Marine natural products

D. John Faulkner

Scripps Institution of Oceanography, University of California at San Diego, La Jolla,CA 92093-0212, USA

Received (in Cambridge, UK) 23rd August 2000First published as an Advance Article on the web 9th January 2001

Covering: 1999. Previous review: 2000, 17, 7.

1 Introduction2 Marine microorganisms and phytoplankton3 Green algae4 Brown algae5 Red algae6 Sponges7 Coelenterates8 Bryozoans9 Molluscs

10 Tunicates (ascidians)11 Echinoderms12 Miscellaneous13 References

1 Introduction

This report is a review of the marine natural products literaturefor 1999. Earlier reports published in this journal cover theperiod from 1977 to December 1998. In comparison with 1998,1

the last year was relatively quiet although steady progress wasreported on most fronts. Once again, sponges were the favouriteorganisms for natural product studies, with tunicates and co-elenterates following close behind. The accelerating advances inmarine biotechnology have made their mark on marine naturalproducts chemistry in the form of a steady increase in papersemphasizing marine microorganisms and symbiotic relation-ships involving marine microbes.2 Studies of the biosynthesis ofmarine natural products, which also bear the mark of the latestgenetic techniques, are reviewed elsewhere in this journal.3

Marine natural products continue to be prime targets for syn-thesis although papers reporting partial and formal syntheses,which are not included in this review, far outnumber the moreuseful papers that record total syntheses and, in particular,synthetic studies that redefine the structures of marine naturalproducts. This report continues to emphasize the bioactivity

B

D. John Faulkner, born in Englandin 1942, received his BSc and PhDdegrees from Imperial College,London, where he studied syn-thetic organic chemistry under theguidance of Sir Derek Barton.He received postdoctoral trainingfrom R. B. Woodward at HarvardUniversity and W. S. Johnson atStanford University before joiningthe faculty of the Scripps Institutionof Oceanography, University ofCalifornia at San Diego, in 1968.Recognizing the need to ‘do some-thing more marine’, he began a newcareer in marine natural productschemistry. He is currently Professorof Marine Chemistry

of new marine natural products while specifically excludingbiochemical and pharmacological studies of known marinenatural products. The patent literature, which is not coveredin detail in this report, was the subject of a review entitled“Marine natural products as therapeutic agents”.4 The formatfor this review is identical to its predecessor.

A number of reviews of specific topics appeared during1999. An excellent review of “Marine opisthobranch molluscs:Chemistry and ecology in sacoglossans and dorids” 5 coveredthe period 1988–1998 while the mini review “Chemical defenceand evolutionary trends in biosynthetic capacity among doridnudibranchs (Mollusca: Gastropoda: Opisthobranchia)” 6

explores the complex relationships between taxonomy andnatural products chemistry. Different families of marinenatural products are highlighted in “Pyrroloquinoline andpyridoacridine alkaloids from marine sources”,7 “The dola-statins, a family of promising antineoplastic agents”,8 “Bio-genesis and biological function of marine algal oxylipins” 9 and“Total synthesis and chemical biology of the sarcodictyins”.10

Topics of more general interest include “Toxins from seacucumbers (Holothuroids): chemical structures, properties,taxonomic distribution, biosynthesis and evolution”,11

“Emerging harmful algal blooms and human health: Pfiesteriaand related organisms”,12 “Steroids from sponges: Recentreports”,13 and “Discovery and development of antineoplasticagents from natural sources”.14 Broader-based reviews thatinclude many marine natural products include “The diversityof naturally occurring organobromine compounds” 15 and“Peroxy natural products”.16 Three reviews that are intendedfor general audiences are “Testing the water”,17 “Productsof chemistry – Exploring the ocean – Stating the case forchemistry” 18 and “Chemistry of marine natural products:yesterday, today and tomorrow”.19 Forty-two articles onvarious aspects of marine biotechnology, some of which reviewaspects of marine natural products chemistry, were featured ina special issue of the Journal of Biotechnology.20

2 Marine microorganisms and phytoplankton

Marine microorganisms continue to be the subject of vigorouschemical investigation although studies of marine bacteriamay be decreasing in comparison with those of other micro-organisms. A mixture of four monoacyldiglycosyl-mono-acylglycerols 1–4 were obtained from Flavobacterium marino-typicum (ATCC 19260) but the positions of the different estergroups were not well defined.21 Flavocristamides A 5 and B 6,which are sulfonolipids from a Chryseobacterium (= Flavo-bacterium) sp.,22 have been synthesized from -cysteine.23 Twolysophosphatidyl inositols 7 and 8 were obtained as antifungalagents from a Streptomyces sp. (strain # M428) isolated froma marine sediment.24 A phosphatidyl glyceride 9 and fourquinolone derivatives 10–13 were isolated from a Pseudomonassp. cultured from the sponge Homophymia sp. from New Cale-donia.25 Arenaric acid 14 is a pentacyclic polyether, isolated

DOI: 10.1039/b006897g Nat. Prod. Rep., 2001, 18, 1–49 1

This journal is © The Royal Society of Chemistry 2001

as its sodium salt from an unidentified marine Streptomycessp. (isolate # CNH-248) from a San Diego estuarine sedimentsample.26 The antiinflammatory macrolides lobophorinsA 15 and B 16 were obtained from cultures of a tropical marineactinomycete (strain # CNB-837) that was isolated from thesurface of the brown alga Lobophora variegata from Belize.27

Two aromatic tetraols, luisols A 17 and B 18, were produced byan unidentified Streptomyces sp. (isolate # CHN-370) culturedfrom a sediment sample from an estuary near San Diego.28 Thecytotoxic thiazole alkaloid agrochelin 19, which was obtainedfrom a marine Agrobacterium sp., formed a complex withZn2� ions.29,30 Cultures of an unidentified marine bacteriumMK-PNG-276A obtained from the reefs off LoloataIsland, Papua New Guinea, have yielded a series of cyclicdecapeptide antibiotics, loloatins A–D 20–23, that inhibitmethicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci and drug-resistant Streptococcus pneu-moniae.31 Salinamides A–E 24–28 are minor antiinflammatory

bicyclic depsipeptides from a marine Streptomyces sp. (isolate# CNB-091) isolated from the surface of the jellyfish Cassiopeiaxamachana from the Florida Keys.32 The absolute configur-ations of the previously-reported 33 salinamides A 24 and B 25have been revised using chiral capillary electrophoresis ofthe derivatized hydrolysates. The prenylated cyclic peptides,cyclomarins A–C 29–31 were isolated as cytotoxins froman unidentified Streptomyces sp. (isolate # CNB-982) froma Mission Bay, San Diego, sediment sample but cyclomarin A30 was later found to possess significant antiinflammatoryactivity.34 Holyrines A 32 and B 33 are possible intermediatesin staurosporine biosynthesis from an actinomycete (strain# N96C-47) from a sediment core sample from Newfound-land.35 The absolute stereochemistry of korormicin 34, which isan antibiotic from a Pseudomonas sp. F-420,36 has been deter-mined by total synthesis.37

Studies of marine fungi appear to be expanding at a muchfaster rate than those of other unicellular organisms. Roselipins

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1A 35, 1B 36, 2A 37 and 2B 38, from the marine fungusGliocladium roseum KF-1040, are highly methylated glycolipids,possibly polypropionates, that inhibit the enzyme diacylglycerolacyl transferase (DGAT).38–40 The absolute stereochemistriesof penostatins A–E 39–43, earlier reported from a Penicilliumsp. isolated from the alga Enteromorpha intestinalis,41 have beendetermined using the modified Mosher’s method and CD

measurements.42 A marine Penicillium sp. (isolate # 386)from the South China Sea contained the pyranolactone 44.43

A Coniothyrium sp. isolated from the sponge Ectyoplasiaferox contained (3S)-(3,5-dihydroxyphenyl)butan-2-one 45and 2-(1(E)-propenyl)-octa-4(E),6(Z)-diene-1,2-diol 46 whilea Microsphaeropsis sp. isolated from the sponge Myxillaincrustans produced microsphaeropsin 47.44 The absolutestereochemistries of trichodenones A–C 48–50, which aremetabolites of Trichoderma harzianum (OUPS-N115) fromthe sponge Halichondria okadai,45 have been determined bytotal synthesis.46 A marine derived strain of Emericella unguis,obtained from both a mollusc and a medusa, produced thechlorinated depside guisinol 51, which exhibited mild anti-bacterial activity.47 Five DNA cleaving antitumour antibiotics,spiroxins A–E 52–56, were obtained from a marine fungalstrain LL-37H248 that had been isolated from an orange softcoral from Vancouver Island.48 An unidentified fungus cultured

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from the Okinawan red alga Ceratodictyon spongiosum pro-duced seragakinone A 57, which possessed mild antimicrobialactivity.49 The Callyspongia vaginalis derived fungus Ulocladiumbotrytis produced the tyrosine kinase (p56lck) inhibitorulocladol 58 and the known antifungal agent 1-hydroxy-6-methyl-8-(hydroxymethyl)xanthone.50 The culture medium ofAsteromyces cruciatus contained (�)-2,4-dimethyl-4,5-dihydro-furan-3-carboxaldehyde 59, while Varicosporina ramulosa pro-duced two new macrodiolides, (6R,11S,12S,14R)-colletodiol60 and (6R,11R,12R,14R)-colletodiol 61.50 The structure ofcolletoketol 62, which is a metabolite of the same obligatemarine mitosporic fungus Varicosporina ramulosa, obtainedfrom an unidentified alga of the genus Cystoseira from Tenerife,Spain, was determined by X-ray crystallography.51

A Penicillium sp. (strain # CNC-350) from the surface of theCaribbean green alga Avrainvillea longicaulis produced twodiketopiperazine dimers, 11,11�-dideoxyverticillin A 63 and11�-deoxyverticillin A 64, both of which exhibited potent invitro cytotoxicity against the HCT-116 cell line.52 A full accountof the synthesis of tryprostatin B 65, which is a metabolite ofAspergillus fumigatus (strain # BM939),53 has been presented.54

The cyclic pentadepsipeptide sansalvamide 66 was produced bya Fusarium sp. (isolate # CNL-292) collected from the surfaceof the seagrass Halodule wrightii from Little San Salvador

Island, Bahamas.55 Sansalvamide 66 was initially reported ashaving selective cytotoxicity against the COLO 205 and SK-MEL-2 cell lines but was later shown to inhibit molluscumcontagiosum virus (MCV) topoisomerase.56 Unguisins A 67and B 68 are GABA-containing cyclic heptapeptides fromthe same culture of Emericella unguis described above.57 Thefermentation broth of the facultative marine fungus Hypoxyloncroceum, which was isolated from driftwood in a mangroveestuary in the Everglades, Florida, produced hypoxysordarin69, which is a potent antifungal metabolite, and hypoxylactone70.58 Nine compounds were isolated from the marine fungusHypoxylon sp. but some of these appear to be possible con-taminants.59 The rearranged sterol dankasterone 71, whichexhibits significant cytotoxicity, was obtained from a Gym-nascella dankaliensis (strain # OUPS-N134) isolated fromthe sponge Halichondria japonica.60 Ergosteryl myristate 72was isolated from an unidentified fungus cultured from the algaSargassum thunbergii from Korea.61 Dendryphiellin C 73, whichis a trinor-sesquiterpene from the deuteromycete Dendryphiellasalina,62 has been synthesized in a convergent manner.63 Themarine protist Thraustochytrium globosum, collected from thesurface of the seagrass Thalassia testudinum in the Bahamas, con-tained the glycosphingolipids thraustochytrosides A–C 74–76.64

Reports of metabolites from marine cyanobacteria wererestricted to filamentous species. Lyngbya majuscula from theFrench Mediterranean coast yielded (�)-7-methoxydo-dec-4(E)-enoic acid 77, the structure of which was confirmedby synthesis.65 Two serinol-derived malyngamides 78 and 79were isolated from an unidentified estuarine cyanobacteriumfrom the King George River in Northwestern Australia.66

Tanikolide 80 is a toxic and antifungal lactone from a

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Madagascan collection of L. majuscula.67 Two nitrogenousmacrolides, madangolide 81 and laingolide A 82, a lower homo-log of laingolide 83,68 were isolated from L. bouillonii collectedin Papua New Guinea.69 The same specimen of L. bouilloniialso contained the modified tetrapeptide lyngbyapeptin A 84,the stereochemistry of which was not determined.70

A mixed assemblage of L. majuscula and Schizothrixcalcicola from Tumon Bay, Guam, contained five acyl depsi-peptides, tumonic acids A–C 85–87 and methyl tumonoates A88 and B 89.71

The cytotoxic cyclic depsipeptides lyngbyastatin 2 90 andnorlyngbyastatin 2 91, which are analogs of the sea hare cyto-toxins dolastatin G 92 and nordolastatin G 93,72 were isolatedfrom L. majuscula from Guam.73 Symplostatin 2 94, which issomewhat similar in structure to dolastatin 13 95, a metaboliteof the sea hare Dolabella auricularia,74 was isolated from Sym-ploca hydnoides from Guam.75 The structure of antillatoxin,which is an ichthyotoxic metabolite of L. majuscula fromCuracao,76 has been revised from 96 to 97 as a result of total

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syntheses of both the reported and corrected structures.77,78

The epilithic encrusting cyanobacterium Kyrtuthrix maculansfrom the shores of Hong Kong contained maculactone L 98and three halogenated carbazoles 99–101, which had not

been reported previously as natural products.79 Hyellazole 102,which is a carbazole alkaloid from Hyella caespitosa,80 has beensynthesized using an organometallic approach.81

The cultured marine dinoflagellate Amphidinium sp., col-lected from the coast of NW Spain, contained a monogalac-tosyl triacylglycerol 103.82 Two very long, highly unsaturatedfatty acids 104 and 105 were isolated from seven marinedinoflagellate species.83 Amphidinolide U 106 is a 20-membered

macrolide from a cultured Amphidinium sp. (Y-56) isolatedfrom the flatworm Amphiscolops sp. from Okinawa.84 Adifferent strain of Amphidinium sp. (Y-5) produced colopsinolsA–C 107–109, of which colopsinol A 107 inhibited DNApolymerases α and β and colopsinol C 109 exhibited cyto-toxicity.85,86 The absolute configuration of amphidinol 3 110,which is a metabolite of A. klebsii,87 was determined by analysisof carbon–hydrogen spin-coupling constants.88

Cultures of the toxin-producing dinoflagellate Prorocentrumhoffamnnianum contained the non-cytotoxic macrolide, hoff-manniolide 111.89 The absolute configuration of gambierol112, a toxic polyether from Gambierdiscus toxicus,90 was deter-mined by application of Mosher’s method.91 The structures andpartial stereochemical assignments of prymnesins-1 113 and-2 114, which are hemolytic and icthyotoxic glycosides fromPrymnesium parvum,92 have been determined.93 The total syn-thesis of brevetoxin A 115 from the dinoflagellate Gymnodiniumbreve 94 has been described in detail.95 The structure of 7-deoxy-okadaic acid 116, which is a potent serine/threonine-specificprotein phosphatase inhibitor from Prorocentrum lima, hasbeen confirmed by total synthesis.96

Vannusals A 117 and B 118 were isolated from an Indonesianspecimen of the ciliate Euplotes vannus.97

3 Green algae

The green macro alga Ulvella lens contains a bromoperoxidasethat produces dibromomethane and bromoform.98 A survey

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of the metabolites of Ulva lactata led to the proposal that 4-hydroxybenzoic acid is the most likely biosynthetic precursor of2,4,6-tribromophenol 119.99 Kahalalide K 120 is an additionalcyclic depsipeptide from a Hawaiian species of Bryopsis.100

The structure of caulersin 121, a metabolite of Caulerpaserrulata,101 has been confirmed by total synthesis.102

4 Brown Algae

The sulfonoglycolipid 122 from the Australian brown alga Dict-yota ciliolata was active in the constitutive nitric oxide syn-thetase assay.103 Iyengaria stelleta from Pakistan was reportedto contain a very interesting cyclopropyl ether but the spectraldata do not support the proposed structure.104 An additionalsynthesis of (6S,7S,9R,10R)-6,9-epoxynonadec-18-ene-7,10-diol 123, which is a metabolite of Notheia anomola,105 has beenaccomplished using an oxiranyl anion strategy.106 After per-acetylation, forty-five phloroglucinol derivatives, including

2,4,6-triacetoxychlorobenzene 124, 2[D�]-iododiphloretholpentaacetate 125, 3[A]-chlorobifuhalol hexaacetate 126, 3[A4]-chlorodifucol hexaacetate 127, and larger compounds such astrihydroxyheptaphlorethol-A octadecaacetate 128 were isolatedfrom Carpophyllum angustifolium from New Zealand.107,108

An additional three phlorethols, ten fucophlorethols, ten halo-genated phlorethols, exemplified by 129, and two chlorinatedfucophlorethols were isolated as their peracetates from Cysto-phora retroflexa.109,110 An unusual eleven-membered heterocyclicmetabolite 130 was isolated from Sargassum vachellianum 111

from the South China Sea.112 A specimen of Spatoglossumvariabile from Karachi, Pakistan contained spatazoate131.113 Stypoquinonic acid 132 is a tyrosine kinase inhibitorfrom Stypopodium zonale from the Canary Islands.114 Methoxy-bifurcarenone 133 is an antifungal and antibacterialmeroditerpenoid from a Moroccan specimen of Cystoseiratamariscifolia.115 (�)-Sporochnol A 134, which is the enanti-omer of a fish feeding deterrent from Sporochnus bolleanus,116

has been synthesized using an enantiospecific route from (R)-(�)-malonic acid benzyl ester.117

Three additional diterpenes 135, 136, isolated as their corre-sponding acetates, and 137 were obtained from specimensof Bifurcaria bifurcata from two locations in Brittany.118 Anenantioselective synthesis of the cytotoxic diterpenoid (�)-bifurcadiol 138, obtained from Bifurcaria bifurcata,119 has beenreported.120 A specimen of Stoechospermum marginatum con-tained 5(R),16(S)-diacetoxyspata-13,17-diene 139, the absolutestereochemistry of which was established using Mosher’smethod.121 Secospatacetals A–E 140–144 were obtained fromDilophus okamurai from Japan and the structure of a spatanederivative previously reported from an Australian specimen ofS. marginatum 122 was revised from 145 to 146.123 A differentspecimen of D. okamurai 124 from Japan contained dilkamural147, which may be a hydrolysis product of secospatacetal B141.125

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Spatosterol 148 and varninasterol 149 are new fucosterolderivatives from Spatoglossum variabile from Pakistan.126,113

Six additional fucosterol derivatives, 150–155, were obtainedfrom Turbinaria conoides from Taiwan.127

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5 Red algae

Interest in red algae continues to decline slowly, probably dueto the paucity of bioactivity reported for the halogenatedmetabolites that make up the bulk of their metabolites. As partof a chemotaxonomic study, two C15 acetogenins, japonenynesA 156 and B 157, were isolated from Laurencia japonensisfrom Japan,128 while an undescribed Laurencia sp. from Japancontained bisezakynes A 158 and B 159.129 Laurencienyne B160 is an additional halogenated acetogenin from a Greekspecimen of L. obtusa.130 L. obtusa from Turkey contained thebrominated acetogenin acetate 161.131 The structure of (�)-obtusenyne 162, which is a metabolite of L. obtusa,132,133

has been confirmed by total synthesis.134 The absolute con-figuration of Norte’s obtusenynes 163 (a mixture of 3Z and3E isomers) from L. pinnatifida 135 has also been determined

by total synthesis.136 (�)-Kumausallene 164, a metabolite ofL. nipponica,137 has been synthesized in an enantioselectivemanner.138 A total synthesis of (�)-laurencin 165, isolated fromL. glandulifera,139 was accomplished using an olefin metathesisto form the 8-membered ring.140 A brominated diphenyl ether166 and a brominated dibenzyl ether 167 that were isolatedfrom Odonthalia corymbifera were shown to inactivate α-glucosidase.141

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Plocamium costatum from Tasmania contained an additionalhalogenated monoterpene 168 in addition to the known tri-bromotrichloromonoterpene 169 from P. cartilagineum,142 the13C NMR spectrum of which was recorded for the first time.143

Eleven known compounds, one of which 170 was obtainedpure for the first time, were isolated from a Great BarrierReef specimen of P. hamatum: the structure of the anti-algalmetabolite 171 was confirmed by X-ray analysis.144 Apaka-ochtodenes A 172, the structure of which was determined byX-ray analysis, and B 173 were obtained from a specimen ofPortieria hornemannii from Guam.145 Claviol 174 is a tricyclicbrominated sesquiterpene that was isolated along with fiveknown metabolites from Laurencia claviformis from EasterIsland.146 A total of fourteen chamigrane derivatives, onlytwo of which, 175 and 176, were previously undescribed, wereisolated from L. nidifica from Oahu.147 The cultivated edibleseaweed Porphyra yezoensis from Japan contained two isomericditerpenes 177 and 178, which did not appear to be photo-oxidation products of phytol.148 Aplysin 179, debromoaplysin180, aplysinol 181, debromoaplysinol 182, isoaplysin 183,isolaurenterol 184 and debromoisolaurinterol 185, all of which

are metabolites of Laurencia spp.,149–151 were synthesized usinga diastereoselective radical to polar crossover sequence,152 whileaplysin 179 and debromoaplysin 180 were constructed using asimilar sulfur mediated cyclization strategy.153 A “symmetrical”total synthesis of teurilene 186, which is a polyether metaboliteof L. obtusa,154 required only ten steps from a commerciallyavailable compound.155 The structure of (�)-polycavernos-amide A 187, a toxin isolated from Polycavernosa tsudai,156

was confirmed by two total syntheses.157,158 An additional totalsynthesis of (�)-kainic acid 188, which is an anthelminticmetabolite from Digenea simplex,159 utilizes a short, efficientand highly stereoselective approach.160

6 Sponges

Once again, sponges have provided the largest number ofnew marine natural products, many of which have interestingbiomedical potential. A series of phospholipids that includedfour previously undescribed representatives, 189–192, wereobtained as inhibitors of cholesterol biosynthesis from aKorean specimen of Spirastrella abata.161 A Petrosia sp. from

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Korea contained a cyclitol derivative 193 that inhibited in vitroSV40 DNA replication.162 Oceanapiside 194 is an antifungalbis-aminohydroxylipid glycoside from a Southern Australianspecimen of Oceanapia phillipensis.163 A Caribbean specimenof Plakortis simplex contained the simplexides 195, a group

of immunosuppressive glycolipids that inhibit proliferationof activated T-cells by a non-cytotoxic mechanism.164 Agela-galastatin 196 is a cytotoxic glycosphingolipid from an Agelassp. from Papua New Guinea.165 Myrmekiosides A 197 and B198 from a Japanese Myrmekioderma sp. are mono-O-alkyl-diglycosylglycerols that reverse the phenotype of melanomaH-ras transformed NIH3T3 cells.166 Penaresidin A 199, whichis a potent actomyosin ATPase inhibitor from an OkinawanPenares sp.,167,168 was synthesized in an enantioselectivemanner.169 The asymmetric synthesis of (�)-aplysillamide B200, which is an antimicrobial agent from Psammaplysillapurpurea,170 illustrated the use of a ‘superquat’ reagent asa chiral auxiliary.171 The (2S,3R,4S,6R,12R) configuration of(�)-rottnestol 201, which is a metabolite of a Haliclona sp. from

Rottnest Island, Western Australia,172 has been proposed on thebasis of total synthesis.173

Six additional acetylenic enol ethers, petroraspailynes A1202, A2 203, A3 204, B1 205, B2 206 and B3 207, and thealcohol 208, the absolute configurations of which were

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determined by Mosher’s method, have been isolated from aKorean species of Petrosia.174 Seven additional cytotoxic poly-acetylenes, (3S,14S)-petrocortyne A 209, petrotetrayndiols A210, B 211 and C 212, dideoxypetrosynols E 213 and F 214,and nor-3S,14S-petrocortyne A 215, were also isolated froma Petrosia sp. from Korea.175,176 The isolation of pellynols E–H216–219, together with swinholides, from an undescribed

Theonella sp. from Chuuk Atoll, Micronesia, was unexpectedfrom a chemotaxonomic viewpoint.177 The xestosterol esters220 and 221 of two brominated acetylenic acids were obtainedfrom an Australian specimen of Xestospongia testudinaria.178 Achemoenzymatic synthesis of both the (4E,15Z) and (4E,15E)isomers 179 resulted in assignment of the (3S,4E,15Z) stereo-chemistry to (�)-docosa-4,15-dien-1-yn-3-ol 222, which is acytotoxic metabolite of Cribrochalina vasculum.180–182 The pro-

posed stereochemistry at C-3 for both (3S,4E)-eicos-4-en-1-yn-3-ol 223 and (3S,4E)-19-methylicos-4-en-1-yn-3-ol 224, whichare also metabolites of C. vasculum,180 has been confirmed bytwo independent total syntheses.183,184 Petrofuran 225, from

an Okinawan Petrosia sp.,185 (aka adociaacetylene B from anOkinawan Adocia sp.) 186 has been synthesized using an enantio-selective reduction to produce the two chiral alcohols.187

Studies of Plakortis simplex from the Caribbean resulted inthe isolation of the cyclic peroxide dihydroplakortin 226 andtwo related furans 227 and 228, as well as providing the abso-lute stereochemistry of plakortin 229.188 A subsequent report ofmetabolites from P. simplex described four additional lactones,plakortones E 230 and F 231 and simplactones A 232 andB 233.189 The structures and absolute stereochemistries ofthe cyclic peroxides chondrillin 234 from a Great Barrier Reef

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Chondrilla sp.190 and plakorin 235 from Plakortis spp.191,192 havebeen confirmed by syntheses of (�)- and (�)-chondrillin and(�)- and (�)-plakorin.193 Elenic acid 236, which is a topo-isomerase II inhibitor from an Indonesian Plakinastrella sp.,194

was synthesized by a short efficient route.195 Homo-plakotenin237 and its sodium salt 238, nor-plakotenin sodium salt 239and plakotenin sodium salt 240, some of which significantly

reduced proliferation of rheumatoid synovial fibroblasts, areadditional members of the plakotenin family from a Palauanspecimen of Plakortis lita.196 Benzylthiocrellidone 241, thestructure of which was confirmed by synthesis, was isolatedfrom Crella spinulata: it should be noted that the Australiangroup has previously studied the use of synthetic dimedonederivatives as sunblocks.197 Five additional antifungal andcytotoxic metabolites, theopederins F–J 242–246, were isolatedfrom a Japanese specimen of Theonella swinhoei.198 (�)-Discodermolide 247, a potentially important antimitoticagent from the Caribbean deep-water sponge Discodermiadissoluta,199 has been synthesized on a scale that will enablefuture development as an antimitotic agent.200

The bicyclic macrolides, amphilactams A–D 248–251, arenematocides from the Southern Australian Amphimedon sp.201

A Geodia sp. from Southern Australia contained geodin Amagnesium salt 252, which also has nematocidal activity.202

Haterumalides NA 253, NB 254, NC 255, ND 256 and NE 257are cytotoxic chlorinated macrolides from an Okinawan speciesof Ircinia.203 The calcareous sponge Leucascandra caveolatafrom New Caledonia contained an additional macrolide,

leucascandrolide B 258.204 Four additional cytotoxic macro-lides, sphinxolides E–G 259–261 and reidispongiolide C 262,were isolated from the New Caledonian sponges Neosiphoniasuperstes and Reidispongia coerulea, respectively.205 The relativeand absolute stereochemistry of the mycalolides, exemplifiedby mycalolide A 263 from a Japanese Mycale sp.,206 were deter-mined by chemical synthesis, degradation and spectroscopicanalyses.207 An additional tetramic acid glycoside, aurantosideC 264, was isolated from the lithistid sponge Homophymiaconferta from the Philippines 208 while aurantosides D–F 265–267, which possessed antifungal activity, were isolated fromthe Japanese lithistid Siliquariaspongia japonica.209 S. japonicaalso contained a related series of tetramic acid glycosides,rubrosides A–H 268–275, that induced large intracellularvacuoles in 3Y1 rat fibroblasts.210

The synthesis of macrolides and related complex moleculesfrom sponges has attracted much attention. The absolute con-figuration of (�)-miyakolide 276, which is a weakly cytotoxictetracyclic macrolide from a Japanese Polyfibrospongia sp.,211

was established by a very efficient synthesis of its enantiomer.212

The potent cytotoxin altohyrtin C 277 from Hyrtios altum,213

also known as spongistatin 2 from Spongia sp.,214 has beensynthesized by an enantioselective route.215 A stereocontrolledtotal synthesis of (�)-halichlorine 278, which is an inhibitor ofVCAM-1 expression from Halichondria okadai from Japan,216

has been accomplished.217 (�)-Hennoxazole A 279, which isan antiviral agent from a Polyfibrospongia species,218 has beensynthesized using a convergent enantio-controlled strategy.219

A convergent total synthesis 220 led to the antipodes of calyculinA 280 and calyculin B 281, which are serine-threonine phos-phatase inhibitors from a Japanese specimen of Discodermiacalyx.221,222 The solution structures of calyculin A 280 anddephosphonocalyculin A 282 have been determined usingNMR methods.223

Thirteen additional 5-alkylpyrrole-2-carboxaldehydes 283–295 were isolated from the Caribbean sponges Mycale micro-sigmatosa and Desmapsamma anchorata from Venezuela.224

A general method has been reported for the synthesis ofmycalazol 11 296 from Mycale micracanthoxea 225 and relatedpyrroles.226 Pyrinodemin A 297, the structure of which waselucidated largely on the basis of its EIMS fragmentationpattern, is a cytotoxic pyridine alkaloid from a Japanese species

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of Amphimedon.227 Echinoclathrines A–C 298–300, which showweak immunosuppressive activity, are members of a new classof pyridine alkaloids from an Okinawan species of Echino-clathria.228 Bengamides Y 301 and Z 302 and bengazole Z 303,which were isolated from an Australian Jaspis sp., showedstriking differential cytotoxicity patterns against a panel ofhuman tumour cell lines.229 Bengamide L 304 and six additionalbengazoles 305–310 were isolated from a Pachastrissa sp. fromthe Djibouti coast.230 The first total synthesis of bengazole A311, which is an antifungal agent from a Jaspis sp.,231 employedconsecutive regiocontrolled metalation–addition reactions.232

Neofolitispates 1–3 312–314 are additional pentacyclicguanidine alkaloids from Neofolitispa dianchora from theAndaman Islands, India, that inhibited the hepatitis B virus.233

13,14,15-Isocrambescidin 800 315, a rare metabolite of

Crambe crambe,234 has been synthesized in an enantioselectivemanner.235 The ring junction stereochemistry of the left-handportion of batzelladine F, a metabolite of a Caribbean Batzellasp. that induces p56 lck-CD4 dissociation,236 has been revisedfrom anti 316 to syn 317 as the result of partial synthesis.237,238

An enantioselective total synthesis of batzelladine D 318,from the same Batzella sp.,239 has been described.240 A newmanzamine alkaloid, 1,2,3,4-tetrahydromanzamine B 319,was obtained from a Japanese species of Amphimedon.241 Anenantioselective total synthesis of ircinal A 320, which is ametabolite of a Japanese Ircinia sp.,242 also completes a formalsynthesis of manzamine A 321.243 Studies on the biomimeticsynthesis of the manzamine alkaloids resulted in the totalsynthesis of keramaphidin B 322,244 which was obtained froman Okinawan species of Amphimedon. 245 Halitulin 323 is anunusual cytotoxic alkaloid from Haliclona tulearensis fromSouth Africa.246 Two groups have synthesized motuporaminesA 324 and B 325,247,248 which are metabolites of Xestospongiaexigua,249 and one of these groups also determined the positionof the double bond in motuporamine C 326.248 A new 1,2-dihydroisoquinoline 327 was isolated from Petrosia similisfrom the Mandapam coast of India.250 Renierol 328, which is ametabolite of Xestospongia caycedoi,251 and the correspondingacetate and propionate esters 329 and 330 were synthesizedusing a thermal electrocyclic reaction as the key step.252 Adeep-water Caribbean sponge of the genus Batzella containedsecobatzellines A 331 and B 332, both of which were cytotoxicand inhibited calcineurin, while only secobatzelline A 331inhibited the peptidase activity of CPP32.253 Similar bioactivitywas ascribed to discorhabdin P 333, the structure of whichwas determined by X-ray crystallography, which was isolatedfrom a similar deep-water Batzella sp. from the Bahamas.254

Discorhabdin Q 334 was isolated as a cytotoxic constituentfrom Latrunculia purpurea and at least three Zyzzya species.255

The biomimetic syntheses of discorhabdins C 335 and E 336,which are metabolites of Latrunculia species from NewZealand,256,257 employ cupric chloride-catalyzed oxidativecyclizations of suitably substituted indoloquinonimines.258

Batzellines A 337 and B 338 and isobatzellines A 339 and B 340,which are metabolites of a deep-water Caribbean Batzellasp.,259,260 have all been synthesized using a similar strategy.261

The total synthesis of the cytotoxic agent makaluvamine F 341from Zyzzya cf. marsailis 262 was accomplished using hyper-valent iodine()-induced reactions.263,264 Veiutamine 342, whichis a cytotoxic constituent of Zyzzya fuliginosa from Fiji,265

has been synthesized for the first time.266 Neoamphimedine343, which was obtained from a Xestospongia sp. from thePhilippines and from X. cf. carbonaria from Palau, is a pyrido-acridine topoisomerase II inhibitor that catenates DNA.267

The structure of dysibetaine 344, which is an α,α-di-substituted α-amino acid derivative from Dysidea herbaceafrom Yap, Micronesia, was determined by X-ray crystal-lography.268 Two additional jaspamide derivatives, jaspamides B345 and C 346, were obtained as moderately active cytotoxicagents from a specimen of Jaspis splendens from Vanuatu 269

while the related metabolites, geodiamolides J–P 347–353 andR 354, were isolated as minor metabolites of a Cymbastelasp. from Papua New Guinea.270 In a paper that compares thecytotoxicity of the hemiasterlins with other linear peptides,hemiasterlin C 355 was reported as an additional cytotoxiclinear peptide from an Auletta sp. and two collections ofSiphonochalina species.271 Tokaramide A 356 was isolated as acathepsin B inhibitor with potential anticancer activity from aJapanese specimen of Theonella aff. mirabilis.272 A JapaneseTheonella sp. contained the cytotoxic linear peptide koshik-amide A1 357.273 A mixture of linear and cyclic peptides,pseudotheonamides A1 358, A2 359, B2 360, C 361 and D 362,and dihydrocyclotheonamide A 363, were obtained as serineprotease inhibitors from a Japanese specimen of Theonellaswinhoei.274 Three total syntheses of motuporin 364, which is a

14 Nat. Prod. Rep., 2001, 18, 1–49

potent inhibitor of protein phosphatase type 1 (PP1) froma Papua New Guinea specimen of Theonella swinhoei,275 havebeen reported during 1999.276–278 Arenastatin A 365, which is acytotoxic depsipeptide from Dysidea arenaria,279 has been syn-thesized together with related cyanobacterial cytotoxins.280

Keramamides M 366 and N 367 are additional sulfated cyclicpeptides from an Okinawan Theonella species.281 A differentTheonella sp. from Okinawa contained two additional theo-nellapeptolide congeners 368 and 369, one of which had methyl-sulfinylacetyl group at the N-terminus.282 An X-ray study oftheonellapeptolide Id 370 from an Okinawan specimen ofT. swinhoei 283 revealed that the crystals were highly solvated.284

An Indonesian specimen of T. swinhoei contained the cyclicpeptide barangamide A 371, which is related to the theo-nellapeptolides.285 The Papua New Guinea sponges T. mirabilisand T. swinhoei contained the cytotoxic and HIV-inhibitorydepsipeptides papuamides A 372 and B 373 and papuamidesC 374 and D 375, respectively.286 The cyclic heptapeptidephakellistatin 2 376, which is a cytotoxic constituent of

Phakellia carteri from the Comoros Islands,287 has been syn-thesized in a stepwise manner but the synthetic product didnot possess the biological activity of the natural product.288

Synthesis of the proposed structure of keramamide J 377,which was isolated from an Okinawan Theonella sp.,289 indi-cated that the structure of the natural product should bere-examined.290

Two bromotyrosine derivatives 378 and 379 were describedas constituents of Aplysina cauliformis from the Bahamas.291

14-Oxo-aerophobin-2 380 was among fourteen bromoisoxazolealkaloids isolated from A. insularis from the Bahamas.292 Thediethyl ketal 381 was obtained from a Turkish specimen ofVerongia aerophoba that had been extracted with ethanol.293

Two additional bromotyrosine-derived metabolites, araplysillinIII 382 and hexadelin C 383, were isolated from Aiolochroiacrassa (=Ianthella ardis) from Belize.294 A specimen of Aplysinafistularis insularis from Venezuela contained the cytotoxicmetabolite 11-deoxyfistularin-3 384.295 7-Hydroxyceratinamine385 is an additional cyanoformamide from an Aplysinella sp.

Nat. Prod. Rep., 2001, 18, 1–49 15

from Micronesia.296 The urethane 386 and the correspondingsalt were isolated from Psammaplysilla purpurea from theMandapam Coast of India.297 Iantheran A 387 is an unusualdimeric polybrominated benzofuran that was obtained as aNa,K-ATPase inhibitor from an Australian Ianthella species.298

Six additional bromopyrrole alkaloids, slagenins A–C 388–390 and mukanadins A–C 391–393 were isolated from Agelasnakamurai from Okinawa: the planar structure of mukanadin C393 is the same as that previously reported for dispacamide

D.299,300 A. wiedenmayeri from the Florida Keys containedan additional bromopyrrole alkaloid (4-bromopyrrole-2-carb-oxy)homoarginine 394.301 Two dimeric bromopyrrole alkaloids,nakamuric acid 395 and the corresponding methyl ester 396were obtained from a methanolic extract of A. nakamuraifrom Indonesia.302 Stylissa carteri from Indonesia contained

16 Nat. Prod. Rep., 2001, 18, 1–49

debromostevensine 397 and debromohymenin 398 togetherwith known congeners.303 Axinellamides A–D 399–402 wereobtained as antibacterial agents from an Australian Axinella

species.304 The racemic forms of the pyrrolodiketopiperazines,longamide 403, longamide B 404, longamide B methyl ester 405and hanishin 406, which were isolated from Agelas longissima,A. dispar and Acanthella carteri,305–307 have all been synthesizedin a concise manner.308 A second independent synthesis of (±)-

Nat. Prod. Rep., 2001, 18, 1–49 17

longamide 403 was reported.309 Agelastatin A 407, a cytotoxicmetabolite of Agelas dendromorpha from New Caledonia,310

has been synthesized as its racemate.311

Two additional alkaloids, 408 and 409, of the topsentin classhave been isolated as cytotoxic constituents of Spongosoritesgenitrix from Korea.312 A Southern Australian Echinodictyumsp. contained the antibacterial metabolites echinosulfonic acidsA–C 410–412 and echinosulfone A 413.313 The X-ray structureof 1,3-dimethylisoguanine 414 from Amphimedon viridis,314

indicated that the compound crystallized as a trihydrate and ina different tautomeric form than that previously reported.315,316

Coixol (6-methoxy-2(3H)-benzoxazolinone 415) was isolatedfrom an Indian Oceanapia sp. as a toxin to brine shrimp.317 A

specimen of Dysidea sp. from Okinawa contained S1319 416,which was isolated as a β-adrenoceptor agonist.318 A synthesisof homofascaplysin C 417 from Fascaplysinopsis reticulatus 319

involved a ditryptophan intermediate.320 The bis-indolealkaloid hyrtiosin B 418,321 from an Okinawan specimen ofHyrtios erecta, has been prepared in good yield.322 Two dif-ferent routes were used to synthesize the alkaloid leucettamineB 419, which was obtained from Leucetta microraphis,323

in good yields.324 Isonaamine A 420, which was isolated fromL. chagosensis,325 has been synthesized using a condensationreaction involving tosyl isocyanate to prepare the 2-amino-imidazole ring system.326 The structure of niphatoxin B 421from a Red Sea Niphates sp.327 was confirmed by total syn-thesis.328 Lamellarin O 422, which is a metabolite of Dendrillacactos,329 has been synthesized using a Diels–Alder strategy.330

A Red Sea Smenospongia sp. contained smenotronic acid423, which is an interesting tetronic acid thought to be derivedfrom ilimaquinone.331 A single methanol-addition product,15α-methoxypuupehenol 424, crystallized from methanolduring the work-up of a New Caledonian Hyrtios sp. known tocontain puupehenone 425.332 Puupehenone 425, first isolatedfrom a Verongid sponge,333 was synthesized from (�)-sclareolin an enantiospecific manner.334 An efficient synthesis ofent-chromozonarol 426, which is a metabolite of Dysideapallescens,335 also used (�)-sclareol as a starting material.336

Avarol 427 and the corresponding quinone, avarone 428, whichare cytotoxic metabolites of Dysidea avara,337 have been syn-thesized in an enantioselective manner using a radical additionreaction to incorporate the aromatic ring.338 The structure ofisoavarol 429, also known as neoavarol,339 which is a mero-sesquiterpene from a Pacific Dysidea sp.,340 has been confirmedby an X-ray crystallographic study of the correspondingdiacetate 430.341 The absolute configuration of (�)-hyatella-quinone 431, which is a metabolite of Hyatella intestinalis,342

has been revised as the result of a synthesis of (�)-hyatella-quinone from (�)-sclareolide.343 Nakijiquinone C 432, which isa selective inhibitor of the Her-2/Neu protooncogene froman unidentified sponge of the family Spongiidae,344 has beensynthesized by an enantioselective route.345 Both a stereo-selective total synthesis and an enantioselective formal syn-thesis of metachromin A 433, which is a metabolite ofHippospongia metachromia,346 have been accomplished.347

A number of meroterpenoid sulfates have recently beenreported. An Australian Sarcotragus sp. contained octaprenyl-hydroquinone sulfate 434 and nonaprenylhydroquinone sulfate435 as inhibitors of α1,3-fucosyltransferase VII.348 Two relatedbut non-sulfated meroterpenoids, 1,4,44-trihydroxy-2-octa-prenylbenzene 436 and 4-hydroxy-3-octaprenylbenzoic acid 437were obtained from specimens of Spongia sp. and Ircinia sp.,respectively, collected from the Aegean Sea.349 Adociasulfates1–6 438–443 were obtained as inhibitors of kinesin motorproteins from a Palauan sponge of the genus Haliclona (akaAdocia).350 An Adocia sp. from the Great Barrier Reefcontained adociasulfates 1 438, 7 444 and 8 445, which inhibitvacuolar H �-ATPase.351 Adociasulfates 5 442 and 9 446 wereobtained from Adocia aculeata from the Great Barrier Reef.352

The structure of adociasulfate 1 438 has been confirmed by anenantioselective total synthesis.353 The relative stereochemistryof the ring junction in the upper decalin moiety of akaterpin447, which is an inhibitor of phosphatidylinositol-specificphospholipase C from a Callyspongia sp.,354 was shown to becis by synthesis of model compounds.355

A new furanosesquiterpene, iso-dehydrodendrolasin 448, wasobtained from Euryspongia deliculata from the Great BarrierReef.356 The sequiterpenoids (�)-14-methoxy-14-deacetoxy-spirodysin-1 449 and the corresponding 12,13-dihydro deriv-ative 450 were isolated from an Indian specimen of Dysideafragilis.357 The tricyclic sesquiterpene γ-hydroxybutenolide451 was obtained as an antifouling agent from D. herbaceafrom Palau.358 Dysifragin 452 and caparrapi oxide 453 were

18 Nat. Prod. Rep., 2001, 18, 1–49

isolated from a Taiwanese specimen of D. fragilis.359 Tavac-pallescensin 454 from D. avara contaminated with Pleraplysillaspinifera 360 was synthesized as the racemate from a symmetricalprecursor.361 Pallescensin B 455, which was isolated fromDysidea pallescens,362 has been synthesized as its racemate.363

1,5-Cyclooctadiene was employed as the starting material fora stereoselective total synthesis of kelsoene 456,364 which is ametabolite of Cymbastela hooperi.365 A Taiwanese sponge ofthe genus Parahigginsia contained parahigginols A–D 457–460,parahigginic acid 461, parahigginine 462 and parahigginone463, of which 458–461 were moderately cytotoxic.365,367 Three

Nat. Prod. Rep., 2001, 18, 1–49 19

3-formamidobisabolene derivatives 464–466 were isolatedfrom an Axinyssa sp. from Yap, Micronesia.368 The first totalsynthesis of 9-isocyanoneopupukeanane 467, a metabolite ofCiocalypta sp.,369 has been reported.370 (�)-4-Thiocyanatone-opupukaenane 468, which is a metabolite of an unidentifiedsponge from Pohnpei,371 has been synthesized in an enantio-specific manner.372 The guanidinoimidazole alkaloid stellett-azole A 469 is an antibacterial and Ca 2�/calmodulin-dependentphosphodiesterase inhibitor from a Japanese species ofStelletta.373 The same Stelletta sp. also yielded stellettazolesB 470 and C 471, stellettamide C 472, and bistellettadines A 473

20 Nat. Prod. Rep., 2001, 18, 1–49

and B 474, which also inhibited Ca 2�/calmodulin-dependentphosphodiesterase.374,375

It is interesting that the cytotoxic diterpene 475, which isclosely related to metabolites of brown algae, was obtainedfrom Sigmosceptrella quadrilobata from the Comoros Islands.376

Two cytotoxic cembranoids, flabellatenes A 476 and B 477,which are compounds that are normally associated with softcorals, were isolated from the Antarctic sponge Lissodendoryxflabellata.377 Together with the known major metabolite,(�)-spongia-13(16),14-diene-19-oic acid 478, six additionalspongian diterpenes, the epimeric γ-methoxybutenolides 479–481, the di(methoxy ketal) 482 and the epimeric butenolides483 and 484 were isolated from Spongia matamata from Yap,Micronesia.378 A Spongia sp. from the Philippines containedspongiabutenolides A–D 485–488 in addition to the knownmajor metabolite (�)-spongia-13(16),14-diene-19-oic acid 478:

the structure of spongiabutenolide A 485 was confirmed bysynthesis from the furan 478 using singlet oxygen oxidation.379

The X-ray crystallographic data for ent-isocopal-12-ene-15,16-dialdehyde 489, which is a metabolite of S. officinalis,380 hasbeen presented.381 (�)-Spongia-13(16),14-diene 490, which isalso a metabolite of S. officinalis,382 was synthesized in adiastereoselective manner.383 A trio of amphilectene isonitriles,491–493, and the bicyclic diterpene hydrocarbon 494 were

Nat. Prod. Rep., 2001, 18, 1–49 21

obtained from a Caribbean Cribochalina sp.384 The absoluteconfiguration of kalihinol A 495, which is a metabolite ofan Acanthella sp. from Guam,385 was determined by applicationof the CD exciton chirality method to a bis-p-bromobenzoatederivative.386

An additional C21 terpene lactone 496, that is possiblyderived from cacospongionolide B 497, with which it was foundin a Mediterranean specimen of Fasciospongia cavernosa,was identified by interpretation of spectral data.387 Methylationof the crude extract of a Sigmosceptrella sp. from SouthernAustralia with diazomethane produced a mixture of productsfrom which nuapapuin methyl ester 498 and sigmosceptrellin Dand E methyl esters 499 and 500 were isolated and identified.388

The methyl ester 501, which is a metabolite of Latrunculiabrevis from Australia,389 has been synthesized in an enantio-specific manner.390

22 Nat. Prod. Rep., 2001, 18, 1–49

Halisulfate 7 502 is a sesterterpene sulfate from a speciesof Coscinoderma from Yap, Micronesia.391 An additionalsesterterpene, cacospongionolide F 503, was isolated fromFasciospongia cavernosa from the Northern Adriatic Sea andits absolute stereochemistry was determined using the modifiedMosher’s method.392 The X-ray crystallographic data forscalarolide 504 and scalarin 505, which are metabolites ofsponges of the family Thorectidae,393,394 have been reported.395

Nat. Prod. Rep., 2001, 18, 1–49 23

A specimen of Coscinoderma mathewsi from Pohnpei containedtwo sesterterpenes 506 and 507 that have an unusual cisgeometry about the B/C ring junction.396 Bilosespens A 508 andB 509, which were isolated as an inseparable mixture from anEritrean sample of Dysidea cinerea, are cytotoxic sesterterpeneshaving an unprecedented carbon skeleton.397 (�)-Wistarin 510from a Red Sea Ircinia sp. is the enantiomer of a metabolitepreviously isolated 398 from I. wistaria.399 Phyllofolactones C511 and D 512 are minor homoscalarane sesterterpenes froma Chinese specimen of Phyllospongia foliascens.400 Threeadditional sesterterpenes 513–515 were isolated fromStrepsichordaia lendenfeldi from the Great Barrier Reef.401 Thepolar material from a Great Barrier Reef Carteriospongia sp.contained (�)-3-hydroxypentanoic acid 516 which is sometimesfound as an ester group on scalaranes.402 Manoalide 517, whichis an antiinflammatory agent from Luffariella variabilis,403 hasbeen synthesized in an enantioselective manner.404 A synthesisof ircinin-4 518, a metabolite of Ircinia oros,405 employed apalladium-catalyzed reaction as the key step.406 The absolute

configuration of (�)-spongianolide A 519, which is a cytotoxicsesterterpene from a Spongia sp.,407 was determined by totalsynthesis.408

In addition to known sesterterpenes, an inseparable mixtureof two epimeric epidioxy sterols 520 and 521 was obtained as anantifouling agent from Lendenfeldia chondrodes from Palau.409

An Indian specimen of Petrosia testudinaria yielded an unusual27-nor sterol 522.410 Two C30 sterols, thymosiosterol 523 and

24 Nat. Prod. Rep., 2001, 18, 1–49

24,27-dehydrothymosiosterol 524 were isolated from anundescribed Thymosiopsis sp. from France.411 As part of a studyof multidrug resistance reversal, six new agosterol derivatives,agosterols B 525, C 526, A4 527, D2 528, A5 529 and C6 530 wereisolated from a Japanese species of Spongia.412 An unusualsterol enol ether 531, derived by cyclization of a 9,11-secosterol,was obtained from an Australian specimen of Euryspongia

Nat. Prod. Rep., 2001, 18, 1–49 25

arenaria.413 Glaciasterol B 3-monoacetate 532 is a 9,11-secosterol from Fasciospongia cavernosa from the Mediter-ranean that was toxic to brine shrimp.414 A Corticium sp. fromVanuatu contained plakinamines C 533 and D 534 and threeother steroidal alkaloids 535–537, all of which showed sig-nificant cytotoxicity.415 Tamasterone sulfates 538 and 539 area C-14 epimeric pair of polyhydroxylated sterols from a newspecies of the genus Oceanapia.416 Although haplosamates A540 and B 541, which are inhibitors of HIV-1 integrase fromtwo Philippines Haplosclerid sponges, were reported to bethe first naturally occurring sulfamates,417 re-examination ofthe spectral data has revealed that they are in fact phosphateesters and that the structures must be revised to 542 and543, respectively.418 Crellastatins B–M 544–555 are twelveadditional cytotoxic dimeric 4,4�-dimethylsterols from aCrella sp. from Vanuatu.419,420 A two sponge association ofPoecillastra wondoensis and Jaspis wondoensis contained threecytotoxic and antimicrobial steroidal glycosides, wondosterolsA–C 556–558.421 The Caribbean sponge Ectyoplasia feroxcontained two triterpene oligoglycosides, ectyoplasides A 559and B 560, that showed moderate cytotoxicity.422 Xestoberg-

sterol A 561, which is a metabolite of Xestospongia bergquistiithat inhibits the release of histamine from rat mast cells,423 hasbeen synthesized in 24 steps from stigmasterol.424

The symmetrical diketotriterpenoid 562 was obtainedfrom an Indonesian specimen of Hyrtios erectus.425 The revisedstructure of hippospongic acid 563,426 which is a metaboliteof a Japanese Hippospongia sp.,427 has been synthesized as theracemate.428,429 Three additional triterpenes, 22-dihydroyard-enone 564, abudinol B 565 and muzitone 566, together withpossible degradation products nakorone 567 and durgamone568, were obtained from a Red Sea specimen of Ptilocaulisspiculifer and five new triterpenes, sodwanones N–R 569–573were reported from Axinella weltneri from South Africa.430

7 Coelenterates

Although the chemistry of coelenterates continues to bedominated by terpenoids, there are a few interesting lipids andalkaloids to be reported. The scleractinian coral Madreporaoculata contained a mixture of 10-hydroxydocosapolyenoicacids that was methylated to obtain the methyl esters 574and 575.431 Montiporic acids A 576 and B 577, which are cyto-toxic polyacetylenes from the scleractinian coral Montiporadigitata,432 have been synthesized in good yields.433 Threeadditional butenolides 578–580 related to ancepsenolide 434

were obtained from the Caribbean gorgonian Pterogorgiaanceps.435 The Okinawan soft coral Clavularia viridis hasyielded a number of new prostanoids: 17,18-dehydroclavulone I581 and clavulactone I 582,436 4-epiclavulones II 583 and III584,437 and the truncated derivatives clavirins I 585 and II586.438 Batyl alcohol-3-O-α--fucoside 587 was obtained froma new species of Sinularia from Rangat Island in the Andamangroup.439 An Indian specimen of Sinularia dissecta containedthe known 440 sponge metabolite 588.441 Five additionalalkaloids, zoanthenol 589, 3-hydroxynorzoanthamine 590, 30-hydroxynorzoanthamine 591, 11-hydroxynorzoanthamine 592and 11-hydroxyzoanthamine 593 have been isolated from aZoanthus sp. from the Canary Islands.442 An Indian Zoanthussp. contained known bases together with thyminol 594.126 Thedeep-water briareid soft coral Lignopsis spongiosum fromSouth Georgia Island yielded the β-carboline alkaloid 595.443

The H,K-ATPase inhibitor sinulamide 596 is a tetraprenylatedspermine derivative from a Japanese soft coral of the genusSinularia.444 Two sphingosine derivatives, N-hexadecanoyl-1,3-dihydroxy-2-amino-4,8-octadecadiene 597 and N-heneico-sanoyl-1,3,4-trihydroxy-2-aminotetradecane 598, were isolatedfrom S. crassa from the Andaman and Nicobar Islands.445 Aspart of a pharmacological study that reported the cytotoxicityof africanene 599, it was shown that S. leptaclados from

26 Nat. Prod. Rep., 2001, 18, 1–49

Southern India contained two new sphingolipids, 600 and601.446

Three additional africanene derivatives, 10(S)-hydroxy-9(15)-africanene 602, 9(S),15-epoxyafricanane 603 and 9(S),15-dihydroxyafricanane 604 were isolated as minor constituentsof Sinularia dissecta from Southern India.447 10(S)-Hydroxy-9(15)-africanene 602 and 9(S),15-epoxyafricanane 603 werealso obtained by microbial oxidation of 9(15)-africanene 599using Aspergillus niger and Rhizopus oryzae.448 S. intacta fromIndia contained four additional africanane derivatives, (9R)-9,15-dihydroxyafricanane 605, (9R)-9-methoxy-15-hydroxy-africanane 606, (9S)-9,15-dihydroxyafricanane 607 and theseco-diketone 608.449,450 A specimen of Gorgonia ventalina fromthe Bahamas contained 5,10-epoxymuurolane 609.451 Duringstudies of fish feeding deterrents from the Brazilian gorgonianHeterogorgia uatumani, a new sesquiterpene, heterogorgiolide610, was isolated as an active agent.452 Alertenone 611 is adimer of the cytotoxin suberosenone 612, previously isolatedfrom Subergorgia suberosa,453 that was obtained from anAlertigorgia sp. from Australia.454 Euplexides A–E 613–617 arecytotoxic farnesylhydroquinone glycosides from the Koreangorgonian Euplexaura anastomosans.455 Curcuhydroquinone618, which is a metabolite of Pseudopterogorgia rigida,456 hasbeen synthesized as its racemate.457 The absolute configurationof the secosesquiterpene (�)-anthoplalone 619, which is a cyto-toxic constituent of the sea anemone Anthopleura pacifica,458

was determined by total synthesis.459 Clavularin B 620, whichis a metabolite of the soft coral Clavularia koellikeri,460 hasbeen synthesized by an enantio- and diastereo-controlledroute.461

In addition to several known compounds, a Taiwanesespecimen of the soft coral Nephthea brassica contained boththe sesquiterpene (�)-4α-O-acetylselin-11-ene 621 and thediterpenes brassicolide 622 and brassicolide acetate 623.462

Three additional cembranoids, sartol acetate B 624, epoxy-sartone B 625 and sartone E 626, were obtained from aJapanese Sarcophyton species.463 Sarcophytols A 627 and B 628,which are metabolites of the Okinawan soft coral S. glaucum,464

were synthesized in a concise and efficient manner.465 Thesynthesis of racemic sinulariol B 629, isolated from a Japanesespecimen of Sinularia mayi,466 was accomplished in 10 stepsand ca. 10% yield from geraniol.467 A subsequent paperrecorded the synthesis of (�)-sinulariol B 629 from geraniol.468

Preverecynarmin 630, which was isolated from both Veretillumcynomorium and its specific predator, the opisthobranchmollusc Armina maculata,469 was synthesized from (E,E)-farnesol.470 Lobatrienolide 631 and lobatrientriol 632, whichare metabolites of an Okinawan specimen of S. flexibilis,471

were prepared from (�)-nopinone.472

The Indonesian sea pen Veretillum malayense contained fourditerpenes, malayenolides A–D 633–636, that were toxic to brineshrimp.473 Sandresolides A 637 and B 638 are nor-diterpenesthat were isolated from the gorgonian Pseudopterogorgia elisa-bethae from Columbia.474 An Okinawan soft coral of the genusXenia contained three additional xenicane diterpenes, xeniadiol639, xeniaol 640 and xeniatriol 641.475 In addition to knownmetabolites, the Indian soft coral Sinularia maxima producedtwo furanocembranoids, sethukarailin 642 and sethukarailide643.476 A specimen of the gorgonian Pseudopterogorgiabipinnata from Columbia contained bipinnapterolide A 644,bipinnatins G–I 645–647 and bipinnatolides F–J 648–652,among which the structures of bipinnapterolide A 644 andbipinnatolide F 648 were determined by X-ray crystal-lography.477 Bisgersolanolide 653 is a diterpenoid dimer thatwas also obtained from a specimen of P. bipinnata from thesame location.478 A full account of the synthesis of eleutherobin654, which is an anti-tumour agent from an AustralianEleutherobia sp.,479 has appeared.480

Nat. Prod. Rep., 2001, 18, 1–49 27

The Senegalese gorgonian Eunicella labiata contained twoadditional eunicellin-type diterpenes, labiatins D 655 and E656.481 Obtained from E. cavolinii from the Mediterranean,massileunicellins A–C 657–659 are cytotoxic eunicellin-type diterpenes that contain a second ether bridge.482 Thebriarane class of diterpenoids have dominated reports of newmetabolites from coelenterates. Five such compounds, (�)-4-deacetyljunceellolide D 660, (�)-11α,20α-epoxyjunceellolideD 661, (�)-11α,20α-epoxy-4-deacetyljunceellolide D 662,(�)-11α,20α-epoxy-4-deacetoxyjunceellolide D 663 and (�)-junceellolide A 664, an antipode of a known metabolite, wereobtained from an Indonesian specimen of Junceella fragilis.483

Erythropodium caribaeorum from Jamaica contained threeadditional briaranes, erythrolide E 3-acetate 665, erythrolideF 3-acetate 666 and erythrolide H 16-acetate 667.484 ViolidesC–I 668–674 are additional briarane diterpenes from a Japanesespecies of Briareum (aka Pachyclavularai violacea): 485 theauthors propose that two previously reported 486 analogs berenamed violides A and B. A subsequent paper reported theisolation of violides J -M 675–678 from the same organism and

28 Nat. Prod. Rep., 2001, 18, 1–49

the X-ray crystallographic structure determination of violide J675.487 Excavatolides F–M 679–686 and U–Z 687–692, some ofwhich were cytotoxic, were isolated from a Taiwanese specimenof Briareum excavatum 488,489 while excavatolides N–T 693–699 were obtained from a Western Australian specimen of B.excavatum.490 Having reached the end of the alphabet for theexcavatolides, the next series of compounds from B. excavatumwere named briaexcavatolides A–J 700–709 and the structureof briaexcavatolide B 701 was determined by X-raycrystallography.491

Bishomoisomandapamate 710, which was isolated from anew species of Sinularia from the Indian Ocean, is an analog ofa known metabolite.492 Sarcophyton elegans from the IndianOcean has yielded an additional diterpene, 7-dehydrosarco-phytin 711.493 A full paper has described the isolation ofsarcophytin 712, 7-dehydrosarcophytin 711, 7(15)-dehydro-sarcophytin 713 and isosarcophytin 714 from S. elegans.494

The structure of an unusual cytotoxic norditerpenoid, inelegan-olide 715, which was obtained from Sinularia inelegans fromFormosa, was determined by X-ray crystallography.495 Pseudo-pteroxazole 716, and to a lesser extent, secopseudopteroxazole717 are inhibitors of Mycobacterium tuberculosis H37Rvthat were isolated from Pseudopterogorgia elizabethae fromColumbia.496 P. elizabethae from the same location also con-tained elisabatins A 718 and B 719.497

Two 19-oxygenated polyhydroxy steroids, 24-methylene-cholest-5-en-1α,3β,19-triol 720 and 24-methylenecholest-5-en-3β,7β,9α,19-tetraol 721, were isolated from an Indian Oceanspecimen of Nephthea chabroli 498 while a Chinese specimen ofN. brassica contained 24-methylenecholest-3β,6β,9α,19-tetraol722.499 A specimen of N. brassica from the Indian Oceancontained 4α-methyl-24-methylenecholest-3β,8β-diol 723.500

Nat. Prod. Rep., 2001, 18, 1–49 29

A Formosan Sinularia sp. contained 7β-hydroperoxy-24-methylenecholesterol 724 together with a number of knowncompounds.501 A Sinularia sp. from Southern India yielded11α,12α-epoxy-24-methylenecholest-1α,3β,6β-triol 725 502 whileLobophytum crassum from the same region contained 23,24(S)-dimethylcholest-5,22-dien-3β,7α-diol 726, which was isolatedas the corresponding diacetate.503 Four polyhydroxy steroidsfrom an Indian specimen of S. dissecta, cholest-1β,3β,5α,

6β,11α-pentaol 727, 24-methylenecholest-1β,3β,5α,6β,11α-pentaol 728, 24-methylenecholest-1β,3β,5α,6α,11α-pentaol729 and 11α,12α-epoxy-24-β-methylcholest-1α,3β,6β-triol 730,

30 Nat. Prod. Rep., 2001, 18, 1–49

were identified as their peracetate derivatives.504 PalythoalonesA 731 and B 732 are ecdysteroids from an Okinawan specimenof the zoanthid Palythoa australiae.505 A Dendronephthya sp.

Nat. Prod. Rep., 2001, 18, 1–49 31

32 Nat. Prod. Rep., 2001, 18, 1–49

from Japan contained four 13,17-secosteroids, isogosteronesA–D 733–736, that inhibited settlement of the cyprid larvaeof the barnacle Balanus amphitrite.506 Subsequently, methyl

Nat. Prod. Rep., 2001, 18, 1–49 33

3-oxochola-1,4,22-trien-24-oate 737 from the Dendronephthyasp. and 3-methoxy-19-norpregna-1,3,5(10),20-tetraene 738,22,23-dihydroxycholesta-1,24-dien-3-one 739 and 3-(4-O-acet-yl-6-deoxy-β-galactopyranosyloxy)-19-norpregna-1,3,5(10),20-tetraene 740 from a Japanese specimen of Alcyoniumgracillimum were shown to be toxic to the cyprid larvae ofB. amphitrite.507 Two norpregnane glycosides, 19-nor-pregna-1,3,5(10),20-tetraen-3-O-α-fucopyranoside 741 and 19-norpregna-1,3,5(10),20-tetraen-3-O-β-arabinopyranoside 742,were obtained from the soft coral Scleronephthya pallidafrom Thailand.508 Sinularia gravis from Southern India con-tained (24S)-methylcholest-5-en-3β,25-diol-3-O-α-fucopyrano-side 743.509

8 Bryozoans

Recent research on natural products from bryozoans hascentered as much on synthesis as on structural elucidation. Sixnew brominated alkaloids, amathaspiramides A–F 744–749,were isolated from Amathia wilsoni from New Zealand.510

Convalutamines F 750, which is cytotoxic, and G 751 andconvolutamydine E 752 are additional alkaloids from A.convoluta from Florida.511 Convalutamydine A 753, an alkaloidfrom A. convoluta,512 has been synthesized from isatin asthe racemate.513,514 Debromoflustramines A 754 and B 755,the latter of which is a metabolite of Flustra foliacea,515 havebeen synthesized using a strategy that can be applied to other

34 Nat. Prod. Rep., 2001, 18, 1–49

alkaloids in this group.516 A detailed account of the convergentsynthesis of bryostatin 2 756, which is a cytotoxic macrolidefrom Bugula neritina,517 has been published.518

9 Molluscs

There was only one new paper on the isolation of sea haremetabolites. In addition to known algal metabolites, fourhalogenated sesquiterpenes, algoane 757, the structure of whichwas established by X-ray crystallography, 1-deacetoxyalgoane758, 1-deacetoxy-8-deoxyalgoane 759 and ibhayinol 760 wereisolated from Aplysia dactylomela from the Eastern Capeof South Africa.519 Dolastatin 15 761, which is a cytotoxicdepsipeptide from the Indian Ocean sea hare Dolabella auricu-laria,520 was prepared using a convergent synthesis.521 Thestereostructure of dolastatin I 762, a cytotoxic metabolite ofa Japanese specimen of D. auricularia,522 was confirmed by anenantioselective synthesis.523

The absolute stereochemistry of kahalalide F 763, which is abioactive metabolite of the Hawaiian sacoglossan Elysia rufes-cens and its food source Bryopsis sp.,524 has been determined byacid hydrolysis and hydrazinolysis, followed by chiral analysisof the fragments.525 Volvatellin 764 is an unstable sesquiterpenefrom the Indian sacoglossan Volvatella sp. that is formallyrelated to the green algal metabolite caulerpenyne.526

In the process of defining the de novo biosynthesis of drimaneterpenoids in dorid nudibranchs, an additional sesquiterpene,7-deacetoxyolepupuane 765, was isolated from Dendrodorisarborescens.527 2-Isocyanoallopupukeanane 766, which is a

Nat. Prod. Rep., 2001, 18, 1–49 35

metabolite of the nudibranch Phyllidia pustulosa from Japan,528

has been synthesized in good yield using an intramolecularDiels–Alder reaction to fuse the bridging cyclopentane ringto a bicyclo[3.2.1]octane unit.529 The Okinawan nudibranchReticulidia fungia contained two additional members of a rareclass of sponge metabolites, the carbonimidic dichloridesreticulidins A 767 and B 768.530 The absolute stereochemistry ofthe farnesic acid glyceride derivatives 769–771 from Archidorisodhneri 531 and the drimane derivatives 772 and 773 fromA. montereyensis 532 were determined by total synthesis.533

Austrodorins A 774 and B 775 are tricyclic diterpenoid 2�-monoglyceryl esters from the skin of the Antarctic nudibranchAustrodoris kerguelenensis.534 Two additional glycerides 776 and777 were isolated from A. kerguelenensis and the absolute

configurations of 776 and the known 535 glyceride 778 wereestablished using the modified Mosher method.536 Similarcompounds, anisidorins 1–5 779–783, were obtained from thePatagonian dorid Anisodoris fontaini.537 The absolute con-figuration of anisodorin 5 783 was established by synthesisof the enantiomer.538 The Japanese nudibranch Chromodorisinornata contained three cytotoxic sesterterpenes, inorolides A784, B 785 and C 786, as well as five new scalaranes 787–791.539

Two additional scalaranes 792 and 793 were obtained frommantle dermal formation-like structures of the Indiannudibranch Glossodoris atromarginata and from the sponge,tentatively identified as a Spongia sp., on which it wasgrazing.540

Three new polypropionates, capensinone 794, capensifuran-none 795 and (2E,4S,6S,8S)-2,4,6,8-tetramethyl-2-undecenoicacid 796, were obtained from the South African pulmonatemollusc Siphonaria capensis.541 The prosobranch molluscCoriocella nigra contained an additional cytotoxic stauro-sporine analog, 4�-N-demethyl-11-hydroxystaurosporine 797.542

The synthesis of both dorimidazole A 798 and preclathridine A799, which were isolated from the Indo-Pacific nudibranchNotodoris gardneri,543,544 have been reported.326

36 Nat. Prod. Rep., 2001, 18, 1–49

The occurrence of human intoxication due to ingestion ofshellfish is providing increasing opportunities for chemists toidentify new toxins, which are often related to dinoflagellatemetabolites. Turbotoxins A 800 and B 801 are toxic diiodo-tyramine derivatives from the (inedible) viscera of the Japanesegastropod Turbo marmorata.545 The Chinese bivalve Pinnaattenuata contained isomeric bicyclic ketals, attenols A 802 andB 803, which exhibited moderate cytotoxicity.546 Azaspiracids-2804 and -3 805 are additional toxins isolated from cultivated

Nat. Prod. Rep., 2001, 18, 1–49 37

mussels (Mytilus edulis) that were the source of human intoxi-cation in Ireland in 1995.547 An additional yessotoxin analog,1-desulfoyessotoxin 806, was isolated from the digestive glandsof Norwegian M. edulis.548 The major toxin involved in neuro-toxic shellfish poisoning associated with the New Zealandgreenshell mussel Perna canaliculus was identified as brevetoxinB4 807.549 Feeding experiments have shown that the scallopPatinopectin yessoensis converts dinophysistoxin-1 808 from thedinoflagellate Dinophysis fortii into dinophysistoxin-3 809.550

10 Tunicates (ascidians)

Although tunicates (ascidians) have yielded fewer new metabo-lites than usual during the last year, a greater variety of struc-tural types has been described. For example, didemniserinolsA–C 810–812 are an unprecedented group of serinolipids froman Indonesian species of Didemnum.551 Lissoclinolide 813,which is an antimicrobial metabolite from a Lissoclinumpatella,552 has been synthesized in an efficient manner usingorganozirconium chemistry.553 A second stereoselective syn-thesis 554 of lissoclinolide 813 established that it was identical to

‘tetrenolin’, which had previously been isolated from the fungusMicropolyspora venezuelensis.555 An Okinawan species ofLissoclimum contained the cytotoxic macrolide haterumalide B814 that inhibited cell division in fertilized sea urchin eggs.556

An additional monoterpene, hydroquinone 815, the geo-

metrical isomer of a known metabolite, was isolated fromAplidium savignyi from the Comoro Islands.557 A specimen ofA. longithorax from Palau contained the isomeric longithorolsA 816 and B 817, which were isolated only as their penta-acetates,558 while longithorones J 818 and K 819 559 andlongithorols C–E 820–822 560 were isolated from an Australianspecimen of the same ascidian. Longithorone B 823 fromA. logithorax 561 has been synthesized as the racemate.562

Aplidioxins A 824, the structure of which was determinedby X-ray analysis, and B 825 were isolated from Aplidiopsisocellata from the Philippines.563 The Australian ascidianSynoicum prunum contained three weakly cytotoxic bis-spiroketals, prunolides A–C 826–828, together with the knownmetabolite rubrolide A.564 Five additional lamellarins, the

20-sulfates of lamellarin B 829, C 830 and L 831, lamellarinG 8-sulfate 832 and lamellarin Z 833 were isolated fromDidemnum chartaceum from the Great Barrier Reef: unusuallylong relaxation times were observed for certain signals in their1H NMR spectra.565 Having exhausted the regular alphabet,an inhibitor of HIV-1 integrase from an unidentified ascidianfrom India was named lamellarin α 20-sulfate 834.566 NingalinA 835, which is a metabolite of a Western Australian Didemnumsp.,567 and lukianol A 836 from an unidentified tunicate 568 havebeen synthesized using a Diels–Alder strategy.330 Distapliaregina from Palau contained the antibacterial agent 3,6-dibromoindole 837,569 a structure that had been erroneously

38 Nat. Prod. Rep., 2001, 18, 1–49

proposed as a metabolite of acorn worms.570 The first marineergoline alkaloid, pibocin 838, was isolated as a cytotoxic andantimicrobial agent from a Far-eastern Eudistoma species.571

The cyclized didemnimide alkaloid 839, earlier reported asisogranulatimide from Didemnum granulatum,572 was isolatedin very low yield from D. conchyliatum from the Bahamas.573

Two additional staurosporine derivatives, 3�-demethoxy-3,3�-dihydroxystaurosporine 840 and 11-hydroxy-4�-N-demethyl-staurosporine 841, were isolated from Eudistoma toealensisand a flatworm of the genus Pseudoceros that preys upon theascidian.574 A Polycitorella sp. from Okinawa contained thecytotoxic alkaloids iheyamines A 842 and B 843, the latterbeing optically active and therefore unlikely to be an artifactof acetone extraction.575 Two pyrazine alkaloids, botryllazinesA 844 and B 845, and 2-(p-hydroxybenzoyl)-4-(p-hydroxy-phenyl)imidazole 846 were isolated from a Spanish specimenof Botryllus leachi.576 Trypargimine 847, 1-carboxytrypargine848 and 3�,5�-dibromo-4�-methoxyphenylethylamine 849 wereisolated from an undescribed Eudistoma sp. from Indonesia.577

Didemnolines A–D 850–853, which are β-carboline alkaloidsfrom a Didemnum sp. from Rota, Northern Mariana Islands,578

have been synthesized in a straightforward manner.579

The New Zealand ascidian Botrylloides leachi contained anew purine base, 1,3-dimethylguanine 854.580 Another purinebase, 6-methoxy-7-methyl-8-oxoguanine 855 was isolated fromSymplegma rubra from the Southeastern Brazilian coast.581 Atotal synthesis of aplidiamine, which was isolated from anAplidiopsis sp.,582 provided evidence that the structure shouldbe revised from 856 to 857.583 Lumichrome 858 functions as anatural metamorphosis inducer in the larvae of Halocynthiaroretzi.584

There have been a relatively large number of syntheses ofascidian alkaloids and peptides belonging to classes for whichno new examples have appeared. The absolute configuration

Nat. Prod. Rep., 2001, 18, 1–49 39

of lepadin B 859, which was obtained as a cytotoxic agentfrom Clavelina lepadiformis,585 was determined by totalsynthesis.586,587 The structures and absolute configurationsof clavepictines A 860 and B 861 and pictamine 862 fromC. picta 588,589 have been verified by total syntheses.590,591 Theracemates of cylindricines A 863 and B 864, which are tricyclicalkaloids from an Australian specimen of C. cylindrica,592

have been synthesized in good yields.593 (�)-Cylindricine C 865from C. cylindrica 594 has been synthesized in 12% overallyield from (S)-butane-1,2,4-triol.595 A convergent stereoselec-tive synthesis of the putative structure of lepadiformine 866,

which was isolated as a cytotoxic agent from C. lepadiformis,596

indicated the need to re-examine the structure, stereochemistryand the claim of a zwitterionic form.597–599 In addition, syn-theses of isomeric forms of lepidaformine indicate that it is nota stereoisomer at C-2 or C-13.598

Virenamide B 867, which is a cytotoxic thiazole-containingtripeptide from Diplosoma virens,600 has been synthesized andits optical rotation has been corrected.601 The macrocyclichexapeptide bistratamide D 868 from Lissoclinum bistratum 602

has been synthesized using a convergent strategy usingenantiomerically pure oxazole, thiazole and oxazoline seg-ments.603 A total synthesis of the proposed structure oftrunkamide A 869, which is a cyclic heptapeptide from a

Lissoclinum sp.,604 revealed that the structure of the naturalproduct should be reinvestigated.605 The total synthesis ofmollamide 870, a cytotoxic cyclic peptide from Didemnummolle,606 has been reported.607 The synthesis of tamandarinA 871, which is a cyclic peptide related to the didemnins,was announced before the structural elucidation waspublished! 608,609

11 Echinoderms

In comparison with recent years, very few new metaboliteshave been reported from echinoderms. Two major inositol-phosphoceramides 872 and 873 were identified among thelipids of the crinoid Comanthus japonica.610 The neuritogenicganglioside LMG-2, the major component of which is 874, wasisolated from the Japanese seastar Luidia maculata as a mixtureof closely related compounds having different alkyl chains.611

A similar situation applies to the ganglioside LLG-3 875, whichis a metabolite of Linckia laevigata from Okinawa.612 TheJapanese sea cucumber Stichopus japonicus contained SJG-1876 as the major neuritogenic ganglioside.613 The lengths of theacyl chains in the ceramide moieties can be determined withoutchemical degradation by collision-induced dissociation mass

40 Nat. Prod. Rep., 2001, 18, 1–49

spectrometry of the sodium ion complexes.614 Four additionalsteroidal glycosides, mediasterosides M1 877, M2 878, M3

879 and M4 880, were isolated from the deep-water seastarMediaster murrayi as inhibitors of cell division in fertilized seaurchin eggs.615 Frondoside D 881 is an additional triterpenoidsaponin from the holothurian Cucumaria frondosa.616

12 Miscellaneous

Although there were no reports of novel compounds frommarine worms, -ovithiol A 882, which was isolated as thecorresponding disulfide, was shown to be the egg release

pheromone of the marine polychaete worm Platynereisdumerilii.617 Hallachrome 883, which is a pigment of the marineworms Halla parthenopeia 618 and Lumbriconereis impatiens,619

has been synthesized using a Diels–Alder strategy.620 One of thefew reports of a new natural product from fishes is the isolationof α-tocomonoenol 884 from the eggs of the Pacific salmonOncorhynchus keta.621 5-Deoxytetrodotoxin 885 was isolated asa minor metabolite from the ovaries of the puffer fish Fugupoecilonotus.622 Chinese studies of the puffer fish Fugu vermicu-laris described the isolation of tetrodoine 886 and a numberof tetrodotoxin derivatives, which may or may not beartifacts.623,624

Nat. Prod. Rep., 2001, 18, 1–49 41

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