《天然药物化学》课程参考文献（海洋天然产物）Deep-sea natural products.pdf_大学文库

Deep-sea natural products† Danielle Skropeta* Received 27th May 2008 First published as an Advance Article on the web 9th September 2008 DOI: 10.1039/b808743a Covering: up to the end of 2007 This review covers the 390 novel marine natural products described to date from deep-water (>50 m) marine fauna, with details on the source organism, its depth and country of origin, along with any reported biological activity of the metabolites. Relevant synthetic studies on the deep-sea natural products have also been included. 1 Introduction 2 Reviews 3 Deep-sea life 4 Bryozoa 5 Chordata (ascidians) 6 Cnidaria 7 Echinoderms 8 Microorganisms 9 Mollusca 10 Porifera (sponges) 11 Conclusions 12 References 1 Introduction Over the past 50 years, approximately 20 000 natural products have been reported from marine flora and fauna, and yet less than 2% of those derive from deep-water marine organisms.1 The vast oceans cover 70% of the world’s surface, with 95% greater than 1000 m deep.2 Although difficulty in accessing these depths has previously hindered deep-sea research, today with improved acoustic technology and greater access to submersibles, deep-sea exploration is uncovering extensive deep-water coral reefs that are home to a wealth of species on continental shelves and seamounts world-wide (Fig. 1).3 It has been estimated that the number of species inhabiting the world’s oceans may be as high as 10 million,4 and the ocean fringe with its high concentration of competing species was always thought to have the highest species diversity. On the contrary, recent analyses have shown that the deep sea is one of the most biodiverse and species-rich habitats on the planet, rivalling that of coral reefs and rainforests.4–9 With over 60% of drugs on the market of natural origin, natural products can be considered the foundation of the pharmaceutical industry.10 Although in recent years the pharmaceutical industry decreased its activity in this area, today natural product-based drug discovery is experiencing a renaissance.11 In particular, the marine environment, a rich source of structurally unique, bioactive metabolites, has produced a number of drug candidates that are currently in clinical trials.12–16 In the everexpanding search for sources of new chemical diversity, the exploration of deep-sea fauna has emerged as a new frontier in drug discovery and development. Novel marine actinomycetes obtained from deep oceanic sediments such as the Mariana trench (10 898 m), are a promising source of new and unexplored chemical diversity for drug discovery.17–19 Blunt et al.20 have recorded an approximate doubling in the frequency of cytotoxicity towards the P388 murine tumour cell line from a single deep-water collection at a depth of 100 m off Chasam Rise, New Zealand, compared to the average activity of >5000 shallow-water collections over a 13 year period. Deep-sea hydrothermal vents21 and cold-seeps22 where nutrient-rich fluid seeps from the sea floor, are host to high levels of microbial diversity that are currently being explored as sources of unique biocatalysts able to withstand high pressure and variable temperatures.23–25 Danielle Skropeta Danielle Skropeta obtained her BSc(Hons) degree from Monash University and her PhD degree from the Australian National University. She has held postdoctoral appointments in marine natural products with F. Pietra at Trento University, Italy, and in carbohydrate chemistry with R. R. Schmidt at Konstanz University, Germany, as well as at the University of Sydney and the Heart Research Institute. In 2006 she took up a lectureship at Wollongong University, where she now leads a research team in marine natural products chemistry, with particular interests in deep-sea natural products. School of Chemistry, University of Wollongong, Wollongong, Australia. E-mail: skropeta@uow.edu.au; Fax: +61 24221 4287; Tel: +61 24221 4360 † This paper is contribution #5 from the South East Asian Branch of the SERPENT (Scientific and Environmental Remotely Operated Vehicle Partnership using Existing Industrial Technology) deep-sea project. This journal is ª The Royal Society of Chemistry 2008 Nat. Prod. Rep., 2008, 25, 1131–1166 | 1131 REVIEW www.rsc.org/npr | Natural Product Reports

There are vastly different environmental conditions and oceanographic parameters at play in the deep-sea (Fig. 2).26,27 Pressure increases by 1 atm for every 10 m below sea level, thereby varying from 10 atm at the shelf-slope interface to >1000 atm in the deepest part of the trenches. Consequently, species inhabiting these depths must adapt their biochemical machinery to cope with such pressures. Temperatures taper off rapidly with increasing depth down to 2 C at bathal depths of >2000 m. As lower temperatures reduce the rates of chemical reactions, deep-sea species must adjust their biochemical processes to function at depressed temperatures. Light penetration decreases exponentially with depth, such that below 250 m essentially no light penetrates. In the dark, cold depths of the ocean, vision becomes less important, and it is presumed that chemoreception and mechanoreception play greater roles. The near-bottom current is much slower in the deep sea compared to shallow-water with speeds of around 10 cm s1 at bathyal depths and 4 cm s1 at abyssal depths. The average metabolic rates and growth rates are lower than shallow-water species, however the latter is closely aligned to food availability. In the deep-sea the pH is typically around 828,29 and the salinity about 35% and therefore entirely marine, with a relatively low level of variability. The sediment comprises weathered rock washed into the sea by wind and rivers, as well as planktonic material obtained from the water above.26,27 Deep-sea organisms survive under extreme conditions in the absence of light, under low levels of oxygen and intensely high pressures, all of which may affect their primary metabolic pathways and consequently their secondary metabolites.31,32 For this reason, deep-sea fauna are expected to have a greater genetic diversity than their shallow-water counterparts, and a higher probability of containing structurally unique metabolites. The extraordinarily high level of diversity of deep-sea benthic fauna has been well known, and the mechanism to explain it hotly debated, since the 1960s.5,33–36 Soft-bottom deep-sea fauna are found to be similar at the higher taxonomic level to shallowwater fauna and consist primarily of megafauna such as echinoderms (sea cucumbers, star fish, brittle stars) and anemones; macrofauna such as polychaetes, bivalve molluscs, isopods, amphipods and other crustacea; and meiofauna which primarily comprise foraminifers, nematodes and copepods, while hardbottom deep-sea fauna are dominated by sponges and cnidarians (soft corals, gorgonians). At the species level, however, deep-sea fauna are found to contain a high number of single rare species, with more than half being new to science, and with some taxa comprising almost entirely of new species. In addition, many of the species are found to exclusively inhabit the deep sea, with high levels of biodiversity extending to abyssal depths of 5000 m.26,27 Recent sampling expeditions by the ANDEEP (Antarctic benthic deep-sea biodiversity) project in the Southern Ocean deep sea revealed extremely high levels of biodiversity across a range of taxa including meio-, macro- and megafauna, with the highest levels of species richness amongst the first two. In general, abundance decreased with increasing depth, while species richness increased with the highest number of species found at bathyal depths of 3000 m. Depth and biogeography trends were found to vary between taxa, and there was an apparent higher Fig. 1 Deep-sea marine fauna. (A) A Bolocera sp. anemone (500 m depth, Barents Sea, Norway); (B) A community of anemones, hydroids and corals (100 m depth, North Sea, UK); (C) The basket star Gorgonocephalus caputmedusae (930 m depth, Norway); (D) A colony of the deep-water coral Lophelia pertusa (100 m depth, North Sea, UK). [Images courtesy of SERPENT Project, Southampton, UK]. 1132 | Nat. Prod. Rep., 2008, 25, 1131–1166 This journal is ª The Royal Society of Chemistry 2008

species richness for many taxa of the Southern ocean compared to the Arctic deep sea.7 This review describes the 390 novel natural products isolated to date from deep-sea fauna. The deep sea is variably defined as commencing at depths of anywhere between 100 and 1000 m;2 however, for the purposes of this review deep-sea fauna are defined as those inhabiting depths of greater than 50 m, in order to include those fauna beyond the depths of scuba. The majority of deep-sea natural products included in this review have been isolated from deep-sea sponges, echinoderms and microorganisms obtained using manned submersibles, or from commercial and scientific dredging and trawling operations, and emanate from tropical, temperate and polar regions. Herein, where no biological activity is ascribed to a particular metabolite it is because no such data have yet been reported. 2 Reviews Cold-water marine natural products isolated from organisms collected from habitats below 4 C were covered for the first time in 2007 by Baker et al. in a review that included some deep-water examples.37, ‡ In 2004, Laurent and Pietra reviewed the natural product diversity of the New Caledonian marine ecosystem, including deep-water sponges.38 In 2001, a list of deep-water marine natural products appears in Pietra’s book Biodiversity and Natural Product Diversity. 39 In 2001, Capon published a minireview on natural products isolated from Australian marine sponges obtained from trawling operations.40 In 1998, Bewley and Faulkner reviewed lithistid sponge metabolites from both shallow and deep-water habitats.41 To the best of the author’s knowledge, this is the first comprehensive review to focus solely on marine natural products isolated from deep-sea (>50 m) fauna. 3 Deep-sea life Life in the deep sea involves exposure to high hydrostatic pressures and low temperatures, requiring its inhabitants to adapt their genetic, biochemical and physiological processes and presenting unique challenges in terms of gene regulation, structure and function of proteins and other cellular components, and metabolism and physiology.42,43 A number of deep-sea psychrophilic (cold-loving) and thermophilic (heat-loving) microorganisms have been isolated, and their mechanisms of adapting to high pressure,44–49 and either cold temperatures (in the majority of the deep sea)50–52 or high temperatures (around hydrothermal vents),21,53–55 have been well documented. In contrast, there is a paucity of literature surrounding the adaptation of marine invertebrates to deep-sea life. It is beyond the scope of this review to cover the diverse range of adaptive mechanisms reported for deep-sea fauna; however, some of the key data that has emerged regarding gene regulation, macromolecular structure and metabolism in the deep sea have been summarized below. Intense investigation into the piezophilic psychrophile Shewanella violacea, a bacterium isolated from deep-sea sediment from the Ryukyu Trench at a depth of 5110 m,56 has revealed much about its metabolic pathways. Shewanella violacea survives at atmospheric pressure, but as with several other piezophilic microorganisms, it shows enhanced growth at pressures above atmospheric pressure. Isolation of the genes encoding for the biosynthesis of a number of enzymes, including cytochromes (bd, cA, cB),57,58 glutamine synthetase,59 and RNA polymerase60 have revealed that the expression of these components is pressureregulated. A terminal oxidase (d-type cytochrome) in the respiratory pathway of S. violacea is also expressed at high pressure, resulting in an altered lipid membrane composition that it is Fig. 2 World ocean bathymetric map.30 The vast oceans cover 70% of the world’s surface, with 95% greater than 1000 m deep. ‡ Some of the cold-water marine natural products reviewed by Baker et al.37 were isolated from deep-water habitats, and those compounds, paesslerins A–B (17–18), the 10-hydroxydocosapolyenoic acids (40–42), carolisterols A–C (66–68), guaymasol (108) and epiguaymasol (109), a cyclic tetrapeptide (111), streptokordin (112), g-indomycinone (113), caprolactins A–B (120–121), macrolactins A–F (122–129), (+)-formylanserinone B (135), ()-epoxyserinone A (136) and its enantiomer, hydroxymethylanserinone B (137) and deoxyanserinone B (138), have been included here for completeness. This journal is ª The Royal Society of Chemistry 2008 Nat. Prod. Rep., 2008, 25, 1131–1166 | 1133

more pressure resistant,61 while dihydrofolate reductase isolated from the bacteria has shown increasing activity with increasing pressures up to 100 MPa.62 Pressure-regulated genes have also been discovered in the deep-sea bacterium Photobacterium sp. (strain SS9), including the genes for the outer membrane protein ompH and the porin-like protein ompL.63,64 Furthermore, computational studies on the polyketide synthase pathway have revealed that high pressure may have a beneficial effect on certain secondary metabolic pathways over others.65 The high pressures experienced by deep-sea organisms are expected to affect the conformational shape of proteins and membranes, and their associated activity and binding processes. A range of thermophilic and psychrophilic enzymes have been isolated from deep-sea microorganisms, including a-glucosidase from the deep-sea bacterium Geobacillus from the Mariana Trench,66 a-amylase and lipase from the actinomycete Nocardiopsis and the bacterium Psychrobacter respectively (both obtained from deep-sea sediment from Prydz Bay, Antarctica67,68) and the genes encoding the cold-adapted chaperones DnaK and DnaJ from the deep-sea psychrotrophic bacterium Pseudoalteromonas sp. SM9913, have also been characterised.69 It has been found that proteins in thermophilic organisms, relative to their mesophilic counterparts, show differences in amino acid sequences and 3D structure, such as increased stabilization of a-helices, a greater fraction of proline and b-branched residues and fewer uncharged polar residues, along with increased protein stabilization through crucial electrostatic interactions and a heightened role for molecular chaperones, in particular the heat shock proteins.48,49,70,71 Conversely, psychrophilic proteins and enzymes display a reduced number of interactions involved in protein stability such as decreased proline residues and salt bridges, thereby leading to increased flexibility.51,52,72 Other mechanisms of cold-adaptation42 include the presence of antifreeze proteins73,74 increased levels of trimethylamine oxides75,76 and incorporation of exopolysaccharides into microbial cell membranes.74,77 Membranes comprising tetraether lipids such as those found in deep-sea archaea appear more resistant to higher temperatures than bacterial lipids consisting of labile ester linkages. Moreover, deep-sea organisms have been found to modulate their membrane fluidity and stabilization, through elements such as the incorporation of high levels of polyunsaturated fatty acids,48 and the bacterial genes responsible for the biosynthesis of polyunsaturated fatty acids in deep-sea bacteria have also been reported.78 In the absence of photosynthesis, chemosynthesis is the dominant metabolic pathway in the deep sea. The genome sequence of the deep-sea g-protobacterium Idiomarina loihiensis reveals that the organism obtains its energy from catabolism of amino acids rather than sugar fermentation.74 Other deep-sea invertebrates are involved in highly specialized symbiotic associations, such the hydrothermal-vent-inhabiting tube worm Riftia pachyptila, which is entirely dependent on a sulfuroxidizing, endosymbiotic bacterium for the de novo biosynthesis of pyrimidines,79 and the deep-sea nematode Stilbonema sp., which relies on nitrate reduction by ectosymbiotic bacteria as an alternative electron acceptor to oxygen, thereby allowing it to inhabit deeper, anoxic sediments.80 Taken together, the above adaptions to deep-sea life and their effect on gene regulation and primary and secondary metabolic pathways are certain to give rise to a wealth of interesting new marine natural products. 4 Bryozoa The colonial bryozoans (moss animals, lace corals) are well represented in the marine environment, with over 5000 species described, ranging from shallow-water species to those living at depths of over 4000 m.81–83 The secondary metabolites of bryozoans have been reviewed elsewhere,84–86 and although shallow-water species have furnished such medicinally important compounds as the anti-cancer agent bryostatin 1 isolated from Bugula neritina, 87–89 there appear to be no reports as yet on the isolation, characterisation or bioactivity of secondary metabolites from deep-sea bryozoans. 5 Chordata (ascidians) Shallow-water ascidians, comprising over 2000 known species, have yielded a diverse array of biologically important metabolites90,91 including anticancer agents such as didemnin B from Trididemnum solidum, diazonamide from Diazona angulata, and the recently approved anticancer drug ectinascidian 743 from Ecteinascidia turbinata. 12,92 Deep-water ascidians, which have been well documented from both the Atlantic and Pacific oceans and up to depths of over 8000 m,93–95 present a potentially rich source of interesting new metabolites. To date, only two reports on the secondary metabolites of deep-water ascidians have been reported. A deep-water tunicate belonging to the genus Aplidium, collected by trawling in the Great Australian Bight, has yielded the novel macrolides lobatamides A–F (1–6).96,97 The structures of aplidites E–G, described earlier from the same sponge specimen,14 were revised and the metabolites renamed as the lobatamides G–I (7–9).13 The lobatamides are structurally related to the salicylihalamides isolated from a Haliclona species of sponge, but differing by the presence of the unique conjugated oxime methyl ether. The lobatamides, which were also obtained from shallow-water collections of Aplidium lobatum (SW Australia) and an unidentified Philippine ascidian, exhibited signifi- cant cytotoxicity in the NCI 60 human tumour cell line screen, and are the subject of several recent total syntheses.98,99 The deep-sea ascidian Ritterella rete, collected by dredging at a depth of 300 m on the Norfolk Ridge, New Caledonia, was found to contain six new cytotoxic dendrolasin-type hydroxylated sesquiterpenes (10–15), which are the first examples of furanoterpenes from a marine tunicate.100 6 Cnidaria The phylum Cnidaria, comprising of the four classes Hydrozoa (hydroids), Anthozoa (anemones, corals, sea pens), Scyphoza (jellyfish), and Cuboza (box jellyfish), are well represented in the deep sea. Cnidarians are the second largest source (after sponges) of new marine natural products reported each year, with a predominance of terpenoid metabolites.101–103 Herein, of the four cnidarian classes, only a small handful of examples have been reported on the secondary metabolites produced by 1134 | Nat. Prod. Rep., 2008, 25, 1131–1166 This journal is ª The Royal Society of Chemistry 2008

deep-sea anthozoans, namely from the orders Alcyonacea (octocorals, soft corals, gorgonians), Scleractinia (stony corals), along with one example from the class Scyphoza. Class Anthozoa The Anthozoan class comprises anemones, soft corals, and sea pens, with around 6500 species known across the world, mostly from the tropics. Shallow-water anthozoans have produced a range of biomedically important compounds including the sarcodictyins from the Mediterranean coral Sarcodictyon roseum, eleutherobin from the Australian octacoral Eleutherobia sp., and the pseudopterosins from the soft coral Pseudopterogorgia elisabethae. 12,15 Order Alcyonacea. Papakusterol (16), from the Hawaiian ‘‘papaku’’ for ocean floor, is a cyclopropyl-containing 22-dehydro-24,26-cyclocholesterol obtained from a deep-sea gorgonian mixture, including an Acanthagorgia species, collected by minisubmersible off Makapuu, Hawaii, at a depth of 300–350 m.104 The sub-Antarctic soft coral Alcyonium paessleri, collected from the South Georgia islands by deep-water netting at a depth of 200 m, has yielded the novel sesquiterpenes paesslerins A and B (17, 18), comprising a previously unreported tricyclic skeleton and exhibiting moderate cytotoxicity.105 However, the total synthesis of 17 has cast doubts on its proposed structure.106 The deep-sea gorgonian Corallium sp., collected at 350 m depth off Makapuu, Oahu, Hawaii, was found to contain five new diterpenes, coraxeniolide A–C (19–21), coraxeniolide C0 (22) and corabohcin (23), which are structurally related to the xenicins, isolated from soft corals and brown algae.107 The total synthesis of coraxeniolide A (19) has been reported.108 Another novel xeniolide, the diterpene arboxeniolide-1 (24), was isolated from the gorgonian Paragorgia arborea, recovered from a depth of 280 m by trawling operations west of the Crozet Islands, South Indian Ocean.109 A deep-sea gorgonian of the genus Paramuricea, collected off the northwest coast of Curac¸ao at a depth of 342 m by manned submersible, has furnished the known compound linderazulene (25), along with two new members of the series, 26 and 27. 110 The linderazulenes 25–27 exhibited mild cytotoxicity against the murine P388 leukemia cell line. This journal is ª The Royal Society of Chemistry 2008 Nat. Prod. Rep., 2008, 25, 1131–1166 | 1135

Three novel halogenated azulenes (28–30), along with N,Ndimethylamino-3-guaiazulenylmethane (31), were isolated from a blue gorgonian (Paramuriceidae family), collected from Oahu, Hawaii, at 350 m depth using a submersible,111,112 while the yellow pigment (32), was isolated as a minor metabolite of the gorgonian Placogorgia sp., retrieved from the same location.113 Order Scleractinia. The scleractinian stony corals are reefbuilding corals with around 800 species described world-wide, predominantly from shallow waters.3 Scleractinians have a wide distribution and have been recorded from Antarctica to Norway, and down to depths of 6200 m.114 The first secondary metabolites described from a deep-water scleractinian coral were the novel cholic-acid-type 3-keto steroids 33–37 isolated from the Pacific coral species Deltocyathus magnificus collected by trawling near the Loyalty Islands at a depth of 463 m.114 Along with the novel steroids 33–37, three other known steroidal natural products were obtained. It should be noted that all compounds apart from 33 were obtained after diazomethane treatment. The same group found that the Mediterranean scleractinian coral Dendrophyllia cornigera contained a complex mixture of b-glucosylceramides (b-GlcCer) (38) with a high degree of heterogeneity in both the sphingoid moiety (D18:2, 19:2, 20:2, 20:3) and the a-hydroxy fatty acid chain (C19–C24).115 Four of the major b-GlcCer metabolites of the dendrophylliid coral, collected by dredging at 162 m in northern Corsica, Ligurian Sea, corresponded to the ophidiacerebrosides A–D isolated from the shallow-water sea star Ophidiaster ophidiamus from the Balearic Islands, Spain.116 A further specimen of D. cornigera, collected at a depth of 80 m near the island of Serifos, Mediterranean Sea, was found to contain the novel (20R)-22E-cholesta-4,22-diene-3,6-dione (39), together with three known 3-keto steroids.117 Deep-water corals belonging to the genus Lophelia (Fig. 1) and Madrepora are found at depths of 50 to 2000 m, ranging from the Atlantic to the Indian Ocean, and have been well studied, in terms of their range, distribution and phylogeny.118,119 A specimen of Madrepora oculata recovered near St. Paul Island (S Indian Ocean) by trawling at a depth of 290 m, has yielded the novel 10-hydroxydocosapolyenoic acids 40–42, along with other known 10-hydroxydocosa- and 8-hydroxyeicosa-polyenoic acids,120 while the same coral species collected in Trondheimsfjord, Norway, by dredging at 350–380 m depth, gave 40 and 42. Of the other deep-water scleractinians surveyed in the same study, including Letepsammia formosissima (depth 430 m), Deltocyathus magnificus (depth 463 m), Stephanocyatus spiniger 1136 | Nat. Prod. Rep., 2008, 25, 1131–1166 This journal is ª The Royal Society of Chemistry 2008

(depth 480 m), and Javania lamproticum (depth 561 m) from the Loyalty Islands (Pacific Ocean), only the NE Atlantic Lyophelia pertusa (depth 765 m) was found to contain hydroxypolyenoic acids. Order Zoanthidea. The Pacific gold coral, the colonial anemone Gerardia sp., collected at a depth of 350 m from Hawaii by minisubmersible, has been reported to produce two new fluorescent nitrogenous pigments, pseudozoanthoxanthins I and II (43–44), both derivatives of tetraazacyclopentazulene.121 Class Scyphoza The scyphozan class consists of around 250 known species of jellyfish. Coelenterazine (45) is an imidopyrazinone-containing metabolite connected to the luminescence of several deep-sea fauna, including the bioluminescent jellyfish Auquorea auquorea, 122 the sea pansy Renilla reniformis, 123 and the deep-sea shrimp Oplophorus gracilorostris. 124 Coelenterazine possesses strong antioxidant properties and provides protection from oxidative stress to cells,125 and is a key component of several chemiluminescent assays.126 An analysis of the lipid component of 81 specimens of deep-sea corals revealed six major lipid classes, including sterols, free fatty acids, triacylglycerols, monoalkyldiacyl glycerol, wax, and sterol esters. Compared to their shallow-water counterparts, the deepsea corals contained fewer lipids.127 7 Echinoderms The most abundant species of invertebrate fauna found in the deep sea are the echinoderms (sea urchins, sea cucumbers, sea stars), which are considered to be among the most numerous species on earth based on the sheer volume of deep-sea floor. Echinoderms, of which there are over 6000 species known worldwide, are a prolific source of bioactive glycosylated metabolites, in particular saponins and glycolipids.101,128,129 As with shallowwater echinoderms, the deep-water echinoderms are dominated by steroidal metabolites. Class Asteroidea Asteroids (sea stars, starfish) have a wide geographical spread, ranging from the poles to the tropics, and from shallow-water to depths of over 4700 m. Shallow-water asteroids are well known as a rich source of steroidal metabolites, in particular steroidal oligoglycosides.130,131 Deep-sea asteroids have also proven a rich source of novel sterols. For example, the starfish Henricia downeyae, retrieved from offshore waters (90 m depth) in the northern Gulf of Mexico, was found to produce thirteen novel (46–58) steroidal glycosides, all containing a glucuronic acid moiety atypical for echinoderm glycosides. A further seven known steroidal metabolites were isolated, and the extract of the starfish showed potent antimicrobial activity.132,133 The Pacific starfish Mediaster murrayi, obtained from dredging in the Philippine Sea at 400–600 m depth, was found to contain four new steroidal glycosides, the mediasterosides M1 (59), M2 (60), M3 (61), and M4 (62), and the known 5a-cholestane-3b,6b,8,15a,16b,26-hexaol. Mediasterosides 59–62 contain rare 1/5 glycosidically linked carbohydrate moieties, and mediasterosides 59 and 60 were found to inhibit the division of fertilized sea urchin eggs.134 Three new polyhydroxylated sterols (63–65), along with two known steroids, were isolated from a Pacific deep-water starfish, Rosaster sp., obtained at a depth of 400–500 m off Noumea, New Caledonia.135 Steroid 64 displayed moderate antifungal activity towards Cladosporium cucumerinum. Specimens of the deep-water starfish Styracaster caroli collected at 2000 m depth in New Caledonian waters were found to contain a complex mixture of novel polyhydroxysteroids, including the carolisterols A–C (66–68),136 various 3b,5,6btrihydroxysteroids (69–76) 137 and two minor metabolites with a novel 24-ethyl-25-hydroxy-26-sulfoxycholestane skeleton (77–78).138 The ‘‘living fossil’’ starfish Tremaster novaecaledoniae, collected at a depth of 530 m (New Caledonia), has furnished a range of novel polyhydroxysteroids including the steroids 79–81, four 3b,6a-disulfated steroids 82–85, and four unique polyhydroxysteroids, the steroid 86 and the glycosylated tremasterols A–C (87–89), possessing both sulfation and phosphorylation.139,140 Class Crinoidea The class Crinoidea comprises around 100 species of sea lilies (stalked crinoids) and feather stars (stalkless crinoids), which have been found from Antarctica to the tropics, and from shallow-water to hadal depths.141 The so-called ‘‘living fossil’’ This journal is ª The Royal Society of Chemistry 2008 Nat. Prod. Rep., 2008, 25, 1131–1166 | 1137

Class Ophiuroidea Deep-water ophiuroids were first reported in the early 19th century, and have since been found to inhabit all oceans, and down to depths of over 7000 m.151 Although shallow-water ophiuroids are well known,130 up until now there have been no secondary metabolites described from deep-water ophiuroids. 8 Microorganisms Marine microorganisms are well known as a rich source of diverse and structurally unique metabolites.13,152,153 In recent years, development of methods for sampling, identification and successful culturing of deep-sea microorganisms have uncovered a new resource for drug discovery.154 Archaea An anaerobic culture of the archaeon Thermococcus sp., collected from a deep-sea hydrothermal vent, has yielded the novel glycerol ether lipid 2,3-di-O-dihydro-14,15-geranylgeranylglycerol (104), accompanied by the known lipids, diphytanyl glycerol and dibiphytanyl diglycerol,155 while the lipid fraction of further species of hydrothermal vent archae, such as Thermococcus hydrothermalis isolated from an active chimney on the East Pacific Rise, were also found to comprise diphytanylglycerol and dibiphytanyldiglycerol ethers.156,157 Another deep-sea hydrothermal vent archaeon, the methanogen Methanococcus jannaschii isolated from black smoker sediment at the East Pacific Rise, was found to contain the novel macrocyclic ether 105, 158 with variable lipid compositions at different temperatures and pressure.159,160 Bacteria In 1987, the culture broth of the marine bacteria Alteromonas haloplanktis, isolated from deep-sea mud collected at a depth of 3300 m off the coast of Aomori Prefecture, Japan, was found to produce the novel siderophore bisucaberin (106), which rendered tumour cells sensitive to macrophage-mediated cytolysis.161,162 Bisucaberin has been the subject of a total synthesis,163 and its method of production and use as a antitumour agent has been patented.164 The culture broth of a Bacillus deep-sea floor species obtained from a sediment core at 124 m deep near the Guaymas Basin, Mexico, was found to contain the novel moderately cytotoxic 1140 | Nat. Prod. Rep., 2008, 25, 1131–1166 This journal is ª The Royal Society of Chemistry 2008