Marine natural products

Contents

• 1 Introduction

• 2 Marine microorganisms and phytoplankton

• 3 Green algae

• 4 Brown algae

• 5 Red algae

• 6 Sponges

• 7 Coelenterates

• 8 Bryozoans

• 9 Molluscs

• 10 Tunicates (ascidians)

• 11 Echinoderms

• 12 Conclusions

• Acknowledgements

• References

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Abstract

This review covers the literature published in 2001 for marine natural products, with 497 citations (373 for the period January to December 2001) and includes 793 compounds isolated from marine microorganisms and phytoplankton, green algae, brown algae, red algae, sponges, coelenterates, bryozoans, molluscs, tunicates and echinoderms. The emphasis is on new compounds and new stereochemical assignments (683 for 2001), together with relevant biological activities, source organisms and country of origin. Syntheses that confirm or revise structures or stereochemistries have been included (95), including any first total synthesis of a marine natural product.

Covering: 2001. Previous review: Nat. Prod. Rep., 2002, 19, 1.

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John W. Blunt

John Blunt obtained his BSc (Hons) and PhD degrees from the University of Canterbury, followed by postdoctoral appointments in Biochemistry at the University of Wisconsin-Madison, and with Sir Ewart Jones at Oxford University. He took up a lectureship at the University of Canterbury in 1970, where he is now a Professor. His research interests are with natural products, and the application of NMR techniques to structural problems.

Brent R. Copp

Brent Copp received his BSc (Hons) and PhD degrees from the University of Canterbury, where he studied the isolation, structure elucidation and structure–activity relationships of biologically active marine natural products under the guidance of Professors Blunt and Munro. He undertook postdoctoral research with Jon Clardy at Cornell and Chris Ireland at the University of Utah. 1992–93 was spent working in industry as an isolation chemist with Xenova Plc, before returning to New Zealand to take a lectureship at the University of Auckland, where he is currently a Senior Lecturer.

Murray H. G. Munro

Murray Munro, a Professor in Chemistry at the University of Canterbury, Christchurch New Zealand, has worked on New Zealand natural products all of his professional career. His interest in marine natural products was stimulated by a study-leave period spent with Professor Kenneth Rinehart, University of Illinois, in 1973. A marine chemistry group at Canterbury followed soon after and has been active ever since. In more recent years his research interests have widened to include marine fungi and actinomycetes and drug delivery systems based on polymer therapeutics.

Peter T. Northcote

Peter Northcote, received his BSc and PhD degrees from the University of British Columbia, Canada where he was a member of R. J. Andersen's marine natural products research group. He carried out postdoctoral research with Professors Blunt and Munro at the University of Canterbury before taking a position as a senior research scientist at Lederle Laboratories, American Cyanamid Co. He joined the faculty of the Victoria University of Wellington in 1994 where he is currently a Senior Lecturer in organic chemistry.

Michèle R. Prinsep

Michèle Prinsep received her BSc (Hons) and PhD degrees from the University of Canterbury, where she studied the isolation and structural elucidation of biologically active secondary metabolites from sponges and bryozoans under the supervision of Professors Blunt and Munro. She undertook postdoctoral research on cyanobacteria with Richard Moore at the University of Hawaii before returning to New Zealand to take up a lectureship at the University of Waikato, where she is currently a Senior Lecturer.

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1 Introduction

The previous author of these reviews, Professor D. John Faulkner, died on November 23, 2002. For over 30 years John had been a constant source of inspiration and insights that totally changed the perspective of marine natural products. He was both an exceptional researcher and an inspirational teacher who constantly exhorted his students to greater heights by his own example. From his research he will be remembered for the precision and conciseness he brought to bear and for the wonderful results that unfolded. This review is dedicated to John’s memory.

These reviews were initiated by Faulkner in 1984¹ following his original 1977 overview in Tetrahedron.² Since then 17 further reviews have appeared, with 13 annually since 1990. We are all indebted to Professor Faulkner for this amazing volume of work. These meticulously prepared reviews, notable for their comprehensiveness, accuracy and readability, have become the most highly cited articles for this journal. Earlier in 2002 John relinquished the task of preparing these reviews. With trepidation we agreed to take over the task. Foremost in our minds was the need to maintain the high ‘Faulknerian’ standards.

For this review we follow the same style and layout seen previously. There has been continued growth in the reports from studies on microorganisms, and on synthetic efforts on marine natural products. We have included papers on syntheses if they provide new information on the stereochemistry of previously reported compounds, or provide for a revision of structure. We also report the first total synthesis of any marine natural product. In view of the rapid growth in this area, we believe that it would be timely to dedicate a companion review to this topic.

A number of reviews on a variety of topics appeared in 2001. One group covered natural products from many sources including marine organisms: “Natural products in anticancer therapy”,³ “Endophytes: a rich source of functional metabolites”,⁴ “Simple indole alkaloids and those with nonrearranged monoterpenoid unit”,⁵ “Diterpenoids”,⁶ “Biologically active proteins from natural product extracts”⁷ and “Natural product-based anti-HIV drug discovery and development facilitated by the NCI Developmental Therapeutics Program”.⁸ Cyanobacteria have been well covered by “Marine cyanobacteria – a prolific source of natural products”,⁹ “The toxins of cyanobacteria”,¹⁰ and “Nitrogen-containing metabolites from marine cyanobacteria”.¹¹ Ascidian-derived compounds are partially reviewed in “Recent advances on the research of natural products of ascidians”.¹² Specific compounds have been reviewed in “Chemistry of potent anticancer compounds, amphidinolides”,¹³ “Distribution and origin of tetrodotoxin”,¹⁴ the mini-review “Domoic acid: a fascinating marine toxin”,¹⁵ and “Pectenotoxins – an issue for public health”,¹⁶ while specific compound classes have been covered in “Recent advances in study on cyclic peptides from marine sponges”,¹⁷ “Aquatic animal carotenoids”,¹⁸ “Advances in marine natural products of the indole and annelated indole series: chemical and biological aspects”,¹⁹ and “Marine sulfur-containing natural products”²⁰ which describes the 482 sulfur-containing compounds (excluding sulfates) reported from 1985–1999. Some ecological and taxonomic aspects are reviewed in “Secondary metabolites from Antarctic marine organisms and their ecological implications”,²¹ “Marine chemical ecology: applications in marine biomedical prospecting”,²² and “Marine natural products chemistry as an evolutionary narrative”²³ which includes a taxonomic survey. Other reviews include “Biologically active compounds from marine organisms”,²⁴ “Marine bioprospecting – trawling for treasure and pleasure”²⁵ which highlights the molecular diversity seen in the results obtained by the University of Melbourne's marine natural product group, “Marine pharmacology in 1999: antitumor and cytotoxic compounds”²⁶ which describes the structures reported in 1999 for 30 antitumour and cytotoxic compounds, and “Marine organisms as a source of new anticancer agents”²⁷ which summarises current preclinical and clinical trial data for a range of marine natural products. Volume 6 of “Recent Advances in Marine Biotechnology” contains a series of reviews: “Novel pharmaceutical compounds from marine bacteria”,²⁸ “Recent developments on antimicrobial metabolites from marine sponges”,²⁹ “Bioactive compounds from hard corals”,³⁰ “Novel bioactive compounds from the soft corals: Chemistry and biomedical applications”,³¹ “Pore-forming proteins from sea anemones and the construction of immunotoxins for selective killing of harmful cells”,³² “Bioactive compounds from bryozoans”,³³ “Novel alkaloids from marine bryozoans”,³⁴ “Ion channel toxins as molecular models for the design of new drugs”,³⁵ “Proteinases from marine organisms”³⁶ and “Cooperative antifoulant testing: A novel multisector approach”.³⁷ A new database of 8 000 natural products has been introduced in “Using XML in the marine natural products database”,³⁸ while the MarinLit database³⁹ continues to be updated, and has been used for the preparation of this review.

2 Marine microorganisms and phytoplankton

There continues to be much interest in cultured marine organisms. An acidic polysaccharide isolated from Pseudoalteromonas distincta that was obtained from a marine sponge, contained two unusual acidic amino sugars; 2-acetamido-2-deoxy-D-galacturonic acid 1 and 5-acetamido-3,5,7,9-tetradeoxy-7-formamido-L-glycero-L-manno-nonulosonic acid 2.⁴⁰ A Streptomyces sp. isolated from a shallow sea sediment near Livingston Island, Antarctica was the source of 2-amino-9,13-dimethyl heptadecanoic acid 3, a compound with selective antimicrobial activity.⁴¹ The culture broth of a Streptomyces sp. isolated from sediment collected in Korean waters, yielded six novel lactone-containing metabolites 4–9.⁴² A novel glycerol diether, 2,3-di-O-dihydro-14,15-geranylgeranyl-sn-glycerol 10, was isolated from an anaerobic culture of the archaeon Thermococcus sp., collected from a deep-sea hydrothermal vent.⁴³ A cell-free culture of the marine bacterium Vibrio angustum was the source of the ether [1-(2′-methylpropoxy)-2-hydroxy-2-methylpropoxy]butane 11, which induced both the acylated homoserine lactone (AHL) regulatory system in Agrobacterium tumefaciens and bioluminescence in Vibrio harveyi.⁴⁴ Macrolactins G–M 12–18 were isolated from a culture broth of a Bacillus sp. The strain had been isolated from the red alga Schizymenia dubyi collected from Japanese waters and also contained macrolactins A and F which were previously isolated from an unclassifiable deep-sea bacterium.⁴⁵ The macrolactins exhibited selective antimicrobial activity.⁴⁶ A bacterial isolate from the tissues of an unidentified tube worm collected off Papua New Guinea that was tentatively identified as Bacillus laterosporus yielded the cationic peptide bogorol A 19. This compound displayed reasonably potent activity against both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcal strains (VRE) of bacteria but exhibited no activity against a range of other bacteria and fungi.⁴⁷ A novel β-methoxyacrylate antibiotic possessing a conjugated tetraene moiety was isolated from the culture broth of the marine myxobacterium Haliangium luteum and named haliangicin 20. Haliangicin was susceptible to oxidation in air and had to be kept in solution at −20 °C due to rapid decomposition at room temperature when evaporated to dryness.⁴⁸ Haliangicin inhibited growth of a wide range of fungi but was inactive against bacteria.⁴⁹ Micromonospolides A–C 21–23, macrolides containing a 16-membered lactone ring, were isolated from an undescribed actinomycete Micromonospora sp. These compounds inhibited the gastrulation of starfish (Asterina pectinifera) embryos.^50,51 The crude extract of a halophilic actinomycete, the new species Micromonospora lomaivitiensis, that was isolated from the inner core of the ascidian Polysyncraton lithostrotum, exhibited potent DNA-damaging activity in the biochemical induction assay (BIA) and potent cytotoxicity against a panel of cancer cell lines. Two dimeric diazobenzofluorene glycosides, designated as lomaiviticins A 24 and B 25, were isolated from the extract by BIA-guided fractionation. Both were demonstrated to be potent DNA-damaging agents and lomaiviticin A 24 was shown to cleave double stranded DNA under reducing conditions. Lomaiviticin A possessed a unique cytotoxicity profile as compared to known DNA-damaging drugs such as adriamycin and mitomycin C against a number of cancer cell lines. Both lomaiviticins A and B exhibited potent antibacterial activity against S. aureus and Enterococcus faecium.⁵² A total synthesis of thiocoraline 26, a potent antibiotic that was isolated from Micromonospora sp.,^53,54 has been accomplished and the relative and absolute stereochemistry established. Thiocoraline was also shown to bind to DNA by high-affinity bisintercalation, but with no obvious sequence selectivity. Thiocoraline was exceptionally cytotoxic to the L1210 murine leukaemia cell line with an IC₅₀ value of 200 pM.⁵⁵ The kahakamides A 27 and B 28 are new indole nucleosides that were isolated from the actinomycete Nocardiopsis dassonvillei, obtained from a shallow water sediment sample from Kauai, Hawaii. Kahakamide A 27 exhibited slight inhibition of B. subtilis in a disc-diffusion assay.⁵⁶ (Z,Z)-4,8-Dihydroxyundeca-2,9-dienedioic acid diamide 29 was obtained from an unidentified marine actinomycete.⁵⁷

Marine-sourced fungi continue to be of interest. A total synthesis of (±)-epoxysorbicillinol 30, a pigment isolated from the fungus Trichoderma longibrachiatum that was separated from a Haliclona sponge,⁵⁸ has been accomplished in 13 steps from diethyl methylmalonate.⁵⁹ The sesquiterpene lactone, 8-hydroxy-9-oxo-7(11)-eremophilien-12,8-olide 31 was isolated from the marine fungus Hypoxylon oceanicum from the South China Sea.⁶⁰ The isocoumarin avicennin A 32 was isolated from a mangrove endophytic fungus from the South China Sea,⁶¹ while the mangrove fungus Xylaria sp., also from the South China Sea, yielded xyloketals A–E 33–37. Xyloketal A 33 is a potent inhibitor of acetylcholine esterase.⁶² The unusual allenic ether, xyloallenolide A 38, was isolated from a Xylaria sp. from the South China Sea along with an aromatic allenic ether 39 which had not been previously reported from a natural source.⁶³ Chlorogentisylquinone 40 was isolated from the culture broth of an unidentified marine fungus, and was shown to inhibit sphingomyelinase activity of rat brain membranes.⁶⁴ The marine fungus Aspergillus versicolor, isolated from the sponge Xestospongia exigua from Bali, was the source of six chromone derivatives, the aspergiones A–F 41–46,⁶⁵ and four further compounds, aspergillone 47, aspergillodiol 48, aspergillol 49 and 12-acetylaspergillol 50.⁶⁶ An inhibitor of anaerobic electron transport, nafuredin 51, was isolated from Aspergillus niger, isolated from a marine sponge collected in Palau. Nafuredin proved to be a highly selective inhibitor of NADH-fumarate reductase (NFRD) from the pig roundworm Ascaris suum. Biosynthetic studies of nafuredin were carried out.⁶⁷ The alkaloid circumdatin G 52 was isolated from the culture broth of the fungus Aspergillus ochraceus, isolated from sediment collected in the Sea of Japan.⁶⁸ A new macrocyclic trichothecene, 12,13-deoxyroridin E 53 was isolated from the filamentous fungus Myrothecium roridum that was obtained from woody material collected in Palau. 12,13-Deoxyroridin E was active against human leukaemia HL-60 and murine L1210 cell lines.⁶⁹ The macrosphelides E–I 54–58 have been isolated from Periconia byssoides, separated from the sea hare Aplysia kurodai. The absolute stereostructures of the macrosphelides were determined on the basis of spectroscopic analyses and chemical transformations. The absolute configuration of the known compound macrosphelide C 59 was established by X-ray analysis and application of the modified Mosher method. Macrosphelides E–H 54–57 inhibited the adhesion of HL-60 cells to human umbilical vein endothelial cells (HUVEC).⁷⁰ The absolute stereochemistry of spiroxin A 60, a DNA-cleaving bisnaphthospiroketal from a marine-derived fungus,⁷¹ has been determined as (2S,3R,4S,2′S,3′R,4′S) by application of the exciton chirality method following derivatisation.⁷² A Pestalotia species of fungus isolated from the surface of the brown alga Rosenvingea sp. from the Bahamas, produced a chlorinated benzophenone antibiotic pestalone 61 only when a unicellular marine bacterium was co-cultured in the fungal fermentation. It was not detected when either organism was cultured individually. Pestalone 61, whose structure was confirmed by X-ray analysis, exhibited only moderate in vitro cytotoxicity in the National Cancer Institute's (NCI) 60 human tumour cell line panel but showed potent activity against MRSA and VCE.⁷³ A culture broth of the marine fungus Halorosellinia oceanica collected in Thailand was the source of an ophiobolane sesterterpene halorosellinic acid 62 and of 4-methyl-2-hexylidene-3-methylsuccinate 63. The relative stereochemistry of halorosellinic acid was assigned by analysis of NOESY data. Halorosellinic acid 62 exhibited moderate antimalarial activity against Plasmodium falciparum but only weak antimycobacterial activity.⁷⁴ 3-Methyl-6,8-methoxy-2-aza-9,10-anthraquinone (scorpinone) 64 was isolated from the mycelium of a cultured Bispora-like fungus from sediment collected in the Bahamas, and the structure determined by X-ray analysis.⁷⁵ Investigations of cultures of the mycelium of an unidentified fungus isolated from the red alga Ceradictyon spongiosum in Okinawa resulted in the isolation of two linear dodecapeptides, dictyonamides A 65 and B 66. Dictyonamide A 65 inhibited cyclin-dependent kinase 4 while dictyonamide B 66 was inactive.⁷⁶ Hortein, 67, was isolated from the fungus Hortaea werneckii obtained from the Mediterranean sponge Aplysina aerophoba. Hortein possesses an acenaphtho[1′,2′:7,8]naphthalene ring system which is unique among natural products.⁷⁷ Cultures of Cladosporium herbarum isolated from the sponge Callyspongia aerizusa collected from Bali yielded the 12-membered macrolide pandangolide 3 68, the macrolide dimer pandangolide 4 69 and a new acetyl derivative 70 of 5-hydroxymethylfuran-2-carboxylic acid, (also known as Sumiki's acid). Compound 70 inhibited the growth of B. subtilis and S. aureus in an agar plate diffusion assay.⁷⁸ The penochalasins D–H 71–75 were isolated from a strain of Penicillium sp. originally separated from the green alga Enteromorpha intestinalis. The compounds were all moderately cytotoxic to P388 murine leukaemia cells.⁷⁹

Cyanobacteria continue to yield novel structures. Apratoxin A 76, a cyclic depsipeptide of mixed peptide-polyketide origin, has been isolated from the cyanobacterium Lyngbya majuscula collected from Guam. The absolute configurations of the amino acid-derived units were determined by chiral HPLC analysis of hydrolysis products. The absolute stereochemistry of the new dihydroxylated fatty acid unit, 3,7-dihydroxy-2,5,8,8-tetramethylnonanoic acid was established through analysis by Mosher's method. The solution conformation of apratoxin A 76 was mimicked by molecular modelling. Apratoxin A exhibited potent cytotoxicity in vitro against KB and LoVo cell lines but was toxic in vivo to mice and was poorly tolerated.⁸⁰ A different population of L. majuscula from Guam was the source of two further cyclic depsipeptides, pitipeptolides A 77 and B 78. Pitipeptolides A and B exhibited weak cytotoxicity against LoVo cells and both compounds were active in the antimycobacterial diffusion susceptibility assay but were less active than a control. Pitipeptolides A and B also stimulated elastase activity.⁸¹ Antillatoxin B 79, an N-methyl homophenylalanine analogue of antillatoxin,⁸² was isolated from samples of L. majuscula from Puerto Rico and the Dry Tortugas. Antillatoxin B was ichthyotoxic to goldfish and activated sodium channels in mouse neuro-2a neuroblastoma cells.⁸³ A Panamanian collection of L. majuscula was the source of four new metabolites, pseudodysidenin 80, dysidenamide 81, nordysidenin 82 and dragonamide 83. The first three of these are closely related to dysidenin⁸⁴ and isodysidenin,⁸⁵ isolated from the sponge Dysidea herbacea. This is the first reported instance of the isolation of such compounds from a free-living cyanobacterium, most likely indicating that similar metabolites isolated from sponges are metabolites of associated cyanobacteria. Dragonamide contains a unique C8-alkynoate unit.⁸⁶ Somamides A 84 and B 85 were isolated from mixed assemblages of the cyanobacteria L. majuscula and Schizothrix sp. from Fiji. The absolute stereochemistries of the amino acid residues for 84 were determined by Marfey's analysis. These depsipeptides are analogous to symplostatin 2, isolated from the cyanobacterium Symploca hydnoides⁸⁷ and dolastatin 13, originally isolated from the sea hare Dolabella auricularia⁸⁸ but most likely originating from its cyanobacterial diet.⁸⁹ The first total synthesis of lyngbyabellin A 86, a peptolide isolated from L. majuscula from Guam,⁹⁰ has been described. Lyngbyabellin A was synthesised in 58% yield by a convergent strategy.⁹¹ A culture of the marine cyanobacterium Oscillatoria sp. yielded a diacylgalactolipid 87.⁹² The total stereochemistry of symplostatin 1 88, a metabolite of Symploca hydnoides,⁹³ was completed by determination of the stereochemistry of the N,N-dimethylisoleucine unit to be (S,S).⁹⁴ The same paper reported the isolation of dolastatin 10 from a Symploca species, suggesting that cyanobacteria are the ultimate producers of this metabolite, rather than the sea hare Dolabella auricularia from which it was originally isolated.⁹⁵ Symplostatin 1, a microtubule inhibitor, was a very potent cytotoxin both in vitro (KB and LoVo cell lines) and in vivo (with mice). It was, however, very toxic, causing lethality on day 1 when injected intravenously at low doses.⁹⁴ Seven compounds, 89–95, of which five were polychlorinated acetamides, were isolated from Microcoleus lyngbyaceus collected from Chuuk, Micronesia. Compound 95 was tentatively identified as an aminotridecane but the placement of the amino group could not be determined as the compound decomposed before mass spectral studies could be carried out. A positional isomer of compound 93 was synthesised in six steps from δ-decanolactone.⁹⁶

Stereoselective synthesis of an HI/JK ring model of prymnesins 1 and 2, glycosidic toxins isolated from the red tide phytoflagellate Prymnesium parvum,⁹⁷ was accomplished. Comparison of the NMR data with those of the natural toxins confirmed the original stereochemical assignments.⁹⁸ The first total synthesis of euplotin A 96, a cytotoxin of the ciliated protist Euplotes crassus⁹⁹ has been achieved. The synthetic strategy employed retro-cycloaddition reactions of readily available 5-acyl-4-alkyl-4H-1,3-dioxins.¹⁰⁰ Ostreocin D 97, a new analogue of palytoxin, was isolated from the dinoflagellate Ostreopsis siamensis. The structure was determined as 42-hydroxy-3,26-didemethyl-19,44-dideoxypalytoxin by 2D NMR analysis of ostreocin D and the ozonolysis products.¹⁰¹ 3D Fourier transform and gradient enhanced NMR spectroscopies allowed the full assignment of the ¹H and ¹³C NMR spectra of palytoxin 98 and the N-acetylpalytoxin analogue 99. Notably, the ¹⁵N NMR spectrum of N-acetylpalytoxin 99 could be assigned without ¹³C or ¹⁵N enrichment.¹⁰² The modestly cytotoxic (L1210 and KB cell lines) amphidinolides T2 100, T3 101 and T4 102, 19-membered macrolides structurally related to amphidinolide T1,¹⁰³ have been isolated from two strains of the dinoflagellate Amphidinium sp.¹⁰⁴ The absolute configurations of 100–102 and of amphidinolide T1 103 were determined by comparison of NMR spectroscopic data with those of synthetic model compounds. The biosynthetic origin of amphidinolide T1 103 was probed using singly and doubly labelled ¹³C sodium acetate and ¹³C-labelled sodium bicarbonate. Results suggested that amphidinolide T1 103 was generated through nonsuccessive mixed polyketides and that the main carbon source of amphidinolide T1 was derived from carbon dioxide. Amphidinolide T5 104 was later isolated from the same extract of Amphidinium sp., and the stereostructure of amphidinolide T1 103 was confirmed by a X-ray analysis.¹⁰⁵ The absolute stereochemistry of amphidinolide C 105, a 25-membered macrolide from Amphidinium sp.¹⁰⁶ was determined by a combination of NMR spectroscopic analyses, degradation experiments and synthesis of the C1–C7 segment.¹⁰⁷ The first total synthesis of the related 19-membered lactone amphidinolide K¹⁰⁸ has been accomplished.¹⁰⁹ The relative and absolute stereochemistry of the synthetic material 106 was confirmed by X-ray analysis, showing that 106 is the antipode of the natural product.

Spirolides A 107, C 108 and 13-desmethylspirolide C 109 were isolated from the annual accumulation of contaminated scallops and phytoplankton obtained from Nova Scotia as well as from batch cultures of the dinoflagellate Alexandrium ostefeldii, isolated from the phytoplankton assemblages. Spirolides B 110 and D 111 were previously isolated from contaminated shellfish in the same area.¹¹⁰ All of the spirolides display “fast-acting” toxicity in the traditional mouse bioassay due to the presence of a cyclic imine moiety. Spirolides containing a vicinal dimethyl group in the seven-membered ring were found to be resistant to oxalic acid hydrolysis.¹¹¹ The relative stereochemistry of 13-desmethylspirolide C 109, excepting that at one stereogenic centre, was determined from NMR data by application of the ConGen molecular modelling programme. 13-Desmethylspirolide C 109 was found to have the same stereochemistry as pinnatoxins A^112,113 and D¹¹⁴ in the regions of common structure. The relative stereochemistries of spirolides B 110 and D 111 were also partially determined by comparison of NMR data with those of 13-desmethylspirolide C 109 and further use of ConGen.¹¹⁵

Spiro-prorocentrimine 112, a novel macrocyclic lactone, was isolated from a culture of a benthic Prorocentrum sp. obtained from epiphytes of coral reef seaweeds in Taiwan. This lactone was much less toxic than other known marine cyclic imine toxins in the intraperitoneal mouse bioassay.¹¹⁶ A new ester derivative of okadaic acid, DTX-6 113 was isolated from a culture of a strain of Prorocentrum lima.¹¹⁷ A culture of the marine diatom Rhizosolenia setigera, originally collected in France, was the source of highly branched isoprenoid pentaenes and hexaenes 114–117.¹¹⁸ Two galactopyranosyldiacylglycerols 118 and 119 were isolated from a cultured strain of the marine bacillariophycean microalga Nitzschia sp.¹¹⁹

3 Green algae

The depsipeptide kahalalide F 120, isolated from the mollusc Elysia rufescens and from Bryopsis sp., the green algal food source,¹²⁰ has been synthesised.¹²¹ HPLC, NMR spectroscopic and biological activity studies indicated that the stereochemistry proposed by Scheuer et al.¹²² must be that of a less biologically active diastereomer. Four glycerol derivatives, codiosides A–D 121–124 and a new derivative of trans-phytol, codioester 125 were isolated from an Arabian Sea collection of the green alga Codium iyengarii.¹²³

4 Brown algae

The brown alga Sargassum crispum collected from the Red Sea was the source of sargassinone 126.¹²⁴ The weakly cytotoxic (to P388 cells) hedaols A–C 127–129 were isolated from the Japanese brown alga Sargassum sp., and the absolute stereochemistry of hedaol A 127 established by the modified Mosher's method.¹²⁵ A dolabellane diterpene, hydroclathrol 130, was isolated from the brown alga Hydroclathrus tenuis.¹²⁶ The first enantiospecific synthesis of (+)-cyclozonarone 131, a sesquiterpene benzoquinone from the brown alga Dictyopteris undulata, has been achieved, utilising polygodial as starting material. The absolute configuration of the naturally occurring (−)-cyclozonarone was established as (5R,10R) by comparison of optical rotation and spectral data with those of (+)-cyclozonarone.¹²⁷ Four novel acyclic diterpenes 132–135 were isolated from the brown alga Bifurcaria bifurcata collected off the Atlantic coast of Morocco.¹²⁸ Two new aurones, 4′-chloro-2-hydroxyaurone 136 and 4′-chloroaurone 137 were isolated from Spatoglossum variabile collected off Karachi, Pakistan.¹²⁹ A synthesis of (all-Z)-henicosa-1,6,9,12,15,18-hexaene 138 starting from (all-Z)-icosa-5,8,11,14,17-pentaenoic acid (EPA) has been completed.¹³⁰ Compound 138 was originally isolated from the brown alga Fucus vesiculosus.¹³¹

5 Red algae

The red alga Laurencia majuscula collected from the South China Sea was the source of two compounds, the sesquiterpene 8-bromochamigren-1-en 139 and a derivative of stigmastadiendiol 140.¹³² The first total synthesis of the L. microcladia metabolite (+)-rogioloxepane A 141,¹³³ has been accomplished.¹³⁴ A total synthesis of (±)-aplysinal 142 from Marginisporum aberrans¹³⁵ has been carried out¹³⁶ and an asymmetric total synthesis of (−)-isolaurallene 143, originally isolated from L. nipponica yamada has also been achieved.¹³⁷Laurencia pannosa from Malaysia was the source of three novel antibacterial metabolites: pannosanol 144 and pannosane 145 are halogenated sesquiterpenes with an unusual rearranged chamigrene skeleton while (3Z)-chlorofucin 146 is a halogenated C15 acetogenin.¹³⁸L. luzonensis from Okinawan waters yielded five bromosesquiterpenes, isopalisol 147, luzonensol 148, luzonensol acetate 149, luzonensin 150 and (3Z,6E)-1-bromo-2-hydroxy-3,7,11-trimethyldodeca-3,6,10-triene 151 and a new bromoditerpene 3-bromobarekoxide 152. X-Ray analysis of 152 determined that the A/B and B/C ring junctions were both trans, in contrast to the trans, cis relative stereochemistry reported for the debrominated compound barekoxide, isolated from the sponge Chelonaplysilla erecta.¹³⁹ Reductive debromination of 152 and comparison of the NMR and optical data with those reported for barekoxide, confirmed that the absolute configuration of barekoxide is correctly represented as 153.¹⁴⁰ Ma'iliohydrin 154, a cytotoxic tribrominated chamigrene was isolated from a Laurencia sp. from the Philippines. Ma'iliohydrin exhibited cytotoxicity in the NCI 60-cell line human tumour screen and displayed especially potent activity against the NCI/ADR-RES breast cancer cell line.¹⁴¹L. scoparia collected in Brazilian waters was the source of four sesquiterpenes 155–158. Scopariol 155 has a rearranged chamigrane skeleton while isorigidol 156, is a β-chamigrene, as are the geometric isomers 157 and 158.¹⁴² An X-ray crystal structure of 156 established the absolute stereochemistry as (3R,6S,9S,10S).¹⁴³ An X-ray analysis of ma'ilione 159, first isolated from L. cartilaginea¹⁴⁴ determined the absolute stereochemistry as (6S,9R,10S).^142,143 Compound 156 and ma'ilione 159 exhibited moderate in vitro anthelmintic activity against the parasitant stage of Nippostrongylus brasiliensis.¹⁴² Four squalene-derived triterpenes, martiriol 160, pseudodehydrothyrsiferol 161, dioxepandehydrothyrsiferol 162 and 16-epihydroxydehydrothyrsiferol 163 were isolated from L. viridis collected off the Canary Islands.¹⁴⁵ Calenzanol 164, a sesquiterpene with a previously unreported ring system, was obtained as the major metabolite of L. microcladia off Elba Island in the Mediterranean. Calenzanol was found to be unstable, undergoing rearrangement at 40 °C to a novel indene.¹⁴⁶ Two halogenated C15 acetogenins, lembynes A 165 and B 166 were isolated from an unrecorded species of Laurencia collected in Malaysian waters. Lembyne A 165 displayed modest antibacterial activity against a range of marine bacteria.¹⁴⁷L. mariannensis from Okinawa contained (12E)-lembyne A 167.¹⁴⁸ The halogenated sesquiterpene (6R,9R,10S)-10-bromo-9-hydroxychamigra-2,7(14)-diene 168 was isolated from L. majuscula from Okinawa and is the first report of this compound from a natural source. Both compounds 167 and 168 were active against a range of marine bacteria.¹⁴⁸ Prevezols A 169 and B 170 are brominated diterpenes isolated from L. obtusa from Greek waters.¹⁴⁹ A lanostanoid lactone, 5α-lanosta-8-en-3β,22ξ-dihydroxy-22(R),24(S)-lactone 171 was isolated from Hypnea cerricornis from the South China Sea.¹⁵⁰ The Taiwanese red alga Ceratodictyon spongiosum which contains the symbiotic sponge Sigmadocia symbiotica yielded the novel sterol n-nonadecanoic acid 24-methylenecholesteryl ester 172.¹⁵¹ Armatols A–F 173–178 are bromotriterpene polyethers isolated from an Indian Ocean collection of Chondria armata.¹⁵² A Chilean collection of Plocamium cartilagineum yielded three tetrahydrofuran derivatives, furoplocamioids A–C 179–181, which contain a chlorobromo vinyl moiety.¹⁵³P. cartilagineum from the Mediterranean was the source of four polyhalogenated homosesquiterpenic acids 182–185.¹⁵⁴ Two bromoditerpenes, sphaerolabdiene-3,14-diol 186 and bromosphaerone 187, were isolated from a collection of Sphaerococcus coronopifolius from the Atlantic coast of Morocco. Compound 187 exhibited antibacterial activity against S. aureus.¹⁵⁵

6 Sponges

Once again, sponges have provided the greatest number of new marine natural products and have attracted considerable synthetic attention. An acetylated tetrahydroxyceramide 188 was isolated from an acetylated extract of Fasciospongia cavernosa collected on the South East coast of India.¹⁵⁶ Three sulfated ceramides, calyceramides A–C 189–191 with neuraminidase inhibition activity were obtained from a Japanese collection of Discodermia calyx.¹⁵⁷ A sponge of the genus Calyx, collected in Sulawesi, Indonesia, yielded a ketosphingolipid, calyxoside 192 with DNA-damaging properties.¹⁵⁸ The keto substitution of 192 was located by reductive amination of a penta-acetate derivative and analysis of MS fragmentation, while the relative and absolute stereochemistry was proposed from CD analysis of the perbenzoyl aglycone.¹⁵⁸ Three glycosphingolipids 193–195 were obtained from Aplysinella rhax collected in New Caledonia.¹⁵⁹ A presumably new species of Haliclona from Queensland contained four unsaturated aminoalcohols 196–199 with antifungal properties.¹⁶⁰ (2S,3R,11S,12R,2‴R,11‴S,12‴R)-Plakoside A 200 was synthesised^161,162 and found to have optical rotation and spectroscopic data identical to plakoside A from Plakortis simplex.¹⁶³ The spectroscopic data were also identical to the previously synthesised (2S,3R,11R,12S,2‴R,11‴R,12‴S) diastereomer 201; the absolute stereochemistry of the cyclopropyl groups remains unknown.

Three furan-containing fatty acid derivatives, plakorsins A–C 202–204, and an epoxide, plakortic acid 205 were isolated from Taiwanese P. simplex specimens.¹⁶⁴ The sponge Spirastrella abata collected from Korean waters yielded four phosphatidylcholines 206–209 of which 208 and 209 showed an inhibitory effect on the biosynthesis of cholesterol.¹⁶⁵Callyspongia fallax collected in the Caribbean was found to contain the methoxylated acids 210–215.¹⁶⁶ Two antimicrobial lysoplasmanylinositols 216–217 were isolated from a Japanese Theonella swinhoei.¹⁶⁷ (−)-Halicholactone 218 from Halichondria okadai¹⁶⁸ was synthesised stereoselectively using chiral (diene)Fe(CO)₃ complexes.¹⁶⁹ Three dithiocyanates, thiocyanatins A 219, B 220, and C 221, were isolated from an Oceanapia species collected from South West Australia. These compounds have nematocidal activity and their structures were confirmed by synthesis.¹⁷⁰Acarnus bicladotylota collected from the South West coast of India yielded the acetylenic cycloperoxides, peroxyacarnoic acids C 222 and D 223 which were isolated as their methyl esters.¹⁷¹ A further series of cytotoxic polyacetylenic alcohols 224–236, have been isolated from a Korean Petrosia species that has previously yielded similar compounds.^172,173 The absolute stereochemistry of (−)-adociacetylene B 237 from Adocia sp.¹⁷⁴ was confirmed from a synthesis of both (+) and (−)-isomers employing enzymatic resolution.¹⁷⁵

The amphiasterins A1–4 238–241, B1–5 242–246, C1–4 247–250, D1–3 251–253 and E1 254 have been isolated from Plakortis quasiamphiaster collected in Vanuatu.¹⁷⁶ The magnesium salt of the previously reported ancorinoside A, isolated from an Ancorina species, has been reported as a new compound.¹⁷⁷ Three ancorinosides, B 255, C 256 and D 257, isolated from a Japanese collection of Penares sollasi, were found to be inhibitors of membrane type 1 matrix metalloproteinase.¹⁷⁸ The moderately antifungal plakinic acid F 258 and epiplakinic acid F 259 together with plakortolide F 260 were obtained from a Plakinastrella species collected in the Seychelles.¹⁷⁹ The name plakortolide F was also given to a different peroxide lactone 261 which was isolated along with plakortolide G 262 from a Jamaican Plakinastrella onkodes collection. The absolute stereochemistry of 262 was proposed from a combination of optical rotation and molecular modelling data.¹⁸⁰ The cytotoxic methyl capucinoate A 263 and the related compound 264 were isolated from a Dominican collection of P. onkodes;¹⁸¹ a structure with the same gross connectivity was reported earlier at a conference.¹⁸² In the same paper the isolation of glánvillic acid A 265 and B 266 from a Dominican Plakortis halichondrioides was also reported. The compounds were separated and characterised as the methyl esters.¹⁸¹ An Okinawan specimen of P. lita yielded two further cyclic peroxide acids, the haterumadioxins A 267 and B 268 with moderate cytotoxicity.¹⁸³ Four further plakortides, I–L 269–272 were reported from an undescribed species of Plakortis collected in Jamaica.¹⁸⁴ A γ-lactone, plakortone G 273, mildly active against Plasmodium falciparum, was isolated from an apparently different undescribed Jamaican Plakortis species.¹⁸⁵

The absolute stereochemistries of the salicylihalamides A 274 and B 275 from Haliclona sp.¹⁸⁶ have been revised following a re-interpretation of Mosher ester derivatives¹⁸⁷ and enantioselective syntheses of both enantiomers of each.^188–190 Two hydroxypyranones tetillapyrone 276 and nortetillapyrone 277 were obtained from the Thai sponge Tetilla japonica.¹⁹¹ Onnamide F 278, isolated from the South Australian sponge Trachycladus laevispirulifer, was found to be a potent nematocide.¹⁹² A further six bengamides 279–284 with varying in vitro antitumour activity were obtained from Fijian collections of Japsis cf. coriacea.¹⁹³

A Vanuatuan specimen of the genus Spongia was found to contain a cytotoxic macrolide spongidepsin 285,¹⁹⁴ while the cytotoxic macrolide, dactylolide 286, was found in a Vanuatuan sponge of the genus Dactylospongia.¹⁹⁵ The enantioselective synthesis of (+)-zampanolide¹⁹⁶ has established the absolute and relative stereochemistry of the (−)-antipode 287 isolated from Fasciospongia rimosa.¹⁹⁷ Three further, potently cytotoxic, chondropsin macrolide lactams were reported from three different sponges: 73-deoxychondropsin A 288 was isolated from an Australian Ircinia ramosa, chondropsin C 289 was found in a Philippine Ircinia species,¹⁹⁸ while an Australian Chondropsis species yielded chondropsin D 290.¹⁹⁹ A Vanuatuan specimen of the genus Haliclona was found to contain the in vitro antitumour macrolide haliclamide 291.²⁰⁰

The weakly cytotoxic heptapeptide, wainunuamide 292 was isolated from Stylotella aurantium collected in Fiji.²⁰¹ The total synthesis of cis,cis-ceratospongamide 293 from the red alga Ceratodictyon spongiosum and symbiotic sponge Sigmadocia symbiotica²⁰² has been reported.²⁰³ Hymenamide C 294 from Hymeniacidon sp.²⁰⁴ has been synthesised using solid support methodology.²⁰⁵ A total synthesis of phakellistatin 11 295, isolated from Phakellia sp.,²⁰⁶ revealed that the synthetic product is much less cytotoxic than the originally isolated sample.²⁰⁷ A collection of Sidonops microspinosa from Sulawesi, Indonesia was found to contain the HIV-inhibitory depsipeptide microspinosamide 296.²⁰⁸ The structures of two potent anti-inflammatory peptides, halipeptin A 297 and B 298, isolated from a member of the genus Haliclona from Vanuatu, were proposed from an analysis of spectroscopic data.²⁰⁹ Two iron-chelating peptides, haliclonamide A and B, isolated from a Haliclona species collected in Palau were proposed to have structures 299 and 300 respectively on the basis of spectroscopic analysis.²¹⁰

A potent, neurologically-active amino acid, neodysiherbaine A 301 has been reported as a minor metabolite of a Micronesian Dysidea herbacea. The relative and absolute stereochemistries were determined by asymmetric total synthesis.²¹¹ The enantioselective synthesis of both (+)- and (−)-dysibetaine 302, isolated from D. herbacea,²¹² has established the absolute configuration as (S,S).²¹³ Two polychlorinated thiazoles 303 and 304 were isolated from Queensland specimens of D. herbacea.²¹⁴ From the same collection, several polychlorinated dipeptides 305–309 were reported separately; the absolute stereochemistries were determined by comparison of optical rotation data.²¹⁵ The methyl esters 305–307 are considered to be artifacts of methanolic extraction. An undescribed species of Dysidea collected in the Philippines yielded the proline-derived dysideaprolines A–F 310–315 together with the enol-ether containing barbaleucamides A 316 and B 317.²¹⁶

Two antifungal bromopyrroles, 3-bromomaleimide 318 and 3,4-dibromomaleimide 319, were found in Axinella brevistyla collected in Japan.²¹⁷ (−)-Haliclorensin, isolated from Haliclona tulearensis,²¹⁸ and assigned the structure 320, was synthesised by two independent groups and found to be spectroscopically non-identical with the natural product.^219,220 Subsequently, a re-isolation and re-investigation of the spectroscopic data led to a revised structure 321 that was confirmed by enantioselective synthesis of both enantiomers.²²¹ Both enantiomers of stellettadine A 322 from Stelletta sp.²²² were synthesised from (S)- and (R)-citronellal.^223,224 The (S) isomer was found to have a negative rotation similar to the natural compound which had previously been assigned as (R).²²³ (−)-Stellattamide B, originally reported from a Stelletta sp. with a (6″S) configuration,²²⁵ has now been established as (1S,4S,8aR,6″R) 323 by total synthesis.²²⁶ (+)-Batzelladine F, originally isolated from Batzella sp.,²²⁷ recently re-assigned as Monanchora arbuscula,²²⁸ was originally assigned structure 324. The structure has been revised to 325 on the basis of the enantioselective synthesis of both the revised and putative structures.²²⁹ Mirabilin G 326 was isolated from a South Australian Clathria species.²³⁰ The Palauan sponge Protophlitaspongia aga yielded 3,4,5,6-tetrahydro-6-hydroxymethyl-3,6,dimethylpyrimidine-4-carboxylic acid 327 that was found to inhibit the settling of larvae of the barnacle Balanus amphitrite.²³¹ The wondonins A 328 and B 329 were isolated from an association of Poecillastra wondoensis and a Japsis species from Korea.²³² Naamine B 330 from Leucetta chagosensis²³³ has been synthesised.²³⁴

Hyrtios erecta collected in Okinawa yielded two selective inhibitors of neuronal nitric oxide synthase 331 and 332.²³⁵ An asymmetric synthesis of (+)-chelonin B 333 from Chelonaplysilla sp.²³⁶ employing a Sharpless asymmetric dihydroxylation established the stereogenic centre as (S).²³⁷ The synthesis of the (−)-enantiomer of (+)-hamacanthin A 334 isolated from Hamacantha sp.²³⁸ established the stereogenic centre as (S).²³⁹ Xestomanzamine B 335 from Xestospongia sp.²⁴⁰ was synthesised via a Pictet–Spengler condensation of tryptamine with a vicinal tricarbonyl substituted imidazole.²⁴¹ A manzamine dimer, neo-kauluamine 336, was isolated from an undescribed genus of the family Petrosiidae collected from Sulawesi, Indonesia along with the antipodes of 8-hydroxymanzamine 337 and manzamine F 338. These antipodes were found to have potent in vivo activity against Plasmodium berghei.²⁴² The manzamines have been isolated from a variety of sponge genera from various orders. The authors speculate that some of these sponges may be members of this new genus of the Petrosiidae family.²⁴²

A revised structure 339 for pyrinodemin A 340 from Amphimedon sp.²⁴³ has been proposed from spectral comparison of the natural product to the synthesised structures.²⁴⁴ Pyrinodemin B 341 from the same sponge²⁴⁵ was also synthesised.²⁴⁴ Variolin B 342 from Kirkpatrickia varialosa²⁴⁶ was synthesised via a tandem deoxygenation and cyclisation of a triarylmethanol intermediate.²⁴⁷ Two bromoquinolones 343 and 344 were isolated from Okinawan specimens of Hyrtios erecta: 343 is a known synthetic compound.²³⁵ A Haliclona species from the Philippines contained 1-hydroxymethyl-7-methoxyisoquinolin-6-ol 345.²⁴⁸ The structure of renieramycin H, previously described from Haliclona cribricutis as 346²⁴⁹ has been re-assigned as 347 on the basis of spectral comparison to synthetic model compounds.²⁵⁰ Subsequently, it was found that this structure was assigned to cribrostatin 4 on the basis of X-ray analysis.²⁵¹ The NMR spectra of the two compounds were found to be identical, and accordingly, the trivial name renieramycin H must be given to this structure. Makaluvamine P 348, with cytotoxic and antioxidant activity, was isolated from the Vanuatuan sponge Zyzzya cf. fuliginosa.²⁵² Two Xestospongia species collected in Palau and the Philippines contained the DNA-cleaving agent deoxyamphimedine 349.²⁵³

The absolute stereochemistry of (R)-(−)-axinellamine A 350, isolated from Axinella sp.²⁵⁴ was determined by synthesis of the (S)-isomer.²⁵⁵ The enantiomers of (+)-slagenin B 351 and (−)-slagenin C 352 from Agelas nakamurai²⁵⁶ were synthesised stereospecifically, establishing the absolute stereochemistry as (9R,11R,15R) and (9R,11S,15S) respectively.²⁵⁷ A total synthesis of phorbazole C 353 from Phorbas aff. clathrata²⁵⁸ was achieved with the central oxazole ring formed by cyclodehydration of an acylaminoketone.²⁵⁹ The N-methyloroidin derivative, sventrin 354, reported from the Bahaman sponge Agelas sventres, was found to be a feeding deterrent to the reef fish Thalassoma bifasciatum.²⁶⁰Axinella carteri from the Philippines afforded ugibohlin 355, a dibromopyrrole derivative.²⁶¹A. brevistyla from Japan was found to contain 12-chloro-11-hydroxyldibromoisophakellin 356 and N-methylmanzacidin C 357. Both displayed antifungal and cytotoxic activity.²¹⁷N-Methyldibromoisophakellin 358, isolated from the Bahaman sponge Stylissa caribica, was found to inhibit the feeding of the reef fish T. bifasciatum.²⁶²

The weakly cytotoxic methoxypurine, mucronatine 359, was isolated from the French Mediterranean sponge Stryphnus mucronatus.²⁶³Zyzzya fuliginosa from the Philippines afforded 3,7-dimethylguanine 360.²⁶⁴ A weak inhibitor of CDC2 kinase, microxine 361, a taurine-bearing purine derivative, was isolated from an Australian Microxina species.²⁶⁵

Purealidin N 362 from Psammaplysilla purea²⁶⁶ was synthesised with the oxime formed from addition of hydroxylamine chloride to a silyl-enol ether.²⁶⁷ Inhibitors of the novel mycobacterial enzyme mycothiol S-conjugate amidase, the bromotyrosine-derived alkaloids 363 and 364, were isolated from an Australian Oceanapia species; the absolute stereochemistry of 363 was determined by comparison of the optical rotation to similar compounds.²⁶⁸Pseudoceratina purpurea collected in Okinawa contained zamamistatin 365, a growth inhibitor of the adherent bacterium Rhodospirillum salexigens. The absolute stereochemistry was determined by analysis of the Mosher's acid derivatives.²⁶⁹ Aplyzanzine A 366 was reported from an Aplysina species collected near Zanzibar.²⁷⁰ A Suberea species from Okinawa yielded the cytotoxic suberedamines A 367 and B 368. Chemical degradation to (S)-tyrosine allowed assignment of the absolute configurations.²⁷¹ Archerine 369, isolated from the Caribbean sponge Aplysina archeri, displayed antihistamine activity in isolated guinea pig ileum.²⁷² The tokaradines A 370, B 371 and C 372, isolated from Pseudoceratina purpurea collected in southern Japan, were found to be toxic to the crab Hemigrapsus sanguineus.²⁷³Suberea aff. praetensa, collected in Thailand, yielded 11,17-dideoxyagelorin A 373 and B 374.²⁷⁴

Four polybrominated phenols 375–378 were isolated from Phyllospongia dendyi collected in Palau. These compounds were found to be toxic to a variety of micro- and macro-algae.²⁷⁵Dysidea dendyi collected from the North West coast of Australia yielded two tetrabrominated dibenzo-p-dioxins, spongiadioxins A 379 and B 380.²⁷⁶ Iantheran B 381, isolated from an Ianthella species collected from the Great Barrier Reef, Australia was found to be a Na/K-ATPase inhibitor.²⁷⁷

The merosesquiterpenoids hippochromin A 382 and B 383 were isolated as acetates from a Taiwanese specimen of Hippospongia metachromia.²⁷⁸ Two rearranged merosesquiterpenoids dysidenone A 384 and B 385 and the related selective PLA₂ inhibitor, dysidine 386 were isolated from a sponge of the genus Dysidea collected in Vanuatu.²⁷⁹ Dactyloquinones A 387 and B 388 were reported from a Dactylospongia elegans specimen collected in Okinawa.²⁸⁰ Smenospondiol 389 from a Smenospongia sp.,²⁸¹ also known as dictyoceratin A from Hippospongia sp.²⁸² was synthesised by titanium-mediated tandem radical cyclisation as a racemic mixture.²⁸³ Two racemic and one asymmetric syntheses were reported for (+)-frondosin B 390, isolated from Dysidea frondosa,²⁸⁴ establishing the configuration of the stereogenic centre as (R).²⁸⁵ A diterpene-4-hydroxybenzoic acid derivative, subersic acid 391, with human lipoxygenase inhibitory activity was isolated from a Papua New Guinean Suberea species together with a diterpene described below.²⁸⁶ The hipposulfates A 392 and B 393, isolated from an Okinawan Hippospongia cf. metachromia, were found to have moderate cytotoxicity.²⁸⁷ The New Caledonian sponge Coscinoderma mathewsi afforded the CDC25 phosphatase inhibitor (+)-coscinosulfate 394 along with an unnamed congener 395.²⁸⁸ The relative and absolute stereochemistry of 394 was confirmed by total asymmetric synthesis.²⁸⁹ Interestingly, halisulfate 1, previously isolated from a Halichondria sp.,²⁹⁰ was reported with the same relative stereochemistry. Halisulfate 1 has a reported optical rotation of −27.3° while that of coscinosulfate is +5°; differences in ¹H–¹H coupling constants near the sulfate groups were noted,²⁸⁸ but unfortunately the NMR solvent used was different in the two studies.

The sesquiterpenoid furodysin lactone 396 and a related amino acid derivative, pyrodysinoic acid 397, were obtained from a blue/grey encrusting member of the genus Dysidea collected from the Philippines.²⁹¹ A specimen of Dysidea herbacea collected from Lizard Island, Australia was found to contain 6-hydroxyfurodysinin 398.²¹⁴ Three carbonimidic dichlorides, 399–401, and two related α,β-unsaturated aldehydes 402 and 403, were isolated from Stylotella aurantium collected from Okinawan waters.²⁹² The North Queensland sponge Ulosa spongia also contained 401 along with the related diol 404.²⁹³ Two enantiomeric syntheses of (+)-kelsoene 405 from Cymbastela hooperi²⁹⁴ have established the absolute stereochemistry.^295,296

Three weakly cytotoxic C19 norditerpene peroxides, aikupikoxides B 406, C 407, and D 408 were isolated from Diacarnus erythraenus collected from the Red Sea along with a related norsesterterpenoid discussed below.²⁹⁷ The hamigerans 409–412, isolated from Hamigera tarangaensis²⁹⁸ were synthesised via an intramolecular Diels–Alder trapping of a photochemically generated hydroxy-o-quinodimethane.²⁹⁹ (+)-Subersin 413 was isolated from a Papua New Guinean Suberea species.²⁸⁶ The absolute stereochemistry was proposed by comparison of its optical rotation to that of a similar structure. The structure of cacospongin A, isolated from a Philippine sponge of the genus Cacospongia, has been re-assigned to the same diterpene skeleton with no stereochemistry specified.³⁰⁰ The ¹³C and ¹H NMR data are identical to that of 413 but the sign of the optical rotation is opposite, suggesting an enantiomeric relationship. Spongia zimocca subspecies irregularia from China yielded the norditerpenoid zimoclactone B 414 and the diterpenoid zimoclactone C 415.³⁰¹ A South Australian species of Phorbas yielded phorbasin B 416 and its acetate, phorbasin C 417.³⁰² A quite remarkable cumulated ketene containing compound, irciniketene 418 with moderate cytotoxicity, has been reported from Ircinia selaginea collected in Guangxi Province, China.³⁰³ A Cacospongia species collected in Okinawa contained (−)-cacofuran A 419 and the acetate, cacofuran B 420. The absolute stereochemistry was determined from an analysis of the MPTA esters of 419 and by X-ray analysis.³⁰⁴ It was noted that both compounds inhibited the development of fertilised sea urchin eggs. The tricarbocyclic epipolone 421 and epipolol 422 were obtained from Epipolasis reiswigi collected in Puerto Rico.³⁰⁵

The C21 norsesterterpenoid originally reported with conjugated double bonds 423³⁰⁶ has been revised to 424 on the basis of more complete spectroscopic data obtained from a sample isolated from an Australian specimen of Spirastrella papilosa.³⁰⁷ The absolute stereochemistry was determined by degradation and the name (−)-isotetrahydrofurospongin-1 is proposed for this bisfuranoterpene. Two unusual trisnorsesterterpenoid lactams, the sarcotragins A 425 and B 426 were isolated from a Sarcotragus species from Jaeju Island in Korean waters.³⁰⁸ Five cytotoxic furanosesterterpenoids, the sacotins A–E, 427–431 were reported from a different specimen of Sarcotragus sp. collected at Cheju Island, Korea.³⁰⁹ The absolute stereochemistries of 429–431 were determined by comparison of CD spectra. The Red Sea sponge Diacarnus erythraenus was found to contain the antiviral and cytotoxic C24 norsesterterpenoid muqubilone (aikupikoxide) 432 by two independent groups.^310,297 (−)-Idiadione 433 from Spongia idia³¹¹ was synthesised from (−)-citronellal, establishing the stereogenic centre as (S).³¹² A Palauan species of Thorectandra yielded the cytotoxic thorectandrols A 434 and B 435.³¹³ The cytotoxic kohamaic acids A 436 and B 437 were isolated from an Ircinia species from Okinawa.³¹⁴ Three tricarbocyclic sesterterpenoids 438–440 of the cheilanthane class isolated from a Queensland Ircinia sp. were found to be inhibitors of MSK1 and MAPKAPK-2 protein kinases.³¹⁵ Five inhibitors of in vitro HIV-1 envelope-mediated fusion, the phyllolactones A–E 441–445, were obtained from specimens of Phyllospongia lamellosa.³¹⁶

An undescribed species of Gellius from the Caribbean coast of Panama yielded four acetylenic sterols, gelliusterol A–D 446–449; gelliusterols A, B and C were found to be moderately cytotoxic.³¹⁷ Stigmast-5-en-7-on-3β-ol 450 was obtained from Polymastia sobustia from the South China Sea.³¹⁸ A cytotoxic and apoptosis-inducing rearranged sterol, orostanal 451 was obtained from Stelletta hiwasaensis collected in Japan.³¹⁹ The 6–5–6–5 fused ring system has only been found previously in the terrestrial plant Taiwania cryptomeriodes;³²⁰ the absolute stereochemistry of 451 was established from analysis of the CD spectrum. A South China Sea specimen of Geodia japonica yielded 26-methylergosta-5,24(28)-dien-3β-ol 452 along with several nortriterpenoids discussed below.³²¹ Two steroidal alkaloids, plakinamine E 453 and F 454 exhibiting moderate cytotoxicity, antifungal activity and nucleic acid-cleaving properties, were isolated from an undescribed species of Corticium collected at Guam.³²² A sulfated sterol ester, clathsterol 455 with anti-HIV-1 reverse transcriptase activity was obtained from an Eritrean sponge of the genus Clathria.³²³ Two phosphorylated sterol sulfates isolated from a Japanese Cribrochalina species are inhibitors of membrane-type matrix metalloproteinase.³²⁴ The structures were assigned as 456 and 457. However, 456 was found to be identical to haplosamate A 458 previously isolated from two haplosclerid sponges from the Phillipines,³²⁵ requiring a structural revision of 458 to 456 and for assignment of haplosamate B as 459. The absolute stereochemistry of 456 was determined by Mosher's method. A Philippine sponge of the genus Xestospongia contained two sulfated sterols, ibisterol B 460 and C 461 and an epoxysteroid 462 that were found to be inhibitors of HIV-1 integrase.³²⁶ (+)-Agosterol A 463 from Spongia sp.³²⁷ was synthesised from ergosterol.³²⁸ The unusual 15-keto steroid, xestobergsterol 464 from Xestospongia bergquisti³²⁹ has been synthesised from stigmasterol.³³⁰

Two nortriterpenes of the isomalabaricane class, geoditins A 465 and B 466 were isolated from Geodia japonica from the South China Sea.³²¹ A Japsis species collected near Tonga yielded three cytotoxic isomalabaricanes, 29-hydroxystelliferin E 467, 29-hydroxystelliferin A 468 and stelliferin G 469.³³¹ The glycosylated triterpenoid, stelliferin riboside 470, was obtained from a Fijian collection of G. globostellifera.³³² In an extensive re-investigation of two populations of the Red Sea Sponge Siphonochalina siphonella, sipholenols G 471, F 472 and H 473, sipholenone D 474, sipholenoside A 475 and B 476, siphonellinol B 477, neviotine B 478 and dahabinone A 479 were isolated.³³³ The relative concentrations of these and previously described triterpenoids were compared between the two populations. An N-acetyl aminoglycoside, formoside B 480, isolated from the Caribbean sponge Erylus formosus was found to be an anti-feedant against the ecologically relevant reef fish Thalassoma bifasciatum.³³⁴ The moderately cytotoxic N-acetyl aminoglycosides, erylosides G–J 481–484 were obtained from Korean specimens of Erylus nobilis.³³⁵ A Caribbean sponge, Ectyoplasia ferox, afforded the norlanostane glycosides feroxosides A 485 and B 486.³³⁶ A bacteriohopanoid, (32R,33S,34S)-32,35-anhydrobacteriohopanetetrol 487 was isolated in significant quantities (0.2% dry weight) from the Bahaman sponge Plakortis simplex.³³⁷ A compound having the structure proposed for hippospongic acid A 488, isolated from Hippospongia sp.,³³⁸ was synthesised by two independent groups.^339,340 It was noted, however, that the spectral details of the synthetic product did not match the natural compound, and a revised structure for (+)-hippospongic acid A 489 was proposed and confirmed by enantioselective total synthesis.³³⁹

A Caribbean collection of P. simplex contained the heptaisoprenylhexasaccharide, plaxyloside 490. Isolation and structural elucidation were performed on the peracetate.³⁴¹

7 Coelenterates

The chemistry of the coelenterates continues to be predominantly terpenoid or steroid in nature. The structure and absolute stereochemistry of eunicenone A 491, a tetraprenylated cyclohexenone metabolite isolated from the gorgonian Eunicea sp.,³⁴² has been confirmed by total synthesis.³⁴³ In two separate accounts, eight briarane skeleton diterpenoids briaexcavatolides K–N 492–495³⁴⁴ and O–R 496–499³⁴⁵ were isolated from the gorgonian Briareum excavatum. Relative stereochemistry was secured by X-ray analysis for 492, 496 and 497. In a separate study, the same organism contained the diterpenes, briantheins A–C 500–502.³⁴⁶ The relative stereochemistry of 500 was established by NOESY NMR experiments and the preparation of MTPA esters helped establish the absolute stereochemistry. Brianthein A 500 reversed MDR in a human carcinoma cell line. A Western Pacific collection of the gorgonian B. stechei contained eleven briarane diterpenes, the milolides 503–513 and several known metabolites.³⁴⁷ A consequence of the NMR assignments of 503–513 was the revision of the relative stereochemistry of solenolide C 514,³⁴⁸ also isolated from the organism. New examples of xenicane diterpenes acalycixeniolides H–L 515–519, were isolated as cytotoxic components of the gorgonian Acalycigorgia inermis.³⁴⁹ The mildly cytotoxic acyclic sesquiterpenes and norsesquiterpenes 520–526 were isolated from the Caribbean gorgonian Plexaurella grisea.³⁵⁰ The structure and absolute stereochemistry of (−)-astrogorgiadiol 527, isolated from the gorgonian Astrogorgia sp.,³⁵¹ has been secured by total synthesis.³⁵² Thirteen polyoxygenated sterols 528–540 were isolated from an Indonesian collection of the gorgonian Isis hippuris.³⁵³ Of the compounds tested, spiroketal-containing sterol 528 exhibited the most potent cytotoxicity. A Taiwanese collection of I. hippuris contained two polyhydroxylated sterols isihippurols A 541 and B 542, as well as nine known sterols.³⁵⁴ The gorgonian Euplexaura anastomosans contained two farnesylhydroquinone derivatives euplexides F 543 and G 544.³⁵⁵ Both metabolites exhibited mild cytotoxicity and inhibited PLA₂. Two antimycobacterial diterpenes and a bisditerpenoid 545–547 were isolated from the sea whip Pseudopterogorgia elisabethae.³⁵⁶ A racemic synthesis of colombiasin A 548, also isolated from P. elisabethae,³⁵⁷ has been reported.³⁵⁸ An Indian Ocean collection of the gorgonian Pseudopterogorgia sp. contained the antibacterial ceramide derivative 549.³⁵⁹ The structure reported for the antimycobacterial diterpene pseudopteroxazole 550³⁶⁰ and its C-1 diastereomer 551 have been synthesised but neither have the same spectroscopic data as the natural product.³⁶¹ The revised structure of pseudopteroxazole was proposed to be 552. Examination of the Caribbean gorgonian Eunicea sp.³⁶² afforded two cembrane glycosides, calyculaglycosides D 553 and E 554, and the (+)-antipode of the known cembrane nephthenol 555.³⁶³ Chemical conversions and closer comparison with the spectroscopic data observed for 553 and 554 required revision of the previously published structures of calyculaglycosides A–C³⁶⁴ to 556–558. The Caribbean gorgonian Plexaurella grisea contained six sterols 559–564 and several known compounds.³⁶⁵ Many of the sterols exhibited in vitro antitumour activity towards the HT-29 cell-line. A mildly cytotoxic sesquiterpene, junceol A 565, was isolated from the sea pen Virgularia juncea.³⁶⁶ Briarane skeleton terpenoids, cavernulin A 566 and B 567 were isolated from a Cavernularia sp.³⁶⁷ A metabolite containing an aromadendrane-type skeleton, 3-acetoxyspathulenol 568, was isolated from the soft coral Parerythropodium fulvum.³⁶⁸ Paesslerins A 569 and B 570, the first examples of metabolites containing the 2,8,8,10-tetramethyltricyclo[4.3.2.0^2,5]undecane (paesslerane) skeleton, were isolated from a South Georgia Island collection of the pink soft coral Alcyonium paessleri.³⁶⁹ The structure of the cytotoxic sterol 571, isolated from A. patagonicum,³⁷⁰ has been confirmed by total synthesis.³⁷¹ The diterpenes pachyclavulariaenones A–C 572–574 were isolated from the soft coral Pachyclavularia violacea.³⁷² The structure and relative stereochemistry of 574 was confirmed by X-ray analysis. Seven diterpenes, pachyclavulariolides G–L 575–580, and secopachyclavulariaenone A 581, and the two known analogues pachyclavulariolide 582³⁷³ and pachyclavulariolide E 583³⁷⁴ were also reported from P. violacea.³⁷⁵ The structures of 575, 576, 582 and 583 were secured by X-ray analysis. Several accounts of the total synthesis of the revised structure of sclerophytin A 584,^376,377 cladiell-11-ene-3,6,7-triol 585³⁷⁸ and 6-acetoxycladiell-7(16),11-dien-3-ol 586³⁷⁹ have been reported.^380–382 Two diterpenes caribaeorane 587 and 15-hydroxycaribaeorane 588 were isolated from the soft coral Erythropodium caribaeorum as their C-4 methylketals 589 and 590.³⁸³ The observation of facile ketal formation suggests that the C-4 methylketal contained in the antimitotic drug lead eleutherobin 591³⁸⁴ is an artifact of isolation. In addition to three known diterpenes that included 2-hydroxynephthenol 592,³⁸⁵ three norditerpenes, chabrolols A–C 593–595 were isolated from the soft coral Nephthea chabroli.³⁸⁶ X-Ray analysis of 592–595 secured the respective relative stereochemistries. Six dolabellane diterpenes 596–601 have been isolated as the cytotoxic components of the Formosan soft coral Clavularia inflata.³⁸⁷ An Okinawan collection of C. viridis contained three chlorinated steroids, yonarasterols G, H, and I 602–604.³⁸⁸ The absolute stereochemistry of 603 was equated with the stereochemically-defined analogue stoloniferone-c³⁸⁹ by chemical conversion. In a separate study, five halogenated prostanoids 605–609 were obtained from C. viridis.³⁹⁰ Absolute stereochemistries were assigned based upon chemical conversion and the modified Mosher's method for 605 and by subsequent comparison of CD data for 606–609. Eight sesquiterpenes, tubipolides A–G 610–616 and tubiporone 617 were isolated as mildly cytotoxic components of the Formosan stolonifer Tubipora musica.³⁹¹ Specimens of the soft coral Cladiella sp. collected from Andaman and Nicobar Islands contained the sterol 618 and glycolipid 619,³⁹² while an Andaman Island collection of the same genus contained a mixture of cerebroside homologues 620.³⁹³ The soft coral Sinularia dissecta yielded the sesquiterpene 621.³⁹⁴ Absolute stereochemistry of 621 was deduced from interpretation of CD data and by preparation of MTPA esters. The soft corals Sarcophyton trocheliophorum and Lithophyton arboreum, collected in the Red Sea, contained six novel fatty acid derivatives 622–627.³⁹⁵ The structure and absolute stereochemistry of (−)-13-hydroxy-11,12-epoxyneocembrene 628, also isolated from S. trocheliophorum,³⁹⁶ has been secured by total synthesis.³⁹⁷ The soft coral S. molle contained the known diterpene lactone sarcophinone 629³⁹⁸ and the new diastereomer isosarcophinone 630.³⁹⁹ Both compounds exhibited in vitro antitumour activity. Two cembrene alcohols, one new, acutanol 631 and one known, sarcophytol A 632,⁴⁰⁰ have been reported from the soft coral S. acutangulum.⁴⁰¹ The absolute configuration of 632 was confirmed by the preparation of the NMA ester. A polyhydroxylated sterol sardisterol 633 was isolated from the soft coral S. digitatum.⁴⁰² The structure and absolute configuration of stolonidiol 634, isolated from the soft coral Clavularia sp.,⁴⁰³ was established by total synthesis.⁴⁰⁴ Pyridinium alkaloids are predominantly the preserve of sponges. However, a new pyridinium alkaloid, montipyridine 635, has been reported from the stony coral Montipora sp.⁴⁰⁵ Also isolated from the same genus were a range of cytotoxic diacetylenes 636–645.⁴⁰⁶ Absence of optical activity for 641–643 and the formation of diastereomeric mixtures of MTPA esters suggested that 641–643 were isolated as racemic mixtures. A crystal structure to 1.9 Å resolution was reported for the pore-forming toxin equinatoxin II (EqtII) purified from the sea anemone Actinia equina.⁴⁰⁷ Two polypeptide toxins, RSAP I and II, of molecular masses 5008 and 4992 Da respectively, have been purified from the sea anemone Actinia ceri.⁴⁰⁸

8 Bryozoans

Despite their history of yielding novel natural products, there continues to be very little new work reported on bryozoan metabolites, although some syntheses have been carried out. Total syntheses of the Flustra foliacea metabolites flustramine A 646⁴⁰⁹ and flustramides A 647⁴¹⁰ and B 648⁴¹¹ have been accomplished⁴¹² and the first synthesis of (−)-debromoflustramine B 649, also from F. foliacea,⁴¹³ has been achieved.⁴¹⁴

9 Molluscs

The relative and absolute stereochemistry of (−)-membrenone C 650, isolated from Pleurobranchus membranaceus,⁴¹⁵ has been secured by synthesis.⁴¹⁶ Several accounts of stereoselective syntheses of (+)-testudinariols A 651 and B 652, ichthyotoxic metabolites from P. testudinarius,⁴¹⁷ have been reported.^418–420 Aplydactone 653, a structurally unprecedented sesquiterpene was isolated from the sea hare Aplysia dactylomela.⁴²¹ The absolute stereochemistry of the metabolite was established by X-ray analysis. The complete ¹H and ¹³C NMR assignments of the A. dactylomela metabolites johnstonol 654, pacifenediol 655, pacifidiene 656, and pacifenol 657 have been reported.⁴²² Two tryptophan-derived dipeptides 658 and 659 were isolated from a New Zealand collection of the sea hare A. dactylomela.⁴²³ The absolute stereochemistry of 658 was determined by synthesis of deoxo-diastereomers and comparison of CD spectra. A novel glycosphingolipid, EGL-II 660 has been isolated from eggs of the sea hare A. kurodai.⁴²⁴ The stereochemistry of (−)-aplyolide A 661, an ichthyotoxic metabolite from A. depilans,⁴²⁵ has been confirmed by synthesis.⁴²⁶ A Japanese collection of the sea hare Dolabella auricularia contained auriculol 662, a novel cytotoxic squalene metabolite.⁴²⁷ The structure and absolute stereochemistry was confirmed by synthesis. Fourteen drimane sesquiterpenes, dendocarbins A–N 663–676 were isolated from the nudibranch Dendrodoris carbunculosa.⁴²⁸ The ethoxy groups present in 671, 672 and 673 suggest that these compounds are probably artifacts of the use of ethanol to extract the organism. Compound 672 exhibited cytotoxicity towards MDR tumour cell lines. The relative and absolute stereochemistry of (+)-shahamin K 677, which was isolated from Chromodoris gleniei,⁴²⁹ has been confirmed by synthesis.⁴³⁰ Nine metabolites 678–686 were identified in chemical studies of the South African nudibranch Leminda millecra.⁴³¹ GC-MS analysis of potential octacoral prey species identified two likely dietary sources for some of the metabolites, including 679. Attenols A 687 and B 688, cytotoxic spiro-acetals isolated from the Chinese bivalve Pinna attenuata,⁴³² have been synthesised enantioselectively.⁴³³ A novel shellfish-derived chlorosulfolipid toxin 689 was isolated from Mytilus galloprovincialis.⁴³⁴ The absolute stereochemistry of 689 was determined by a combination of molecular modelling and Mosher's methodology. From the digestive glands of the same species were isolated three bioactive alkaloids, oxazinins 1–3 690–692.⁴³⁵ The absolute stereochemistry of oxazinin-1 690 was subsequently secured by derivatisation and NMR analysis.⁴³⁶ Pinnatoxins B 693 and C 694, isolated from the Okinawan bivalve Pinna muricata, are the most active members of the pinnatoxin family of marine toxins.⁴³⁷ The LD₉₉ of the isolated 1 : 1 mixture of 693 and 694 was 22 µg kg⁻¹. By chemical transformations, the absolute stereochemistries of 693 and 694 were equated to the synthetically defined absolute stereochemistry of pinnatoxin A.⁴³⁸ The structurally related pteriatoxins A–C 695–697 were isolated from the bivalve Pteria penguin.⁴³⁹ Based upon spectroscopic similarities, the absolute stereochemistry of the polyether macrocyclic core of the toxins was proposed to be the same as that observed for the pinnatoxins. The absolute stereochemistry of pinnamine 698, a toxin isolated from Pinna muricata,⁴⁴⁰ has been confirmed by synthesis.⁴⁴¹ The absolute stereochemistry of pinnaic acid 699, a toxin also isolated from P. muricata,⁴⁴² has been secured by a combination of synthetic and degradative studies.⁴⁴³ Two new members of the AZP (azaspiracid poisoning) inducing class of toxins 700 and 701 were reported from a collection of the mussel Mytilus edulis.⁴⁴⁴ The absolute configuration at C-3 was secured by degradation of 701 and comparison with synthesised fragments. Five carotenoids 702–706 have been reported from the oyster Crassostrea gigas⁴⁴⁵ and carotenoids 707–711 were also reported from the spindle shell Fusinus perplexus.⁴⁴⁶ Two novel fatty acids 712 and 713 were isolated from the siphonarid limpet Siphonaria denticulata. The structures were confirmed by synthesis.⁴⁴⁷

10 Tunicates (ascidians)

The chemistry of ascidians continues to be dominated by amino acid-derived metabolites, although there are a growing number of examples based upon terpene and alkyl biosynthesis. A collection of the Mediterranean tunicate Sidnyum turbinatum afforded a range of antiproliferative alkyl sulfates 714–717⁴⁴⁸ while subsequent further examination of the same species afforded turbinamide 718, a novel cytotoxic sulfated polyhydroxylated amide.⁴⁴⁹ Continued investigation of the Brazilian ascidian Didemnum granulatum has led to the isolation of the novel alkaloid 6-bromogranulatimide 719, and the known analogue granulatimide 720, confirming the latter as a natural product.⁴⁵⁰ Meridianins A 721 and C–E 722–724, originally isolated from Aplidium meridianum,⁴⁵¹ have been synthesised in good yield from N-tosylacetylindoles.⁴⁵² Segoline C 725, the enantiomer of previously reported segoline B,⁴⁵³ has been reported from an Indian Ocean collection of Eudistoma bituminis.⁴⁵⁴ Differences observed in the ¹³C NMR data for segolines C and B suggests some discrepancies with the earlier assignments of segoline B resonances. The (−)-enantiomer of 1,2,3-trithiane 726, previously isolated as the (+)-enantiomer from Aplidium sp.⁴⁵⁵ has been reported from the New Zealand ascidian Hypsistozoa fasmeriana.⁴⁵⁶ The structurally related alkaloids fasmerianamine A 727 and B 728 were also reported from the ascidian. In two separate accounts, nine mono- and di-chlorinated diterpenoids, the haterumaimides A–I 729–737 were isolated as cytotoxic components from Okinawan collections of Lissoclinum sp.^457,458 The absolute stereochemistries of 729–732 and 734, 736 and 737 were determined by chemical modification and application of the modified Mosher's method, while relative stereochemistries were determined for 733 and 735 only. A full account of the synthesis of tamandarin A 738 and B 739, cytotoxic cyclic depsipeptides isolated from a Brazilian collection of an unidentified didemnid ascidian,⁴⁵⁹ and related compounds, has been reported.⁴⁶⁰ The methyl ester derivatives of previously reported endoperoxide stolonoxides A 740 and C 741, isolated from Stolonica socialis^461,462 have been identified as potent inhibitors of the mitochondrial respiratory chain.⁴⁶³ The absolute stereochemistry of minalemine A 742, originally isolated from Didemnum rodriguesi,⁴⁶⁴ has been defined by stereospecific synthesis.⁴⁶⁵ The ascidian Pseudodistoma obscurum collected in Cadiz, Spain, has afforded the unsaturated amino alcohols 743–748 of which 744–748 were characterised as the diacetate derivatives.⁴⁶⁶ The absolute configuration of 743 was determined as (2S,3R) by Mosher's method. The first syntheses of (−)-lepadins A 749 and C 750, and a new synthesis of (−)-lepadin B 751 have been reported,⁴⁶⁷ confirming the relative and establishing the absolute configuration of the alkaloids first reported from Clavelina lepadiformis.^468,469 A South African collection of Pseudodistoma sp. yielded four alkaloids, comprising three aliphatic amines 752–754 and a β-carboline alkaloid 755.⁴⁷⁰ Mosher's methodology was used to assign the absolute configuration of 752. Two monocyclic piperidine alkaloids, uoamines A 756 and B 757 have been reported from the ascidian Aplidium uouo.⁴⁷¹ The structure of a modified pterin 758 isolated from a Fijian Eudistoma species of ascidian was secured using ¹H–¹⁵N NMR spectroscopic techniques,⁴⁷² while the trimethylguanine derivative 759 was reported from the New Zealand ascidian Lissoclinum notti.⁴⁷³ Three members of the eudistomin-family of alkaloids 760–762 were reported from the ascidian Eudistoma gilboverde collected in Palau.⁴⁷⁴ An Australian collection of Polycarpa aurata contained three simple p-methoxybenzoyl derivatives 763–765.⁴⁷⁵ The first example of a marine alkaloid bearing the rare N-O-methylindole functionality, pibocin B 766 was isolated from a Eudistoma sp. ascidian collected in the Sea of Japan.⁴⁷⁶ A simple biomimetic synthesis of the pyridoacridine alkaloid styelsamine B 767, isolated from an Indonesian collection of Eusynstyela latericius,⁴⁷⁷ has been reported.⁴⁷⁸ Mild oxidation of styelsamine B yielded cystodytin J 768.⁴⁷⁹ In two elegant accounts, total synthesis has dictated that the structures originally proposed for (−)-diazonamide A and B⁴⁸⁰ be revised to 769⁴⁸¹ and 770⁴⁸² respectively. A ceramide derivative 771 was isolated from a Dayawan Bay collection of Styela canopus.⁴⁸³ An antimicrobial 6.2 kDa peptide, dicynthaurin 772 which is comprised of two 30-residue monomers, has been reported from hemocytes of the solitary ascidian Halocynthia aurantium.⁴⁸⁴ Investigation of the hemocytes of S. clava has afforded the clavanins and styelins, high molecular weight α-helical antimicrobial peptides.⁴⁸⁵

11 Echinoderms

The sea cucumber Holothuria leucospilota has afforded three ganglioside molecular species 773–775. The structures of the ceramide portion of all three species are heterogeneous mixtures of alkyl homologues.⁴⁸⁶ Studies of the star fish Asterias rathbuni collected in the Bering Sea resulted in the isolation of two novel steroidal glycosides 776 and 777.⁴⁸⁷ Two saponins, frondoside F 778 and E₂779 were isolated from a collection of the sea cucumber Cucumaria frondosa.⁴⁸⁸ Two new steroids 780 and 781 have been reported from the Pacific starfish Lysastrosoma anthosticta.⁴⁸⁹ Novel gangliosides CJP2 782 and CJP3 783 were isolated from the feather star Comanthus japonica.⁴⁹⁰ The starfish Aphelasterias japonica yielded four sulfated steroids, including the new example 784.⁴⁹¹ Two sulfated triterpene glycosides with anti-HSV (Herpes simplex virus) activity 785 and 786 were reported from the Antarctic sea cucumber Staurocucumis liouvillei.⁴⁹² Four novel nonmethylene-interrupted polyunsaturated fatty acid derivatives 787–790 were identified in extracts of the brittle star Ophiura sarsi.⁴⁹³ Hedathiosulfonic acids A 791 and B 792 were isolated as acute toxicity-exhibiting constituents of the deep-sea urchin Echinocardium cordatum.⁴⁹⁴ A triterpene glycoside patagonicoside A 793, bearing a novel aglycon moiety, was reported from the sea cucumber Psolus patagonicus.⁴⁹⁵ The glycoside exhibited potent antifungal activity towards the pathogen Cladosporium cucumerinum.

12 Conclusions

Over the previous 30 years there has been a marked increase in the number of marine natural products reported annually. During the period 1996–2000 there was, however, a decrease in the number of new compounds reported and the numbers for 2001 are following the same trend (Fig. 1). These numbers suggest we are observing a lessening in the rate of discovery of new compounds from the marine environment.^496,497

Fig. 1 Marine Natural Products, 1965 onwards.

Also depicted graphically in Fig. 1 is the rate of discovery of N-containing compounds over the same period.⁴⁹⁶ The relative dearth of N-containing compounds reported earlier has been well compensated for in recent years, which is perhaps a reflection of the greater emphasis that is now placed on finding bioactive compounds. Of course, bioactivity could also be correlated with other possible structural indicators such as polyethers.

The breakdown of discoveries by phylum for 2001 is shown graphically in Fig. 2. Sponges continue to dominate as a source of new compounds followed by coelenterates and the grouping of microorganisms and phytoplankton.

Fig. 2 Distribution of Marine Natural Products by Phylum, 2001.

Acknowledgements

We thank Eleanor Becker, Liesl Marsh, Kathryn Stillwell and Ekkehard Unger for assistance in collecting data for the preparation of this review.

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