33R- 34R= 36R CO.Nle CO:Me OH 37 20:3)and the a-hydroxy fatty acid chain (C19-C24).Four of 第骨 the major met cora corresponded to the ophidiacerebrosides A-Disolated from the Three novel halogenated azulenes (28-30),along with N.N- SperOharcropAimfomteBa an-guiazulenylmethane (31).were isolated from HO、R OH the yellow pigment (32),was isolated as a minor metabolite of the gorgonian Placogorgia sp.retrieved from the same a8 入R OH 38R.Raalphetic chain A furthe specin of D contain the novel (20R)-2E-cholesta4-diene-3.6-dione (39) together with three known 3-keto steroids. 39 30 R:=H.Ra Br Deep-water corals belonging to the genus Lophelia (Fig.1)and Ma ca Io he Indian described from a deep-water scleractinian coral were the nov cholic-acid-type 3-keto steroids 33-37 isolated from the Pacific ith the nove along with othe steroids 33-37,three ther known steroidal natural products rcobatndh be noted that all comp ounds apart from 80m depth.gave0 and 42 The same group found that the Mediterranean scleractinian coral Dendrophyllia cornigera contained a complex mixture of Deltocyathus magnificus(depth 463 m).Stephanocyatus spiniger 1136|Nat.Prod.Rep,.2008,25,1131-1166 This journal isThe Royal Society of Chemistry 2008
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 48 m).and Javania lamproricum (depth 561 m)from the 7 Echinoderms The most abundant species of invertebrate fauna found in the CO.H ms, which the are over 6000 speci known world HO 40 COH deep-waterchnredomnaed by steroidal metabolites 41 ☑ass Asteroidea CO2H 4700 s to the tropics,and from 42 asa rich source of steroidal metabolites.in particular steroidal Order Zoanthidea.The Pacific gold coral.the colonial oligoglycosides. Deep-sea asteroids have also proven a rich anemone Gerardia sp.collected at a depth of350mfrom Hawaii by minisubmersible has been reported to produce northern Gulf of Mexico.was found to produce thirteen novel I).oetivoft MeRN、 The obtaine ontain four osidcs.the mediasterosides M 43 R=Me and the 44R=H found to inhibit the division of Class Scyphoza ertilized sea urchin eggs. Steroid 64 displayed moderate antifungal activity of the deep-water starfish Sryracaster caroli collected at 2000m depth in New Caledonian waters were found and is a key componen h trihydroxysteroids (69-76) and two minor metabolite (v24-cthyl-2-hydroxy- Caledonia)has fumished oxyste uding the steroids HO both suation and phosphor- ylation An analysis of the lipid com Class Crinoidea onent of 81 sp imens of dee corals revealed six major lipid classes including fatty The class Crinoidea comprises around 100 species of sea liie (stalke ods)and tea ther stars (stak ess cnnoids nd which This journal is e The Roval Society of Chemistry 2008 Nat.Prod..Rep,2008,25,1131-11661137
(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
48 downeyosideC 51downeyoside OH Rd OSO,Na HO the tropics.Although several shallow-water urchin metabolites 400m1 pth off the Heda coast of the Izu Peninsu foLndiopodce"ihenoelhed6thiosufonicaCitAsandB 520 m.from lonia,yielde gymnochromes A D93)and isogymnochrome D(4). relationship with E may be the actual sourceof considered to be conserved traits from Jurassic crinoids.' Class Echinoidea Class Holothuroidea Echinoids (sea urchins)are found in both shallow-and Holothuroids (sea cucumbers)have a wide geographica deep-water and are widely distributed from the polar regions to distribution.ranging from Antarctica to the tropics and from 11381Nat.Prod.Rep,.2008,25,1131-1166 This journal isThe Royal Society of Chemistry00
stalked crinoid Gymnocrinus richeri, retrieved from bathal depths of 520 m, from Norfolk Ridge, New Caledonia, yielded the novel brominated phenanthroperylenequinone pigments, gymnochromes A–D (90–93) and isogymnochrome D (94), considered to be conserved traits from Jurassic crinoids.142 Class Echinoidea Echinoids (sea urchins) are found in both shallow- and deep-water and are widely distributed from the polar regions to the tropics. Although several shallow-water urchin metabolites have been described, to date there is only one example from the deep sea. The sea urchin Echinocardium cordatum, collected at 400 m depth off the Heda coast of the Izu Peninsula, Japan, was found to produce the novel hedathiosulfonic acids A (95) and B (96), constituting the first isolation of thiosulfonic acids from echinoderm species.143,144 The sulfur-oxidising bacteria Thiothrix sp. has, however, been demonstrated as having a symbiotic relationship with E. cordatum145 and may be the actual source of the novel compounds, which have been patented due to their potent antibacterial, antitumour and antifouling activities.146 Class Holothuroidea Holothuroids (sea cucumbers) have a wide geographical distribution, ranging from Antarctica to the tropics and from 1138 | Nat. Prod. Rep., 2008, 25, 1131–1166 This journal is ª The Royal Society of Chemistry 2008
OH SO,N 79R=H 80R=SO怕 68 R:=R2=H.Ra=OH R0 70 R-O 73R= g7R,=HR2■H 0R 8. shallow-water to abyssal depths of 5400 m.The secondary The same group described another specimen of Northern metabolites of shallow-water holothuroids have been Pacific sea cucumber.Synallactes obtained at 540 m reviewed. (103).the first report of triterpene glycosides from the family Ocean near the K Islands,was found to cucumber glycosides. were previo This joumal isThe Royal Society of Chemistry 2008 Nat.Prod..Rep,2008,25,1131-11661139
shallow-water to abyssal depths of 5400 m.147 The secondary metabolites of shallow-water holothuroids have been reviewed,130 and two examples of deep-sea cucumber metabolites have appeared in the literature. The North Pacific sea cucumber Pseudostichipus trachus, collected by deep-water trawling at 300 m in the Pacific Ocean near the Kuril Islands, was found to contain a novel sulfated triterpene glycoside, pseudostichoposide B (97), along with the known pseudostichoposide A (98).148,149 The same group described another specimen of Northern Pacific sea cucumber, Synallactes nozawai, obtained at 540 m depth by bottom trawling in the Sea of Japan, which yielded the synallactosides A1 (99), A2 (100), B1 (101), B2 (102), and C (103), the first report of triterpene glycosides from the family Synallactidae. The novel synallactosides A2–C (100–103) possess carbohydrate chains that were previously undescribed among sea cucumber glycosides.150 This journal is ª The Royal Society of Chemistry 2008 Nat. Prod. Rep., 2008, 25, 1131–1166 | 1139
OH O OH HO OH O OF 92 R SO;H gymnochrome OH OH OH O Br. OR Ho HO、 Br" 0H00H 93R=SO,H gymnochrome D 94 R=SOH isogymnochrome D OH hedathiosulfonic adds L人 102R=H 103 R=CH2OH Archaea An anaerobic culture of the archacon Thermococcus ollectcd from a deephydoh vent.has yielded th 一的 , chimney on th dcep-sea hydrothermal t archaeo the methanogenMeh Class Ophiuroidea 10s.nhvarabtipdeomposiosatdhfaroatemperaturs and pressure Deep-water ophiuroids were first reported in the early1 Bacteria 3300 m off the coast of Aomori Prefecture,Japan,was found to produc the bisucaberin().whichrendered 8 Microorganisms mour ce to macrophage-mediae Marine microorganisms are well known as a rich source of diverse and structurally unique metabol In recen eieormtoaRehocoompn6ntttonad a new resource for drug discovery. Mexico.was found to contain the novel moderately cytotoxic 11401Nat.Prod.Rep,.2008,25,1131-1166 This journal isThe Royal Society of Chemistry00
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