ophiuroid compounds,238 suggesting acloser evolutionary relationship between sea stars and ophiuroidsthan between either of them and the other echinoderms.239 TheFar Eastern sea star Lysastrosoma anthosticta also elaboratespolyhydroxylated sterol sulfates.240

The sea star Lethasterias nanimensis chelifera collected in theSea of Okhotsk yielded a variety of sulfated steroid salts.241,242

Five of these salts were new (279–283), four of which belonged tothe unusual alkaloidosteroid group in which a sulfate group bearsan alkaloidal counter ion. Six additional, previously known, polarsteroids were also found.241 The alkaloid 284 was found in the samesea star.242

Two new sulfated steroids (285, 286) have been isolated fromthe Kuril Isles starfish Pteraster pulvillus.243 Steroid 285 showedhemolytic activity toward mouse erythrocytes (HC50 4.5 × 10−5 M).

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P. tesselatus, from the same region, elaborates similar steroidalsulfates.244

10.2 Triterpene glycosides

Three new monosulfated triterpene glycosides, calcigerosides A–C (287–289), have been isolated from a sea cucumber, Pentameracalcigera, collected from the Peter the Great Gulf in the Sea ofJapan.245 The calcigerosides elaborate a novel pentasaccharidechain not previously observed in sea cucumber triterpene gly-cosides. Two new trisulfated triterpene glycosides were isolatedfrom the Antarctic sea cucumber Staurocucumis liouvillei.246 Thenew steroids, liouvillosides A and B (290, 291), were found to bevirucidal against Herpes simplex type 1 (HSV-1) at concentrationsbelow 10 lg mL−1.246

11 Miscellaneous

A sex pheromone, L-ovothiol A (292), released by the NorthSea male polychaete Platynereis dumerilii, causes egg release infemales.247 The male discharges the egg releasing pheromone withsperm, which causes the female to swim in fast narrow circlesaround the sperm and begin to spawn. The disulfide (293) formedby oxidation of L-ovothiol A has also been isolated.

12 Conclusion

Secondary metabolism in polar and abyssal marine habitats,like that in temperate and tropical habitats, is largely driven byecological requirements of the producing organism.189,248 Com-petition for space, food and other resources, predator avoidanceor deterrence, intraspecies communication and the prevention offouling or other invasive interactions are among the phenomenathat marine invertebrates, algae and microbiota the world overmust contend with. Successful organisms will often have metabolicpathways that have, per chance, evolved secondary products thatbestow ecological advantage. Cold temperatures do not reducethese ecological pressures nor do they limit the metabolic capacityof an organism. Ultimately, high biodiversity, and the concomitantecological pressures of increasing organism-on-organism inter-actions, drives chemical diversity; chemodiversity recapitulatesbiodiversity. In the context of chemodiversity-discovery programs,cold-water habitats are a resource that has yet to be fully exploited.

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13 Acknowledgements

Preparation of this review was supported, in part, by a grant fromthe U. S. National Science Foundation (OPP-0442857).

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