Marine natural products

Contents

• 1 Introduction

• 2 Reviews

• 3 Marine microorganisms and phytoplankton

• 4 Green algae

• 5 Brown algae

• 6 Red algae

• 7 Sponges

• 8 Coelenterates

• 9 Bryozoans

• 10 Molluscs

• 11 Tunicates (ascidians)

• 12 Echinoderms

• 13 Miscellaneous

• 14 Conclusions

• Acknowledgements

• References

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Abstract

Covering: 2004. Previous review: Nat. Prod. Rep., 2005, 22, 15

This review covers the literature published in 2004 for marine natural products, with 693 citations (491 for the period January to December 2004) referring to 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 (716 for 2004), together with their relevant biological activities, source organisms and country of origin. Biosynthetic studies (8), and syntheses (80), including those that lead to the revision of structures or stereochemistries, have been included.

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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. 1992–1993 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 an Associate Professor.

Murray H. G. Munro

Murray Munro, University of Canterbury, Christchurch New Zealand, has worked on natural products, mainly of New Zealand origin, right through his career. Following a sabbatical with Ken Rinehart at the University of Illinois in 1973 interest in marine natural products developed with a particular focus on bioactive compounds. In recent years his research interests have widened to include terrestrial and marine fungi and actinomycetes as well as marine invertebrates.

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 an Associate Professor 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

Previous reviews in this series, published in 2003 and 2004, noted the passing of D. John Faulkner and Paul J. Scheuer, and acknowledged their contributions to the field of marine natural products. Sadly, we now have to note the death of Professor Kenneth L. Rinehart in June 2005. Professor Rinehart had an academic career at the University of Illinois that spanned nearly five decades (1954–2001). Rinehart, like Faulkner and Scheuer, was a pioneer in the study of natural products with significant contributions in the application of mass spectrometry to the solving of natural product structures and the emphasis placed on the search for bioactive compounds sourced from marine organisms. Professor Rinehart pioneered the use of bioassays in the field during collecting expeditions, thus identifying species that should be recollected in larger amounts while still at the site of collection. Lasting contributions from Professor Rinehart will be from his work on the ecteinascidins and didemnins, two of the still relatively few marine natural products in advanced stages of clinical trials (Yondelis™ and Aplidine™).

This review is of the literature for 2004 and describes 716 new compounds from 259 articles, numbers that have increased by ∼10% from those of each of the past few years. As in previous reviews, we show structures only for new compounds, or for previously reported compounds where there has been a structural revision or a newly established stereochemistry. Previously reported compounds for which first syntheses or new bioactivities are described, are referenced, but separate structures are generally not shown.

2 Reviews

In 2004 a larger than customary number of reviews were published covering many different aspects of marine natural products, with two reviews^1,2 giving overall coverage of the 2003 literature. Several reviews describe work derived from regional collections, including Southern Africa,³ the Japanese coasts with emphasis on drug leads from marine invertebrates,⁴ ecosystem comparisons in New Caledonia,⁵ cytotoxic natural products from Taiwan,⁶ bioactive compounds from Brazil,⁷ diterpenes from Dictyotacean brown algae from the tropical Atlantic American region,⁸ and the efforts of Faulkner, Scheuer, Paul and the NCI in Palau.⁹

Reviews with an ecological and/or antifouling focus include an account of biogenic compounds from marine algae with potential as antifouling agents,¹⁰ a general discussion of biofouling and antifouling,¹¹ a review of the recent literature on marine chemical ecology,¹² an account of chemical defence strategies of marine organisms,¹³ and some insights into the antimicrobial defences of selected marine invertebrates.¹⁴ There have been three articles that explore the nature of immune systems in various phyla, including marine invertebrates.^15–17 A somewhat speculative article compares selected marine and non-marine toxins, raising issues such as convergence and the role of symbiotic organisms.¹⁸

Synthetic efforts on marine natural products continue to expand, with reviews covering a variety of topics including trans-fused polycyclic ethers,¹⁹ the convergent syntheses of polycyclic ethers,²⁰ the use of Suzuki–Miyaura cross-couplings for polycyclic ethers,²¹ and the total syntheses of oxazole-containing natural products.²²

Several reviews focus on studies on compounds from specific types of organisms, such as cytotoxic metabolites from marine algae,²³ anticoagulants from marine algae,²⁴ metabolites of marine-derived fungi,²⁵ antimicrobials and antifungals from marine microorganisms,²⁶ toxins from microalgae,²⁷ enzyme inhibitors from marine microbes,²⁸ glycosides from sea cucumbers,²⁹ medicinal and pharmaceutical products from macroalgae,³⁰ bioactive polypeptides from Anemonia sulcata,³¹ metabolites from several species of sponges of the genus Plakortis³² and specifically from Plakortis simplex,³³ peptide and peptide-like pheromones and kairomones from crustaceans,³⁴ toxins from Northern Adriatic mussels,³⁵ metabolites from the gorgonian corals of the genus Junceella,³⁶ and metabolites from symbiotic bacteria.³⁷

A broad range of bioactivities of marine natural products is reviewed in several articles, including marine pharmacology in 2000,³⁸ the merging of the potential of microbial genetics with biological and chemical diversity,³⁹ drugs and cosmetics from the sea,⁴⁰ unconventional natural sources for future drug discovery,⁴¹ new structures and bioactivities for small-molecule natural products,⁴² and marine natural products and related compounds in clinical and advanced preclinical trials.⁴³

Treatments for specific disease types is the subject of several reviews including the search for new candidates for cancer chemotherapy from natural products,⁴⁴ antitumour and cytotoxic compounds reported in 2001–2002,⁴⁵ mechanism-targeted discovery of antitumour marine natural products,⁴⁶ antiviral marine natural products,⁴⁷ antifungal compounds from marine organisms,⁴⁸ and natural antimycobacterial metabolites.⁴⁹

Specific compound classes are reviewed in antimicrobial peptides from marine invertebrates,⁵⁰ bioactive peptides from marine sources,⁵¹ mycosporine-like amino acids,⁵² simple indole alkaloids and those with a nonrearranged monoterpenoid unit,⁵³ bioactive alkaloids,⁵⁴ bisindole alkaloids from sponges,⁵⁵ quinolizidine alkaloids from marine sources,⁵⁶ purines from marine organisms,⁵⁷ siderophores from marine microorganisms,⁵⁸ secosteroids of marine origin (1972–2004),⁵⁹ biologically active natural glycosides,⁶⁰ drimane sesquiterpenoids (1990–2002),⁶¹ diterpenoids (2002),⁶² diterpenoids (2003),⁶³ organohalogen compounds,⁶⁴ marine isocyanides and related compounds,⁶⁵ and allenic compounds.⁶⁶

Research on specific compounds is reviewed in articles on discodermolide,⁶⁷ curacin A,⁶⁸ agelasphin KRN7000,⁶⁹ ecteinascidin 743, aplidine and kahalalide F,^70,71 amphidinolides (1986–2003),⁷² shark-repelling saponins mosesins and pavoninins,⁷³ lamellarins,⁷⁴ and the bisindole alkaloids dragmacidins and hamacanthins.⁷⁵

A brief review on “Drugs from the Sea – Who are the producers?” explores the hypothesis that microorganisms, either by way of ingestion or as symbionts, are the true source of bioactive compounds from marine invertebrates.⁷⁶ Two reviews on the use of mass spectrometry in peptidomics⁷⁷ and analysis of marine toxins⁷⁸ should be of general interest. The Marinlit database⁷⁹ continues to be updated and has again been used as the basis for the preparation of this present review.

3 Marine microorganisms and phytoplankton

Increasingly, the field of marine microbes is becoming a focal point for research and rising numbers of novel compounds continue to be identified. An actinomycete, Micromonospora sp. obtained from Didemnum proliferum (Shishijima Is., Japan), produced the dibenzodiazepine alkaloid, diazepinomicin 1, which exhibited modest antimicrobial activity against selected Gram-positive bacteria.⁸⁰
Gutingimycin 2 is a highly polar trioxacarcin derivative from a Streptomyces species isolated from sediment (Laguna de Terminos, Gulf of Mexico).⁸¹ The absolute configuration was determined by X-ray analysis.⁸² The same Streptomyces species⁸¹ also yielded trioxacarcins D–F 3–5, in addition to the known trioxacarcins A–C.^83–85 The structures and absolute configurations of the new trioxacarcins followed from the X-ray analysis of gutingimycin 2 and the known stereochemistry of L-trioxacarcins A and B.⁸⁵ The trioxacarcins and gutingimycin 2 exhibited strong antibacterial activity against a range of test organisms. The antitumour activity of trioxacarcin D 3 was similar to that previously reported for trioxacarcins A–C,^83–85 while trioxacarcin A and trioxacarcin D 3 were also potently antiplasmodial.⁸⁶
S. acrimycini, isolated from sediment (São Sebastião channel, Brazil), provided two dipeptide derivatives, 8-amino-[1,4]diazonane-2,5-dione 6 and leucyl-4-hydroxyproline 7.⁸⁷ A cultured Nereus™ strain of S. aureoverticillatus isolated from marine sediment (source not given) produced a macrocyclic lactam, aureoverticillactam 8, possessing moderate activity against human tumour cell lines.
Some stereochemistry (2E,6E) could be determined, but other olefins could not be assigned due to spectral overlap.⁸⁸ Two caprolactones 9 and 10 were produced from a Streptomyces species (mangrove sediment, Papua New Guinea). The proposed structures were based on GCMS experiments and proven by synthesis, while the absolute configurations of 9 and 10 were established using chiral GC to compare the natural and synthetic stereoisomers.
Compounds 9 and 10 displayed moderate phytotoxicity and concentration-dependent inhibition of human cancer cell lines, with concomitant low general cytotoxicity.⁸⁹ A Bacillus species obtained from mud near the Arctic pole yielded three cyclopeptides, mixirins A–C 11–13. The absolute stereochemistries of the amino acid residues were determined (Marfey's), but not those of the fatty acid residues. The mixirins A–C inhibited the growth of human colon tumour cells (HCT-116).⁹⁰
Petrobactin sulfonate 14, along with petrobactin,⁹¹ was isolated from the oil-degrading marine bacterium Marinobacter hydrocarbonoclasticus,^91,92 and is the first marine siderophore containing a sulfonated 3,4-dihydroxy aromatic ring. The structure of petrobactin sulfonate was elucidated from spectral data, resulting in a revision of the NMR assignments for petrobactin.⁹³
An actinomycete, Verrucosispora sp. (deep sediment, Sea of Japan), yielded the abyssomicins B–D 15–17, whose structures and relative stereochemistries were supported by X-ray analyses. The absolute stereochemistry of abyssomicin D 17 was determined (Mosher and Helmchen methods) and, through structural analogy, assumed to be the same for abyssomicins B 15 and C 16.⁹⁴ Abyssomicin C 16 was identified as an inhibitor of the pathway between chorismic and para-aminobenzoic acids and was strongly active against Gram-positive bacteria.⁹⁵ Helquinoline 18, and the N-acetylkynuramine 19, were produced by a North Sea bacterium Janibacter limosus. Helquinoline displayed moderate activity against B. subtilis, Streptococcus viridochromogenes and Staphylococcus aureus.⁹⁶
Two cyclic peptides 20 and 21 were isolated from a bacterial Ruegeria species associated with cell cultures of a sponge Suberites domuncula (Gulf of Naples, Italy).⁹⁷ Two further peptides from the culture were known synthetic compounds,^98,99 but isolated for the first time from nature. A known peptide¹⁰⁰ and a new diastereoisomer 22 were also obtained, in addition to a peptide first reported from rabbit skin tissue.¹⁰¹
Cyclopeptides 20 and 21 exhibited moderate activity against B. subtilis.¹⁰² Two cyclodepsipeptides, petrosifungins A 23 and B 24, have been isolated from Penicillium brevicompactum derived from a sponge Petrosia ficiformis (Elba, Italy). The absolute configurations of the amino acids were determined (Marfey's).¹⁰³ A mixed culture of two P. corylophilum strains, (deep water sediment, Fiji/Matuka), provided the known fungal pigments anserinones A and B¹⁰⁴ along with three other pentaketides, (+)-formylanserinone B 25, (−)-epoxyserinone A 26 and (+)-epoxyserinone A 27. Two further minor constituents of the extract, hydroxymethylanserinone B 28 and deoxyanserinone B 29, were isolated but not completely purified.
The relative stereochemistries of 25 and 26 were determined (NOE experiments and molecular mechanics calculations), but the stereochemistry of (+)-formylanserinone B 25¹⁰⁵ was subsequently revised from (9S) to (9R) based on recognition of discrepancies in published data.^104,106 Similarly, the structure of (−)-epoxyserinone A 26 has been clarified as the structure was incorrectly drawn in the original report.¹⁰⁵ The revised stereochemistry for 25 requires the absolute stereochemistry of 26 to be (2R,3S,4S,9R).¹⁰⁷ Anserinone B and (+)-formylanserinone B 25 were the most active against a range of tumour cell lines.¹⁰⁵P. citrinum, isolated from a red alga Actinotrichia fragilis (Okinawa, Japan), was the source of citrinadin A 30 that displayed modest cytotoxicity against L1210 and KB cell lines.¹⁰⁸ A Penicillium species, from a sponge Axinella verrucosa (Elba, Italy), produced the known compound communesin B¹⁰⁹ and the new congeners communesins C 31 and D 32. Communesins B–D exhibited moderate antiproliferative activity against several human leukemia cell lines and were active against brine shrimp.¹¹⁰ A mussel Mytilus edulis (Toyama Bay, Japan Sea) was the source of an Aspergillus species that yielded a polyketide, aspermytin A 33, with the absolute configuration being deduced from the CD spectrum.
Aspermytin A 33 induced neurite outgrowth in rat pheochromocytoma cells.¹¹¹ Golmaenone 34, a diketopiperazine alkaloid, was obtained from an Aspergillus species isolated from a red alga Lomentaria catenata (Ulsan City, Korea). The absolute stereochemistry was established (Marfey's) as were significant radical scavenging and UV-A protecting properties.¹¹²A. pseudodeflectus, isolated from an alga Sargassum fusiform (Miura Peninsula, Japan), was the source of pseudodeflectusin 35, an isochroman cytotoxic against human cancer cell lines.¹¹³ A diketopiperazine dimer 36 was obtained from a marine-derived A. niger supplied by the Australian Institute of Marine Sciences, and the absolute stereochemistry determined (chiral HPLC).¹¹⁴
A. niger, isolated from a sponge Axinella damicornis (near Elba, Italy), yielded seven metabolites; the bicoumanigrin 37, the structurally unusual 4-benzyl-1H-pyridin-6-one derivatives aspernigrins A 38 and B 39 and the pyranonigrins A–D 40–43, which contain the unprecedented pyrano[3,2-b]pyrrole skeleton.
The absolute configurations of aspernigrin B 39 and pyranonigrin A 40 were established by quantum chemical calculations of the CD spectra. Also isolated was the known fungal pigment cycloleucomelone,^115,116 which was moderately cytotoxic against human cancer cell lines in vitro, while aspernigrin B 39 was established as strongly neuroprotective.¹¹⁷ Cultivated mycelium of A. flavipes, isolated from a sea anemone Anthopleura xanthogrammica (Qingdao Bay, eastern China Sea), produced two cerebroside analogues, flavicerebrosides A 44 and B 45, with moderate activities against the KB cell line.¹¹⁸Aigialus parvus, isolated from mangrove wood (Thailand), provided the ketene acetal aigialone 46 and the spiroacetal aigialospirol 47.
X-ray analysis of 46 established the relative stereochemistry only.¹¹⁹ The moderately cytotoxic oxopiperazine metabolites, gliocladins A–C 48–50, and glioperazine 51 were isolated from a strain of Gliocladium species separated from a sea hare Aplysia kurodai (Kata coast, Japan).
Relative stereochemistries at all centres, except for C-3 in 48 and 49 and for C-8 in 51, were determined (NOESY).¹²⁰ Four cytotoxic diterpene glycosides, virescenosides R–U 52–55, were isolated from Acremonium striatisporum originating from a holothurian Eupentacta fraudatrix (Kitovoe Rebro Bay, Sea of Japan).¹²¹
The stereochemistry of C-13 in 55 was determined by comparison against known compounds.¹²²Apiospora montagnei, isolated from the inner tissue of an alga Polysiphonia violacea (North Sea near Helgoland), was the source of myrocin A 56, apiosporic acid 57, methyl 9-hydroxyhexylitaconate 58 and the (−)-enantiomer 59 of the known (+)-hexylitaconic acid.^123–125
Five leptosins O–P 60–64 were obtained from a Leptosphaeria species, originally separated from Sargassum tortile (Tanabe Bay, Japan),¹²⁶ but structural and absolute stereochemistry determinations were performed on the derived acetates. Leptosins O 60 and P 61 exhibited significant cytotoxicity against P388 cells while leptosins O 60 and S 64 were moderately cytotoxic to 39 human tumour cell lines.¹²⁷Emericella variecolor, (marine sediment, Gokasyo Gulf, Japan), provided two new sesterterpenes, 6-epi-ophiobolin G 65 and 6-epi-ophiobolin N 66 along with six previously reported ophiobolins. All isolated compounds were cytotoxic against a neuroblastoma cell line.¹²⁸
The modestly cytotoxic cyclic dipeptides rostratins A–D 67–70 were isolated from Exserohilum rostratum, a fungal strain associated with a marine cyanobacterial mat (Lanai, Hawaii). Absolute configurations of the rostratins were determined (Mosher's).¹²⁹
Peribysins A–D 71–74, from a strain of Periconia byssoides originating from Aplysia kurodai,¹³⁰ are eremophilane sesquiterpenoids of which 73 and 74 represent a new class of furanofuran, and are potent inhibitors of the adhesion of HL-60 cells to HUVEC, with 74 being the most active.¹³¹ An eremophilane sesquiterpene, 7H239-A 75, was obtained from a xylariaceous fungus isolated from a Nypa (mangrove) palm frond (Kuala Selangor, Malaysia) and was cytotoxic towards a variety of cancer cell lines, with some selectivity for the CCRFCEM leukemia line.¹³²
The diterpene phomactin H 76, with a novel skeleton including an oxepane moiety, was obtained from an unidentified surface fungus isolated from a brown alga Ishige okamurae (Tateishi, Japan). The structure and relative stereochemistry were determined by X-ray analysis.¹³³ Two halogenated alkenoates, 77 and 78 were isolated from an unidentified surface fungus of a red alga Gracillaria verrucosa (Jinha, Korea).¹³⁴
A total synthesis, using a Cr(II)–Ni(II) macrocyclisation, has been reported¹³⁵ for racemic phomactin G, from a marine fungal Phoma species.¹³⁶ A Cladosporium species from a brown alga Actinotrichia fragilis (Okinawa, Japan), produced two cytotoxic macrolides, sporiolides A 79 and B 80. Sporiolide A 79 was also moderately antifungal against a range of organisms, while both sporiolides were active against Micrococcus luteus.¹³⁷ Fuscoatrol A 81, a caryophyllene sesquiterpene, was isolated from Humicola fuscoatra associated with an unidentified colonial ascidian (Shikotan Is., Kuril Isles) with the structure being confirmed by X-ray analysis.
Fuscoatrol A 81 displayed moderate antimicrobial activity and was cytotoxic against sea urchin eggs.¹³⁸Lyngbya majuscula (Hector's Bay, Jamaica) was the source of three lipopeptides, jamaicamides A–C 82–84.
Structural elucidation included the use of the Accordion 1,1-ADEQUATE experiment.¹³⁹ This experiment detects ¹H–¹³C–¹³C spin systems for a wide range of ¹³C–¹³C coupling values and permits unequivocal distinction between 2- and 3-bond HMBC correlations. Only the C-23 stereochemistry of jamaicamide A 82 could be determined (Marfey's). Biosynthetic experiments suggested that the jamaicamides result from alternating PKS and NRPS assembly units, confirmed through cloning and identification of the biosynthetic gene cluster. The jamaicamides displayed cytotoxic, sodium channel blocking and ichthyotoxic activities.¹⁴⁰ Eleven chlorinated lipids, taveuniamides A–K 85–95, were isolated from two mixed samples of L. majuscula and Schizothrix sp. (Taveuni Is., Fiji).
Taveuniamides F 90, G 91 and K 95 exhibited relatively potent brine shrimp toxicity.¹⁴¹ From a total synthesis of kalkitoxin and its congeners, the absolute stereochemistry of this potent neurotoxin isolated from L. majuscula¹⁴² could be assigned as (3R,7R,8S,10S,2′R).¹⁴³ Kalkitoxin, from a second total synthesis, exhibited potent activity against HCT-116.¹⁴⁴ A Symploca species (Fingers Reef, Guam) was the source of two cytotoxic compounds, micromide 96 and guamamide 97.
Chiral HPLC and chemical derivatisation followed by comparison with synthetic standards established the absolute stereochemistry of 96.¹⁴⁵ Isolation of 8-hydroxy-3,5-dimethyl-isochroman-1-one¹⁴⁶ from a mangrove fungus (coastal South China Sea) is the first report of this compound from a marine source.¹⁴⁷ A symbiotic dinoflagellate Symbiodinium species, from an acoel flatworm Amphiscolops species (source not given), produced the amphoteric iminium compound symbioimine 98. The absolute stereochemistry was determined by X-ray analysis.
Symbioimine 98 inhibited osteoclastogenesis of the murine monocytic cell line RAW264 and therefore has potential for use as an antiresorptive for prevention and treatment of osteoporosis in postmenopausal women.¹⁴⁸ The cytotoxic 25-membered macrolide amphidinolide C2 99 was obtained from a dinoflagellate Amphidinium species isolated from an acoel flatworm Amphiscolops species (Sunabe, Okinawa).¹⁴⁹ Structural elucidation of (+)-amphidinolide A 100, also from an Amphidinium species,^150,151 has been completed through a combination of NMR analysis and total synthesis.¹⁵² Amphidinolide H¹⁵³ attenuated actin depolymerisation induced by diluting F-actin and enhanced the binding of phalloidin to F-actin and is therefore a useful tool for analyzing actin-mediated cell function.¹⁵⁴ A total synthesis of amphidinolide W 101, a 12-membered macrolide isolated from an Amphidinium species,¹⁵⁵ has been completed with revision of the C-6 stereochemistry.¹⁵⁶
A total synthesis of amphidinolide X¹⁵⁷ has also been reported.¹⁵⁸ A dinoflagellate Amphidinium species, originally isolated from the surface wash of seaweeds (Lingshui Bay, Hainan Province, China), was the source of the potent cytotoxin lingshuiol 102.¹⁵⁹ The same culture yielded two further lingshuiols, A 103 and B 104.¹⁶⁰
Two strains of a dinoflagellate Protoceratium cf. reticulatum (Sanriku, Iwate, Japan) were the source of four potent antitumour compounds, protoceratins 1–4. Protoceratin 1 was identical to the shellfish toxin 2-homoyessotoxin,¹⁶¹ while protoceratins 2–4 105–107 were determined to be the di-, mono- and tri-arabinosides of 2-homoyessotoxin respectively.¹⁶² A Symbiodinium species, isolated in the free-living state from a Hawaiian tide pool, gave the polyhydroxy metabolite zooxanthellamide B 108, a δ-lactone analogue of zooxanthellamide A¹⁶³ which had previously been obtained from the same dinoflagellate.¹⁶⁴
Several Symbiodinium strains obtained from different researchers around Japan produced zooxanthellactone 109. The original strain used for the production was isolated from the foraminifer, Amphisorus hemprichii. The absolute stereochemistry of zooxanthellactone 109, which was modestly cytotoxic against two human squamous cell carcinomas, was also established.¹⁶⁵ The polyether brevenal 110, obtained from laboratory cultures of Karenia brevis as well as collections off the west coast of Florida during a red tide, competes with brevetoxin for a site associated with the voltage-sensitive sodium channel thus protecting fish from the neurotoxic effects of brevetoxin exposure.
Brevenal may have utility as a model compound for the development of therapeutics to prevent, or reverse intoxication in red tide exposures.¹⁶⁶ A study in rats using short-term inhalation exposure to brevetoxin 3¹⁶⁷ suggested that the immune system may be a target of toxicity following brevetoxin inhalation.¹⁶⁸ The rapid effects of brevetoxin-2¹⁶⁹ and saxitoxin¹⁷⁰ on embryonic murine frontal cortex neuronal networks on microelectrode arrays have been reported.¹⁷¹ NMR studies on two synthetic diastereomeric models corresponding to the CDE/FG ring of prymnesins,^172,173 suggested that the earlier stereochemical assignment of the E/F ring juncture in the prymnesins needs to be revised.¹⁷⁴ A total synthesis of oscillarin 111, an antithrombotic peptide from Oscillatoria agardhii,¹⁷⁵ has been achieved, confirming the absolute stereochemistry proposed and correcting the structure of a subunit to the Δ³-pyrroline-containing unit shown. Bioassays confirmed that 111 is a potent thrombin inhibitor while the originally assigned structure is inactive. An X-ray analysis of a ternary complex between oscillarin and α-thrombin has been reported.¹⁷⁶ Synthetic (1S,2S) grenadamide had equal but opposite optical rotation from natural grenadamide from Lyngbya majuscula,¹⁷⁷ which is therefore the (1R,2R)-enantiomer 112.¹⁷⁸
Both enantiomers of xestodecalactone A¹⁷⁹ have been synthesised, and CD and chiral HPLC comparisons have confirmed the (R)-configuration for the natural product.¹⁸⁰ Using inexpensive starting materials, concise total syntheses of the maculalactones A,¹⁸¹ B¹⁸² and C,¹⁸² from a cyanobacterium Kyrtuthrix maculans, have been achieved. Results from optical rotation measurement, chiral HPLC and NMR spectroscopy in the presence of a chiral shift reagent established that natural maculalactone A is present in K. maculans as a partially racemic mixture.¹⁸³ Total synthesis of the Bacillus laterosporus polyketide antibiotics basiliskamide A and B¹⁸⁴ confirmed the assignment of absolute configuration as (7S,8S,9R,10S).¹⁸⁵ The first total synthesis of (+)-phomopsidin, a microtubule assembly inhibitor and isolated from a Phomopsis species,¹⁸⁶ has been achieved via a diastereoselective transannular Diels–Alder reaction.¹⁸⁷ The total synthesis of halovir A,¹⁸⁸ one of a series of linear, lipophilic peptides produced by a Scytalidium species, has been completed as part of a structure–activity relationship study of the series.¹⁸⁹ A one-pot multistep domino reaction from a starting enone of established absolute configuration was used to complete a total synthesis of the mangrove fungus metabolite (+)-xyloketal D.^190,191 The dinoflagellate metabolite yessotoxin¹⁹² has been shown to induce a cyclosporin A-sensitive permeability transition in rat liver mitochondria and Morris Hepatoma 1C1 cells in the presence of permissive levels of calcium, and also induces membrane depolarisation.¹⁹³ The potent ichthyotoxin antillatoxin from Lyngbya majuscula,¹⁹⁴ along with three synthetic stereoisomers, were assessed for ichthyotoxicity and cytotoxicity in five different assay systems. In all assays the natural antillatoxin was the most potent.¹⁹⁵ Euplotin C,¹⁹⁶ a sesquiterpene from a marine ciliate protist Euplotes crassus, displayed moderate activity against the protozoa Leishmania major and L. infantum and mild activity against Candida albicans.¹⁹⁷ An assay for inhibitors of lymphocyte function-associated molecule 1/intercellular cell adhesion molecule-1 (LFA-1/ICAM-1) mediated cell–cell adhesion was used to identify new pharmacologically active compounds from marine cyanobacteria and algae.¹⁹⁸ Six of the sixty marine natural products tested significantly inhibited LFA-1/ICAM-1 mediated cell adhesion after primary and secondary testing. These compounds were cymathere aldehyde,¹⁹⁹ microcolins B²⁰⁰ and D,¹⁹⁸ avrainvilleol,²⁰¹ cymopol²⁰² and hormothamnione diacetate.^203–205 The stereochemistry of a cyclisation product, and results of incorporation experiments with [1-¹³C]- and [1,2-¹³C₂]-acetates, were used to propose the course of geranylgeranyl diphosphate cyclisation in the biosynthesis of the phomactins^{206–208,136} from a marine fungal Phoma species.²⁰⁹ Incubation of a diatom Rhizosolenia setigera with [1-¹³C]-acetate indicated that the polyunsaturated monocyclic sesterterpene and triterpene metabolites are produced predominantly via the mevalonate pathway.²¹⁰

4 Green algae

Very few new secondary metabolites from green algae have been reported. Capisterones A 113 and B 114 are triterpene sulfate esters isolated from Panicillus capitatus (Cat Cay, Bahamas). Both compounds exhibited potent antifungal activity against the marine algal pathogen Lindra thallasiae.²¹¹

5 Brown algae

As noted in previous reviews, terpenes and polyphenolic compounds are the predominant metabolite classes found in brown algae. A sample of Eisenia bicyclis, a very common Pacific-coast Japanese species, was purchased from a Japanese company and yielded a new phloroglucinol derivative 115, and two known phloroglucinols, eckol²¹² and dieckol.^213,214
All three compounds inhibited glycation and α-amylase, so may have an effect on complications of diabetes.²¹⁵ Phloroglucinol²¹⁶ and the derivatives eckstolonol,²¹⁷ eckol,²¹² phlorofucofuroeckol A²¹⁸ and dieckol,²¹³ isolated from Ecklonia stolonifera are tyrosinase inhibitors.²¹⁹ Five meroditerpenes, amentol chromane diacetate 116, cystoseirone diacetate 117, preamentol triacetate 118, 14-epi-amentol triacetate 119 and 14-methoxyamentol chromane 120 were obtained from a Cystoseira species (Canary Islands).²²⁰
Two cytotoxic trihydroxylated diterpenes based on 12-hydroxygeranylgeraniol, 121 and 122, were isolated from Bifurcaria bifurcata (Atlantic coast of Morocco). The absolute configuration at C-12 in both compounds was established (Mosher's), but the stereochemistries of C-6 in 121 and C-7 in 122 could not be unambiguously determined.²²¹Scytosiphon lomentaria, cultured in deep seawater, produced the bisnorditerpene 123.²²²
The secondary metabolite compositions of Dictyota dichotoma (Aegean Sea) and D. linearis (Chios Is., Greece), were examined and new diterpenes isolated; isopachydictyolal 124 from D. dichotoma and 4α-acetyldictyodial 125 from D. linearis.²²³D. dichotoma (Karachi coast in the Arabian Sea) yielded three C-16 oxidised seco-dolastanes, dichotenols A–C 126–128.²²⁴
A new dolabelladiene derivative 129 and the previously isolated 10,18-diacetoxy-8-hydroxy-2,6-dolabelladiene²²⁵ were characterised from D. pfaffii (Northeast Brazil).²²⁶ Both compounds showed strong anti-HSV-1 activity in vitro but little inhibition of HIV-1 reverse transcriptase. 10,18-Diacetoxy-8-hydroxy-2,6-dolabelladiene²²⁵ was the antifeedant component of D. pfaffii against the sea urchin Lytechinus variegatus and generalist fishes.²²⁷ The diterpenes (6R)-6-hydroxydichotoma-3,14-diene-1,17-dial, and the 6-acetate derivative, from D. menstrualis,²²⁸ originally isolated from D. dichotoma,²²⁹ exhibited antiretroviral activity in vitro.²²⁸ Two glycerol derivatives, 130 and 131, were obtained from Sargassum parvivesiculosum (Hainan Province, China).²³⁰
The sesquiterpene-substituted benzoic acid, dictyvaric acid 132, was isolated from Dictyopteris divaricata (Shandong coast, China),²³¹ while seven cadinane sesquiterpenes, 133–139, were obtained from D. divaricata (Qingdao coast, China).
Structures and absolute configurations of 133–139 were established from spectroscopic data and X-ray analysis of 133 and 136.²³² Six dibenzyl bromophenols 140–145,²³³ with different dimerisation patterns, and two propyl bromophenol derivatives, 146 and 147,²³⁴ were isolated from Leathesia nana (Shandong Province, China).
X-Ray analysis determined that 145 was a racemate. Compound 142 showed moderately selective cytotoxicity, and 140 may have been an artifact of isolation.²³³ Surprisingly, compound 146 was reported in another paper by the same authors.²³⁵ The moderately cytotoxic diphlorethohydroxycarmalol 148, from Ishige okamurae (Boso Peninsula, Japan),²³⁶ was characterised by conversion to the known nonaacetate.²³⁷
An enantioselective synthesis of the proposed structures for the bioactive (E)- and (Z)-usneoidones, from Cystoseira usneoides,²³⁸ has been completed by a convergent strategy.²³⁹ However, the spectroscopic data of the synthetic products differed significantly from the reported values. The phlorotannin derivatives 8,8′-bieckol²⁴⁰ and 8,4‴-dieckol,²⁴¹ from Ecklonia cava (Korean coasts), are inhibitors of HIV-1 reverse transcriptase (RT) and protease. Both compounds inhibited the RT more potently than the protease and the inhibitory activity of 8,8′-bieckol against HIV-1 RT was comparable to that of nevirapine, a reference compound.²⁴² Fucosterol^243,244 was isolated from Pelvetia siliquosa and in vivo testing demonstrated that it is the main antidiabetic principle from P. siliquosa.²⁴⁵

6 Red algae

As for the brown algae, terpenes and polyphenolic compounds continue to be the predominant metabolite classes reported from red algae. Laurencia obtusa (Isla Grande, Panama), contained the oxygenated sesquiterpene chamigrenelactone 149.²⁴⁶ The sesquiterpene 150 and a halogenated C15 acetogenin 151, a stereoisomer of neoisoprelaurefucin,²⁴⁷ were isolated from L. obtusa (Tekirova, Turkey).²⁴⁸
Two halogenated diterpenes, 15-bromoparguer-9(11)-ene-16-ol 152 and 15-bromoparguer-7-ene-16-ol 153, were obtained from L. nipponica (Troitsa Bay, Sea of Japan).²⁴⁹ Bioassay-guided fractionation of an extract from L. intricata (Discovery Bay, Jamaica), gave the diterpene laurenditerpenol 154 and the absolute configuration at C-1 was established (Mosher's). 154 was a potent inhibitor of hypoxia-activated hypoxia-inducible factor-1 and of the angiogenic factor hypoxia-induced VEGF in T47D cells.²⁵⁰ Two phenylpropanoic acid derivatives, tichocarpols A 155 and B 156, were isolated from Tichocarpus crinitus (Katsurakoi coast of Japan).
These two compounds, along with floridoside,²⁵¹ also isolated from the alga, exhibited antifeedant activity against the sea urchin Strongylocentrotus intermedius.²⁵² Inositol phosphoceramide 157 was isolated from Gracilaria verrucosa (Sea of Japan) and identified by GC and GCMS analysis.²⁵³Peyssonnelia caulifera (Yanuca Is., Fiji) was the source of two enediyne ω3 monoacyl glycerides, peyssonenynes A 158 and B 159, and a pyrone-containing ω3 fatty acid methyl ester, peyssopyrone 160, but the instability of the peyssonenynes prevented complete stereochemical assignment.
Both peyssonenynes displayed activity at a similar level in a DNA methyltransferase enzyme inhibition assay.²⁵⁴Rhodomela confervoides (Qingdao coast, China) was the source of seven new bromophenol derivatives 161–167, together with two known bromophenol compounds. X-Ray analysis of 161 and 162 supported the structural assignments.
The known synthetic compounds 3-bromo-5-hydroxy-4-methoxyphenylacetic acid²⁵⁵ and 3-bromo-5-hydroxy-4-methoxybenzoic acid,²⁵⁶ were obtained as natural products for the first time.²⁵⁷ Seven brominated diterpenes of the parguerene and isoparguerene series isolated from Jania rubens (Red Sea coast of Egypt) included the novel deoxyparguerol-7-acetate 168. All the isolated diterpenes had anthelmintic activity and exhibited antitumour activity against Ehrlich ascites carcinoma in vitro with isoparguerol derivatives being slightly more effective than parguerol derivatives.²⁵⁸ The first total synthesis of (−)-presphaerene 169²⁵⁹ from Sphaerococcus coronopifolius was achieved from (R)-glyceraldehyde²⁶⁰ and established the relative and absolute stereochemistries of 169 as well as the absolute stereochemistries of the co-occurring sphaeroanes (+)-presphaerol,^261,262 isosphaerodiene 1²⁶³ and isosphaerodiene 2.²⁶³
The first enantioselective total synthesis of (+)-brasilenyne^264,265 was reported, starting from (S)-malic acid.²⁶⁶ Also reported in 2004 was the first total synthesis of the sesquiterpenoid (+)-palisadin B from Laurencia cf. palisada,²⁶⁷ utilising a new method for the formation of trans-anti cyclogeranyl-oxepene systems.²⁶⁸ Furoplocamioid C, prefuroplocamioid, pirene and a tetrachlorinated cyclohexane from Plocamium cartilagineum²⁶⁹ exhibited selective cytotoxicity against human tumour cell lines with pirene showing a specific and irreversible effect on SW480 cells.²⁷⁰ Halogenated metabolites from several species of Laurencia were tested for antibacterial activity against 22 strains of human pathogenic bacteria, including seven strains of antibiotic-resistant bacteria. Laurinterol,²⁷¹ isolaurinterol,²⁷²allo-laurinterol,²⁷³ cupalaurenol²⁷⁴ and 2,3,5,6-tetrabromoindole²⁷⁵ displayed a wide spectrum of antibacterial activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae and vancomycin-resistant Enterococcus faecalis and E. faecium. Laurinterol and allo-laurinterol were particularly effective.²⁷⁶ Studies on vanadium bromoperoxidase isolated from marine red algae have established it as a catalyst in the biosynthesis of brominated cyclic sesquiterpene structures in the algae.²⁷⁷

7 Sponges

Unusual fatty acid derived metabolites are often isolated from sponges, and some motifs seem to be characteristic of the phylum; 2-methoxylated fatty acids are one such group of metabolites. A series of these compounds were synthesised, found to be active against mycobacteria, and proposed as a possible chemical defence mechanism in sponges.²⁷⁸ Two long 2-methyl substituted fatty acids 170 and 171 were isolated as methyl esters from Halichondria panicea (Sea of Japan, Russia).²⁷⁹ A Chinese Spongia species yielded the ceramides spongiamines A 172 and B 173.²⁸⁰
Clarhamnoside 174, a glycolipid containing an unusual L-rhamnose unit, was isolated from the Bahamian Agelas clathrodes.²⁸¹ The relative stereochemistry of the sugar units was determined from proton coupling constants determined with the use of a ¹³C-coupled HMQC experiment. The absolute stereochemistry of the alkyl chain oxymethine of caminoside A, originally isolated from Caminus sphaeroconia,²⁸² has been determined as (10R) by the preparation of a TPP diester of the aglycone.²⁸³ An inhibitor of bacterial proteases, pachymoside A 175, was isolated from Pachymatisma johnstonia (Isle of Man).²⁸⁴
An α-glycosidase inhibitor, penasulfate A 176, was obtained from a Japanese Penares species using recycling HPLC.²⁸⁵Mycale cecilia (Gulf of California, Mexico) yielded fourteen cytotoxic long chain pyrroles, mycalazals 3–13 177–187, and three nitrile-containing congeners, the mycalenitriles 1–3 188–190.²⁸⁶
A Korean Homaxinella species yielded three weakly cytotoxic butenolides, homaxinolides A–C 191–193, along with the moderately cytotoxic cyclopentenone, homaxinone A 194. Also isolated from the same collection was an unsaturated alcohol 195 previously known only as a synthetic intermediate.²⁸⁷
A pair of isomeric bisthiocyanates, thiocyanatins D₁196 and D₂197, and the related thiocyanate-thiocarbamates, thiocyanatins E₁198 and E₂199, were obtained as inseparable pairs from a South Australian Oceanapia species; all compounds were potent nematocides. Several related compounds were also tentatively identified by mass spectrometry.²⁸⁸ An acetylenic acid 200 has been obtained from a Chinese Cinachyrella australiensis.²⁸⁹ A Plakortis species (Canary Islands) contained plakolide A 201, a γ-lactone that inhibits inducible nitric oxide synthase activity.²⁹⁰
Two isomeric cytotoxic trans epoxides, plakorstatins 1 202 and 2 203, were isolated from Plakortis nigra (Sulawesi, Indonesia).²⁹¹ A Dominican Plakortis anglospiculatus provided two highly branched tricylic acids, spiculoic acids A 204 and B 205 which are thought to be the result of a Diels Alderase-catalyzed intramolecular [4 + 2] cycloaddition.²⁹²
A series of glycosphingolipids were partially characterised from four Agelas species using tandem HPLC-ESIMS and HPLC-LSIMS.²⁹³ Dideoxypetrosynol A, a polyacetylene originally obtained from a Petrosia species,²⁹⁴ induced apoptosis in human melanoma cells.²⁹⁵ Manzamenone A²⁹⁶ was a potent inhibitor of β DNA polymerase and only weakly active against the α form of the enzyme.²⁹⁷ A lysophosphatidylcholine, originally isolated from Spirastrella abata,²⁹⁸ has been shown to increase intracellular Ca²⁺ concentration in human leukemia cells.²⁹⁹ Mycalazal 2 and mycalazol 11, pyrrole-containing lipids isolated from Mycale micranthoxea,³⁰⁰ have been synthesised using a Stille coupling.³⁰¹ A synthesis of (2R,5Z,9Z)-2-methoxyhexacosa-5,9-dienoic acid, from Topsentia roquensis,³⁰² has been accomplished using a novel HgO mediated O-alkylation.³⁰³ A racemic synthesis of plakortone E 206³⁰⁴ has established the relative stereochemistry,³⁰⁵ and an asymmetric synthesis of plakortone G 207³⁰⁶ defined both the relative and absolute stereochemistries.³⁰⁷ Two dimeric peroxides, dihalenaquinolides A 208 and B 209, were isolated from a Taiwanese Petrosia elastica.³⁰⁸
A very potent cytotoxin, psymberin 210, related to the pederin family of metabolites, was obtained from a series of Papua New Guinean collections of Psammocinia species.³⁰⁹ In an independent study, a compound named irciniastatin A, having the same NMR characteristics as 210 but claiming different stereochemistry at C-8, and the keto analogue irciniastatin B 211 were isolated from Ircinia ramosa (Borneo).³¹⁰ Four calyculin analogues, calyculin J 212, calyculinamide F 213, des-N-methylcalyculin A 214 and the known calyculinamide A,³¹¹ were obtained from a Japanese Discodermia calyx.
All four compounds were potent inhibitors of protein phosphatase 2A.³¹² A prokaryotic gene cluster, proposed to be responsible for the biosynthesis of onnamide A, has been isolated from the metagenome of Theonella swinhoei. The specific PKS cluster is distinct from many others by the lack of an acyltransferase domain, a characteristic that it shares with the pederin gene cluster. The onnA cluster was found only in the chemotypes of T. swinhoei that produce onnamide A and the theopederins.³¹³ In a series of five consecutive papers the large-scale synthesis of discodermolide is described, culminating in the production of 60 g of enantio-pure material.³¹⁴ Discodermolide, a microtubule stabilizing agent, was originally isolated from a deepwater Discodermia disoluta.³¹⁵ The level of commitment involved in this large-scale synthesis of a highly complex marine natural product is a measure of the importance of the field of marine natural products to medical research and the pharmaceutical industry. Sponges continue to be a rich source of novel and biologically active peptides. The dysinosins B–D 215–217, from a Queensland Lamellodysidea chlorea, were inhibitors of serine protease factor VIIa and thrombin.³¹⁶ The microtubule-destabilizing peptide, milnamide C 218, was obtained from an Auletta species (Papua New Guinea).³¹⁷ Milnamide D 219, isolated from a Cymbastela species and reported in 2003,³¹⁸ was inadvertently omitted from the previous review.¹ An asymmetric synthesis of milnamide A 220³¹⁹ and the subsequent autoxidation to milnamide D established the relative and absolute stereochemistry of these two potent antimitotic compounds.³²⁰
Scleritoderma nodosum (Philippines) contained the cytotoxic cyclic peptide scleritodermin A 221.³²¹ Another Philippine sponge, Clathria (Thalysias) abietina, yielded two isomeric disulfide-bridged heptapetides, microcionamides A 222 and B 223, with cytotoxic and antitubercular activities.³²² An unusually cyclised peptide, callynormine 224, isolated from Callyspongia abnormis (Kenya), represents a new class of heterodectic cyclic peptide, the endiamino peptides, which contain an α-amido-β-aminoacrylamide functionality.³²³Axinella carteri (Caroline Islands) yielded the octapeptide cyclonellin 225.³²⁴ Kendarimide A 226, a linear peptide obtained from a Haliclona species (Sulawesi, Indonesia), reversed P-glycoprotein-mediated multi-drug resistance in mammalian cells.³²⁵ A large depsipeptide, neamphamide A 227, with potent cytoprotective activity against HIV-1 was isolated from a Papua New Guinean Neamphius huxleyi.³²⁶
Phakellistatin 13, recently isolated from Phakellia fusca,³²⁷ has been synthesised, confirming the natural L configuration of the tryptophan residue.³²⁸ Phakellistatin 13 was also converted by photo-oxidation into phakellistatin 3 and isophakellistatin 3, both originally obtained from P. carteri.³²⁹ Miraziridine A, isolated from Theonella aff. mirabilis,³³⁰ has been synthesised and is an inhibitor of three classes of proteases.³³¹ Callipeltin A, originally isolated from a New Caledonian Callypelta species,³³² acts as an ionophore, increasing the contraction of vascular tissues in the presence of Na⁺ ions.³³³ The complex structures and often spectacular biological activity of sponge-derived macrolides and their related congeners provide attractive targets and considerable challenges to natural product and synthetic chemists alike. Examples of these include the two oxazole-containing macrolides neohalichondramide 228, (19Z)-halichondramide 229 and a related ring opened compound secohalichondramide 230 obtained from Chondrosia corticata (Guam),³³⁴ and the three cytotoxic mycalolides, 30-hydroxymycalolide A 231, 32-hydroxymycalolide A 232, and 38-hydroxymycalolide B 233 isolated from a Japanese Mycale magellanica.³¹²
Latrunculeic acid 234, from Negombata (Latrunculia) magnifica³³⁵ (Gulf of Eilat, Red Sea), is clearly related to the latrunculin macrolides, isolated previously from the same sponge.³³⁶ Spongidepsin 235, originally isolated from a Spongia species (Vanuatu),³³⁷ has been synthesised independently by two groups defining both relative and absolute configurations.^338,339 The relative stereochemistry of dictyostatin 236, originally obtained from a Spongia species,³⁴⁰ has been determined (Murata's method), revising the original structure.³⁴¹
Two independent groups have confirmed this relative stereochemistry and absolute configuration by synthesis.^342,343 Five antiproliferative lasonolide congeners, lasonolides C–G 237–241, were isolated from a Forcepia species (west coast of Florida).³⁴⁴
A larger recollection of the producing organism, Spirastrella coccinea, yielded sufficient spirastrellolide A 242 for further spectroscopic examination and derivative preparation.
Originally reported with a molecular formula of C₅₃H₈₆O₁₉,³⁴⁵ an extensive re-analysis led to the determination of a new molecular formula, exchanging H₃O₂ for Cl, and structural revision (as shown). The relative stereochemistries of segments C-3–C-7, C-9–C-24, and C-27–C-38 were established from ROESY data obtained at 800 MHz.³⁴⁶ The synthesis of a series of diastereomers of a degradation fragment of reidispongiolide A 243, originally isolated from Reidispongia coerulea,³⁴⁷ has led to a reassignment of the relative stereochemistry of the C-7–C15 fragment.³⁴⁸ The potent cytotoxin 13-deoxytedanolide, from Mycale adhaerans,³⁴⁹ has been shown to bind to the 60S large ribosomal subunit.³⁵⁰ Two brominated biphenyl ethers 244 and 245 were isolated from Phyllospongia dendyi (Palau), along with a series of related known compounds.
Some of the known dihydroxy congeners showed inhibitory activity towards the assembly of microtubules.³⁵¹ A tricyclic dipeptide betaine, dysibetaine PP 246, and two cyclopropane betaines, dysibetaines CPa 247 and CPb 248, were isolated from an aqueous extract of Dysidea herbacea (Yap, Micronesia).³⁵² A Japanese Spongia species produced the moderately antifungal spongiacysteine 249.³⁵³
Three aromatic amino acid-derived alkaloids, hamigeroxalamic acid 250, hamigeramine 251, and hamigeramide 252 were isolated from a Mediterranean Hamigera hamigera.³⁵⁴ Esmodil 253, known previously as a synthetic drug, has been found as a metabolite of a South Australian Raspailia species.³⁵⁵
A series of twenty new phloeodictine alkaloids 254–273, together with several known congeners, were obtained from Oceanapia fistulosa (New Caledonia).
The compounds were characterised by LCMS from a complex mixture that showed antiplasmodial activity against chloroquine-resistant Plasmodium falciparum.³⁵⁶ Alkylpyridine-derived alkaloids are a characteristic of sponges that continue to provide an assortment of unusual metabolites. Viscosaline 274 was obtained from Haliclona viscosa (Russian Arctic Ocean).³⁵⁷ The same sponge, but from Svalbard in the Norwegian Arctic, yielded haliclamines C 275 and D 276.³⁵⁸ Three inhibitors of histone deacetylase, cyclostellettamine G 277 and dehydrocyclostellettamines D 278 and E 279, were isolated from a Japanese Xestospongia species.³⁵⁹ A Brazilian Pachychalina species yielded the cytotoxic ingenamine G 280, the previously described cyclostellettamine G, and four new congeners, cyclostellettamines H, I, K and L 281–284.³⁶⁰
An Amphimedon species (Southern Japan) contained tetrahydrohalicyclamine 285 and 22-hydroxyhalicyclamine 286, both of which inhibit the growth of mammalian cells.³⁶¹ A new aruguspongine/xestospongine analogue, araguspongine M 287, has been described from Neopetrosia exigua (formerly Xestospongia exigua) from Palau.³⁶²
Hachijodine B, originally isolated from a Xestospongia species,³⁶³ has been synthesised, along with the proposed structure of ikimine B originally isolated from an unidentified sponge,³⁶⁴ but the spectra of the synthetic ikimine B did not match that of the natural product suggesting a possible incorrect assignment of the original structure.³⁶⁵ Three manzamine alkaloids 288–290 have been isolated from an Indonesian Acanthostrongylophora species. The activities of several known manzamine alkaloids as potent antiinflammatory, antifungal, and anti-HIV-1 agents were also reported.³⁶⁶ Indole-based alkaloids are well represented among sponge metabolites. Three further iodinated indole alkaloids, plakohypaphorines D–F 291–293 are reported from Plakortis simplex (Bahamas).
Plakohypaphorines B–D have significant antihistamine activity.³⁶⁷ The weakly cytotoxic guanine-containing 6-hydroxydiscodermindole 294 was obtained from Discodermia polydiscus (Bahamas).³⁶⁸ An antifouling alkaloid, 8,9-dihydrobarettin 295, has been isolated from Geodia barretti.³⁶⁹ The recently reported revised structure for barettin,³⁷⁰ from G. baretti,³⁷¹ has been synthesised confirming the revised structure.³⁷² Using LCMS, barettin has been detected at biologically-significant concentrations in water surrounding live G. barretti specimens.³⁶⁹ An enantiospecific synthesis of the (+)-dragmacidin F has established the absolute configuration of the natural product as (4′S,6″S,6‴S).³⁷³ Two thiomethyl-containing β-carbolines, dragmacidonamines A 296 and B 297, were isolated from a Dragmacidon species (Adaman Islands, India).³⁷⁴ A Thorectandra species (Palau) produced a β-carboline alkaloid 298 with moderate cytotoxicity.³⁷⁵
A series of fused bisindole-derived compounds 299–306 in the fascaplysilin series were isolated from Fascaplysinopsis reticulata (Indonesia).³⁷⁶
Pyrroloquinones and pyrroloiminoquinones are associated with sponges, particularly members of the Order Poecilosclerida. Zyzzyanone A 307, which is moderately cytotoxic and inhibits division of fertilised sea urchin eggs, was isolated from an Australian Zyzzya fuliginosa.³⁷⁷ Two β-D-ribopyrroloquinoline alkaloids 308 and 309 were obtained from a South African Strongylodesma aliwaliensis.³⁷⁸
Four new discorhabdins, 3-dihydro-7,8-dehydrodiscorhabdin C 310, 14-bromo-3-dihydro-7,8-dehydrodiscorhabdin C 311, discorhabdin V 312, and 14-bromo-1-hydroxydiscorhabdin V 313 were isolated from the South African Tsitsikamma pedunculata. In the same article, the tsitsikammanamines A 314 and B 315 are reported from T. favus along with 1-methoxydiscorhabdin D 316 and 1-aminodiscorhabdin D 317 from Latrunculia bellae.³⁷⁹ Also isolated from L. bellae was discorhabdin G*, identical in structure with discorhabdin I 318 which was reported, along with discorhabdin L 319, from Latrunculia brevis (Argentina).³⁸⁰
Fortunately, some of the confusion over the earlier naming of the discorhabdin series has been resolved in a 2005 review on pyrroloiminoquinones.³⁸¹ Cribrostatin 7 320, a cytotoxic quinone alkaloid was obtained from a Petrosia species (Philippines).³⁸² A Chinese Cinachyrella australiensis contained isolumichrome 321.²⁸⁹ Bisdemethylaaptamine 322 and the 9-O-sulfate analogue 323 were isolated from an Indonesian Aaptos species.³⁸³ The racemic spiro-polycyclic aromatic alkaloid lihouidine 324, obtained from a new species of Suberea (Lihou reef, Coral Sea), showed cytotoxic activity.³⁸⁴
Syntheses of 7-methoxy-1,6-dimethylisoquinoline³⁸⁵ from a Xestospongia species,³⁸⁶ 6-hydroxy-7-methoxyisoquinolinemethanol³⁸⁷ from a Haliclona species,³⁸⁸ and cribrostatin 6³⁸⁹ from a Cribrochalina species,³⁹⁰ have been completed. Renieramycin A, from a Reniera species,³⁹¹ had antileishmanial activity.³⁹² A Leucetta species (Papua New Guinea) provided spiroleucettadine 325 which showed antibacterial activity against Enterococcus durans.³⁹³Leucetta chagosensis (Sulawesi, Indonesia) contained naamines F 326 and G 327 as well as kealiinines A–C 328–330. Naamine G was strongly antifungal.³⁹⁴Monanchora unguifera (Jamaica) provided 1,8a;8b,3a-didehydro-8α-hydroxyptilocaulin 331, together with the known 8β isomer, which co-crystallised in perfect order with an approximate inversion centre.³⁹⁵
Monanchorin 332, a new bicyclic metabolite and the pentacyclic crambescidin acid 333, previously reported as the ethyl ester,³⁹⁶ have both been isolated from Monanchora ungiculata (Maldive Islands).³⁹⁷ Two phakellin alkaloids, 334 and 335, active as human lipoxygenase inhibitors, were found in an Agelas species (Papua New Guinea).³⁹⁸
An Okinawan Agelas species provided the nagelamides A–H 336–343 and 9,10-dihydrokeramadine 344. The nagelamides were antibacterial, while nagelamide G inhibited protein phosphatase 2A activity.³⁹⁹
A systematic analysis of CD spectra and Mosher acid derivatives suggested that the configuration of longamide A, from Agelas longissima,⁴⁰⁰ be revised to (4R).⁴⁰¹ (±)-Sceptrin,^402,403 from Agelas sceptrum,⁴⁰⁴ and (±)-dibromosceptrin⁴⁰³ from Agelas conifera,⁴⁰⁵ have both been synthesised. The conversion of ageliferin into sceptrin using microwave irradiation also revealed a possible alternative biosynthetic pathway linking the pyrrole-imidazole alkaloids.⁴⁰⁶ The synthesis of dehydrobatzelladine C, originally isolated from two Monanchora species³⁹⁶ has been reported.⁴⁰⁷ The first enantiospecific synthesis of agelastatin A, isolated from Agelas dendromorpha,⁴⁰⁸ has been achieved.⁴⁰⁹ The HIV-active alkaloid batzelladine A, from a Batzella species,⁴¹⁰ has been synthesised in an enantio-pure form.⁴¹¹ Crambescidin 800, originally isolated from Crambe crambe,⁴¹² caused myelogenous leukemia cells to differentiate into erythrocytes.⁴¹³ The schulzeines A–C 345–347 were isolated from Penares schulzei (Hachijo-kojima Is., Japan).⁴¹⁴
The configurations of these unusual sulfonated long chain aromatic alkaloids, potent inhibitors of yeast α-glucosidase, were determined from a combination of chemical degradation and modified Mosher's method. A series of bromotyrosine alkaloids, the purpurealidins A–H 348–355, were reported from a Psammaplysilla purpurea (India).⁴¹⁵
Purpurealidin B 349 was antibacterial. Two potent antagonists of the sarcoplasmic reticulum calcium channel RyR1-FKBP12, the sulfonates 356 and 357, were isolated from Ianthella basta (Guam), along with 34-O-sulfatobastadin-9 358.⁴¹⁶ A sulfur-containing nucleoside, hamiguanosinol 359, was obtained from a Mediterranean Hamigera hamigera.³⁵⁴
A bromotyrosine oxime that inhibits mycothiol-S-conjugate amidase, isolated from an Oceanapia species,⁴¹⁷ has been synthesised.⁴¹⁸ The same molecule was also synthesised independently through a trifluoromethyloxazole intermediate.⁴¹⁹ A total synthesis of the eurypamides, first isolated from a Palauan Microciona eurypa,⁴²⁰ resulted in revised stereochemistry for eurypamide A 360 and confirmed the structures of eurypamides B–D.⁴²¹ Two macrocyclic merosesquiterpenoids, likonides A 361 and B 362, were obtained from a Kenyan Hyatella species.⁴²² 17-O-Isoprenyldictyoceratin-C 363 was isolated from a Philippine Spongia species.⁴²³ An amino-merosesquiterpenoid, 5-epi-smenospongorine 364, isolated from Dactylospongia elegans (Flores, Indonesia), caused the differentiation of K562 leukemia cells into erythrocytes.⁴²⁴
A Papua New Guinean Psammocinia species contained chromarols A–E 365–369, inactivators of human 15-lipoxygenase through a redox mechanism similar to that reported for a range of known meroterpenoids.⁴²⁵ Makassaric acid 370 and subersic acid 371, isolated from an Acanthodendrilla species (Sulawesi, Indonesia), were inhibitors of MAPKAP kinase 2.⁴²⁶Petrosia (Strongylophora) corticata (Papua New Guinea) contained the anti-invasion active meroditerpenoid strongylophorine-26 372.⁴²⁷
A series of merosesquiterpenoids from a variety of sponge sources were assessed for hemolytic and cytotoxic properties.⁴²⁸ Similarly, a further range of sponge-derived merosesquiterpenoids were active as antioxidants.⁴²⁹ Smenospongine, originally isolated from a Smenospongia species,⁴³⁰ caused K562 leukemia cells to differentiate into erythrocytes.⁴³¹ A series of polyprenylated hydroquinones and benzoic acids of sponge origin inhibited phosphatase CDC25A.⁴³² Puupehenone, originally isolated from a Hawaiian sponge,⁴³³ inhibited the differentiation of endothelial cells into tubular structures, an important step in angioneogenesis.⁴³⁴ Chloropuupehenone⁴³³ has been synthesised.⁴³⁵ An aromatic sesquiterpenoid 373 was isolated from a Didiscus species (Thailand).⁴³⁶Stylotella aurantium (Great Barrier Reef) yielded a carbonimidic dichloride stylotellane D 374.⁴³⁷ The weakly antibacterial hyrtiosenolides A 375 and B 376 were isolated from a Red Sea Hyrtios species.⁴³⁸
The boneratamides A–C were isolated as their methyl esters 377–379 from an Indonesian Axynyssa aplysinoides.⁴³⁹ The relative stereochemistry of boneratamide A 377 was established by X-ray analysis, while boneratamides B 378 and C 379 differ in their relative configurations at either one or both of C-18 and C-23. The antimicrobial germacrane sesquiterpenoid 380, and the bis-urea analogue 381, were obtained from an Axinyssa species (Thailand).⁴⁴⁰ Two sesquiterpene isothiocyanates 382 and 383 were obtained from an Okinawan Stylissa species.⁴⁴¹
The biosynthesis of the carbonimidic dichloride sesquiterpenoids, the stylotellanes A and B, was examined in the producing organism Stylotella aurantium (Great Barrier Reef). Feeding experiments with ¹⁴C-labeled metabolites established that CN, SCN, and farnesyl isothiocyanate were intermediates in the biosynthetic pathway to these dichloroimines.⁴⁴² A total synthesis of hamigeran E,⁴⁴³ from a New Zealand Hamigera tarangaensis, has been reported.⁴⁴⁴ (6R,7S)-7-amino-7,8-dihydro-α-bisabolene, from a Halichondria species,⁴⁴⁵ has been synthesised.⁴⁴⁶ Helianane, isolated from Haliclona fascigera,⁴⁴⁷ was synthesised employing a vacuum thermolytic ring expansion step.⁴⁴⁸ A Kenyan Raspailia species gave two purine alkaloid-derivatised diterpenes asmarines G 384 and H 385 and the diterpenoid barekol 386, together with several related known compounds.⁴⁴⁹ A Raspailia species (Madagascar) produced further asmarines, I–K 387–389, and the diterpenoid nosyberkol 390.⁴⁵⁰
A furanoditerpenoid 391, and two related norditerpenoids 392 and 393, that inhibit the lyase activity of DNA polymerase β, were obtained from an unidentified Dictyoceratid sponge from Papua New Guinea.⁴⁵¹ A bright yellow encrusting Aplysillid sponge, tentatively identified as Aplysilla sulfurea from S. E. Queensland, contained the cytotoxic and nematocidal compound chromodorolide C 394, along with the known A and B congeners.⁴⁵²Acanthella cavernosa (Philippines) provided 10-formamido-kalihinol F 395 and 15-formamido-kalihinol F 396, both of which inhibited bacterial folate biosynthesis.⁴⁵³
A norgracilane 397 and three new aplysulfurane-type spongian diterpenoids 398–400 were isolated from Dendrilla membranosa (South Shetlands, Antarctic),⁴⁵⁴ and by forming complexes between (R) and (S) 2,2,2-trifluoro-1-(9-anthryl)ethanol and the γ-methylbutenolide of 397 the absolute stereochemistries were established (as drawn). Aplysulfurane-type spongian diterpenoids, with antiinflammatory properties, were also reported from a New Zealand Chelonaplysilla violacea.⁴⁵⁵ Two compounds from this series, named as pourewic acid A 398 and cadlinolide C 399, were found in both collections along with the formate-containing pourewanone 401, methyl pourewate B 402, 15-methoxypourewic acid B 403, and an inseparable mixture of the diastereoisomeric cadlinolides D 404, with relative stereochemistries established as drawn.
The optical rotation of the New Zealand-derived pourewic acid A, which was small, was comparable to but opposite in sign to that reported for the Antarctic sample, but the measurements were made in different solvents (CH₂Cl₂vs. CHCl₃). Further resolution of the absolute stereochemistries will require more rigorous chiroptical evaluation of the samples. In contrast, an Anvers Is., Antarctic, collection of Dendrilla membranosa yielded the aromatic antimicrobial spongian diterpenoids, membranolides B–D 405–407.⁴⁵⁶ The three diterpenoid isocyanides 408–410, isocyanate 411, and isothiocyanate 412 were isolated from the same Okinawan Stylissa species that had yielded the previously described isothiocyanate sesquiterpenes 382 and 383.⁴⁴¹
All metabolites displayed weak cytotoxicity. The biosynthetic origins of the isocyanide and isothiocyanate carbon of a variety of sesqui- and diterpenes isolated from Amphimedon terpenensis and an Axinyssa species (Great Barrier Reef), have been investigated. For all compounds specific incorporation of ¹⁴C-thiocyanate was demonstrated.⁴⁵⁷ A racemic synthesis of kalihinol C, first isolated from an Acanthella species,⁴⁵⁸ has been reported.⁴⁵⁹ Three cytotoxic norsesterterpenoids, tasnemoxides A–C 413–415, have been isolated from a Red Sea Diacarnus erythraenus.⁴⁶⁰ An Acanthodendrilla species (Indonesia) provided the cytotoxic acantholides A–E 416–420.

Acantholide B 417 was antimicrobial.⁴⁶¹ A Korean Psammocinia species contained three cytotoxic sesterterpenoids, psammocinins A₁421, A₂422 and B 423.⁴⁶² (6Z)-Neomanoalide-24,25-diacetate 424 was obtained from a Palauan Luffariella species.⁴⁶³ A Brachiaster species (Thailand) yielded the same manoalide congener 424, the (E) isomer 425 and the potently antitubercular 12-deacetoxyscalarin-19-acetate 426.⁴⁶⁴
Five moderately cytotoxic sesterterpenoids, three scalaranes 427–429 and two linear furanoterpenoids 430 and 431, were obtained from a Korean Smenospongia species.⁴⁶⁵
Hyrtios erectus (Hainan Is., China) contained the linear furanoterpenoid 5,10-dihydroxyfurospinulosine-1 432, two formylhyrtiosal congeners 433 and 434, and 12α-O-acetylhyrtiolide 435.⁴⁶⁶Stoeba extensa (Japan) gave the cytotoxic furanosesterterpenoid shinsonefuran 436 along with halisulfate 7 437.⁴⁶⁷
The C-8 stereochemistry of halisulfate 7, originally isolated from a Coscinoderma species,⁴⁶⁸ has been revised to that shown on the basis of careful NOE analysis.⁴⁶⁷ A scalarane-type sesterterpenoid 438, and a related oxycyclic congener 439, were obtained from a Madagascan Phyllospongia madagascarensis.⁴⁶⁹ Two different, undescribed Madagascan species of Lendenfeldia contained a linear furanoterpenoid 440 with potent HIV-1 reverse transcriptase inhibitory activity, along with four scalarane-type sesterterpenoids 441–444.⁴⁷⁰
Suberites caminatus (King George Is., Antarctica) contained oxaspirosuberitenone 445 and 19-epi-suberitenone 446.⁴⁷¹ In an independent study, a Suberites species, also collected from King George Is., Antarctica, yielded suberitenones C 447 and D 448, and suberiphenol 449.⁴⁷²
Untenospongin B from an Okinawan Hippospongia species,⁴⁷³ has antimicrobial activity.⁴⁷⁴ A structural comparison of the PLA₂ inhibitory activity of the petrosaspongiolides, isolated from Petroaspongia nigra,⁴⁷⁵ was reported.⁴⁷⁶ Using bioassay-guided fractionation, heteronemin⁴⁷⁷ was reisolated as a farnesyl transferase inhibitor from Hyrtios reticulata.⁴⁷⁸ Cacospongionolide E from Fasciospongia cavernosa⁴⁷⁹ has been synthesised.⁴⁸⁰ A synthesis of (−)-(18S)-variabilin from Ircinia variabilis⁴⁸¹ has been achieved.⁴⁸² Four cytotoxic steroids 450–453 were obtained from Axinellacf.bidderi (Yemen, Indian Ocean).⁴⁸³Phorbas amaranthus (Florida) contained four moderately cytotoxic nor-ring A steroids, phorbasterones A–D 454–457 of which 456 and 457 were isolated as C-24 epimeric mixtures.⁴⁸⁴
Nakiterpiosin 458 and nakiterpiosinone 459, both potent cytotoxins, were obtained from Terpios hoshinota (Okinawa).⁴⁸⁵ An Italian Cliona nigricans produced the potently cytotoxic polychlorinated steroids clionastatins A 460 and B 461.⁴⁸⁶ The C31 steroid, ophirasterol 462, was isolated from a Colombian Topsentia ophiraphidites.⁴⁸⁷
Two steroidal saponins, erylosides K 463 and L 464, were isolated from a Jordanian specimen of the same sponge, Erylus lendenfeldi, from which eryloside A was originally isolated.^488,489Rhabdastrella aff. distincta (Hainan Is., China) provided four isomalabaricane-type triterpenoids isogeoditins A 465 and B 466, 13-(E)-isogeoditin A 467, and 22,23-dihydrostellettin B 468.⁴⁹⁰

8 Coelenterates

There was a slight increase in new chemistry identified from coelenterates in 2004 compared to the number reported in 2003. The glycerol derivative 469 was reported from a gorgonian Junceella juncea (South China Sea).⁴⁹¹ The acyl glycerol ethers 470 and 471 and ceramide 472 were isolated from a Lobophytum species (Indian Ocean).⁴⁹² The stereochemical assignment of 472 was achieved by analysis of derivatives of hydrolysis products. The sphingosines 473 and 474 were obtained as mildly antibacterial components of an Indian Ocean gorgonian Pseudopterogorgia australiensis.⁴⁹³ Structurally-related lipids 475⁴⁹⁴ and 476⁴⁹⁵ were isolated from Junceella juncea and a Lobophytum species respectively, with stereochemical assignments of 475 being made by analysis of hydrolysis products.
An Alcyonium species (Senegal) was the source of glycolipids 477 and 478.⁴⁹⁶ The chloromacrolactones, lytophilippines A 479, B 480 and C 481, were isolated as bioactive constituents from a Red Sea hydroid Lytocarpus philippinus.⁴⁹⁷
The absolute configuration of 479 was established based upon comprehensive derivatisation and chemical degradation studies in concert with J-based analysis and molecular modeling. The moderately cytotoxic pentapeptide gymnangiamide 482 was isolated from a Philippines hydroid Gymnangium regae.⁴⁹⁸ Chemical degradation and derivatisation, followed by HPLC analysis allowed the determination of the absolute configuration of 482. The related clavulazols, A 483 and B 484, are two new pyrazine derivatives from Clavularia viridis (Taiwan).⁴⁹⁹ Furanones 485 and 486 were obtained, in addition to a number of other compounds, from a Taiwanese soft coral Sinularia nanolobata.⁵⁰⁰
The absolute configuration of 485, and by association 486, was established by comparison with spectroscopic data previously reported for synthetically-derived 485. Prostanoids 487–493 were also isolated from a Taiwanese C. viridis.⁵⁰¹
The absolute configurations of all compounds were assigned by comparison of CD spectra with that for clavulone I. 492 was the most potent cytotoxin in the series. The structurally-related punaglandins, originally isolated in 1985 from a Hawaiian Telesto riisei,^502,503 inhibit ubiquitin isopeptidase activity⁵⁰⁴ while several members of a synthetically-derived library of punaglandin-related analogues exhibited similar cytotoxic potency to that observed for the natural product punaglandin 3.⁵⁰⁵ An unusual bicyclic prostanoid, carijenone 494, was obtained from an Eastern Pacific octocoral Carijoa multiflora.⁵⁰⁶ The absolute configuration of (+)-tricycloclavulone 495, from an Okinawan Clavularia viridis,⁵⁰⁷ has been established by enantioselective total synthesis.⁵⁰⁸ The guaiane-skeleton sesquiterpenes menverins A–D 496–499 were isolated from Menella verrucosa (South China Sea).⁵⁰⁹ The instability of the compounds was noted, particularly that of 497 which was observed to dehydrate to 500 in the NMR tube (CDCl₃).
Bioassay-guided fractionation of a Taiwanese soft coral Lemnalia cervicorni yielded the known mildly cytotoxic sesquiterpene lemnalol as well as the inactive metabolites cervicol 501, isolemnalol 502 and the ketone 503.⁵¹⁰ The ketone 503 was isomeric with 4-oxo-α-ylangene⁵¹¹ and exhibited identical ¹³C and NOESY NMR data consistent with an α-orientation of the isopropyl group. Sarcophyton glaucum (Kitungamwe Reef, Kenya) yielded, in addition to other known compounds, the mildly cytotoxic sesquiterpene guaiacophine 504.⁵¹²
Five nardosinane-skeletoned sesquiterpenes, armatins A–E 505–509, were isolated from a Taiwanese Nephthea armata.⁵¹³ Diketone 510 was also reported for the first time as a natural product. Isis hippuris (coast of Taiwan) was the source of isishippuric acids A 511 and B 512.⁵¹⁴ Sesquiterpene 512 exhibited moderate in vitro cytotoxicity towards tumour cell lines. Cladidiol 513, a mild inhibitor of acetylcholinesterase, was obtained from a Cladiella species (Andaman Is., India).⁵¹⁵
Sesquiterpenes 514–517 were isolated from Clavularia koellikeri (Okinawa).⁵¹⁶ Mosher's method secured the absolute stereochemistry of 515, which on acetylation gave 514 securing the absolute configuration of this compound as well. The absolute configuration of 517, previously reported as a synthetic intermediate,⁵¹⁶ followed from comparison of the [α]_D with literature values.⁵¹⁶ (+)-Cyclocolorenone 518, previously known as a terrestrial metabolite, and the 1α-OH analogue 519 were isolated from a soft coral Nephthea species (Andaman and Nicobar Islands, Indian Ocean).⁵¹⁷ Nanonorcaryophyllenes A 520 and B 521 were obtained from Sinularia nanolobata (Taiwan).⁵⁰⁰
The absolute configuration of 520 was the opposite of a stereochemically-defined microbially-derived metabolite of caryophyllene. The structure of the sesquiterpene alcyopterosin N, from the sub-Antarctic soft coral Alcyonium paessleri,⁵¹⁸ has been confirmed by total synthesis.⁵¹⁹ Nine meroditerpenoids, chabrolonaphthoquinone A 522, chabrolohydroxybenzoquinones A–D 523–526, and chabrolobenzoquinones A–D 527–530, were isolated from a Taiwanese Nephthea chabrolii.⁵²⁰
The merosesquiterpene 531, previously reported as a synthetic intermediate,⁵²¹ has been obtained from a Scleronephthya species (South China Sea).⁵²² Three publications in 2004, presenting new pterosin diterpene glycosides from the soft coral Pseudopterogorgia elisabethae, unfortunately led to duplication in structures and trivial names. Ata et al. reported structures of pseudopterosins P 532 and Q 533 in addition to elisabethins E 534 and F 535 from P. elisabethae (Bahamas).⁵²³
Hydrolysis and comparison of optical rotation data supported the presence of β-L-xylose in both 532 and 533. Both pseudopterosin P and Q, as well as previously reported analogues pseudopterosins A–E and K isolated from the same soft coral specimens, exhibited antibacterial activity towards Gram-positive bacteria, but not towards Gram-negative organisms. Elisabethins E 534 and F 535 were inactive in the same assays. Working with P. elisabethae (Colombian Caribbean), Duque et al. isolated seven diterpene glycosides, pseudopterosins P–V 536–542.⁵²⁴ The absolute configuration of the aglycone of 536 was established by phenolic O-benzylation at C-9, sugar removal by hydrolysis and comparison of NMR and chiroptical data reported for the known benzyl ether. In the case of 536–539, the sugar was identified as an appropriately acetylated α-L-fucopyranoside by hydrolysis, derivatisation and chromatographic analysis, while β-D-arabinopyranoside was the sugar moiety present in 540–542. The structures presented for pseudopterosins U 541 and V 542 are isomeric with those previously reported for pseudopterosins O and N respectively.⁵²⁵ Confusingly, in the original publication that reported pseudopterosins N and O,⁵²⁵ the structures were drawn as bearing xyloside sugar moieties, while the text suggested the structures contained D-arabinose sugars. The NMR data reported for pseudopterosins U and V are not coincident with the values previously reported for pseudopterosins O and N. Rodríguez et al., also working with P. elisabethae (Colombian Caribbean), isolated eleven diterpene glycosides that they named pseudopterosins P 537, Q 538, R 543, S 544, T 536, U–Z 545–550, and two seco-pseudopterosins, H 551 and I 552.⁵²⁶
The absolute configuration of the sugars in 551 and 552 were not determined—they are arbitrarily represented in this review as D. Of the metabolites reported by Rodríguez et al., 543 and 544 represent unique diacetate derivatives. Whereas Duque et al. reported 540–542 claiming the presence of a β-D-arabinose sugar, Rodríguez et al. reported the apparently isomeric structures 549, 545 and 546 respectively as containing an α-D-arabinoside moiety, together with 547 and 548, also containing this moiety. The NMR and optical rotation data reported for the α-/β-anomer pairs 541/545 and 542/546 were identical (but different to pseudopterosins N and O, see above), indicating a lack of congruity between the structures and their stereochemistries. As of October 2005 these issues had not been addressed and resolved in the scientific literature. Diterpenes 537, 538, 545–548, 551 and 552 displayed activity in a number of biological assays including antiinflammatory, cytotoxicity and antiinfective evaluation.^524,526 The relative stereochemistry of the cubitane-skeleton diterpene 553, from Eunicea laciniata (Barbados), was determined by use of a T-ROESY NMR experiment.⁵²⁷ Cembranes 7,8-dihydroflabellatene A 554 and B 555 were isolated from extracts of a sea pen Gyrophyllum sibogae (South Africa).⁵²⁸ The relative stereochemistry of 554 was secured by X-ray analysis (Mosher's method failed), while the absolute configurations of 554 and 555 were equated to those of the known sponge metabolites 556 and 557.⁵²⁹ Cembrane 554 exhibited potent antiproliferative activity towards tumour cell lines. Sarcophydiol 558 was isolated from a Sarcophyton species (Hainan Is., China).⁵³⁰
Cembradienes 559–563 were obtained from a Eunicea species (Colombian Caribbean).⁵³¹ The structure and relative configuration of 559 was established by X-ray analysis, confirming that 559–562 contained the unusual C2–C12 ether linkage, while the inter-relationships between 559–562 were established by chemical conversion. Mild growth inhibition of Plasmodium falciparum was observed for 559, 560 and 562. Of three norditerpenoids, scabrolides E–G 564–566, from a Taiwanese Sinularia scabra, 564 was a modestly potent growth inhibitor against two tumour cell lines.⁵³²
Cembratrienes 567 and 568, containing the rare (12Z) geometry, were isolated from a new species of Sarcophyton (Great Barrier Reef).⁵³³ The same study also led to the determination of the absolute configuration (MPA ester) of sarcoglaucol-16-one 569⁵³⁴ and, by comparison of CD spectra, sarcophine 570.⁵³⁵ The acetate derivative 571, also present in a Kenyan Sarcophyton glaucum, was identified as a natural product.⁵¹² A number of rearranged and halogenated semisynthetic derivatives of sarcophine have been prepared and evaluated in a range of biological assays.^536,537 Neodolabellan-skeleton diterpenes 572 and the modestly cytotoxic 573 were isolated from an Okinawan soft coral Clavularia koellikeri.⁵¹⁶
The structure and relative stereochemistry of 572 were established by X-ray analysis, while oxidation of 573 yielded 572. The absolute configuration of 573, and hence of 572, was secured (Mosher's). Nanolobatins A–C 574–576 were reported from Sinularia nanolobata (Taiwan).⁵⁰⁰ All three diterpenes exhibited modest cytotoxicity towards tumour cell lines. The structure and relative configuration of ciereszkolide 577, a rearranged cembrane from a Caribbean sea plume Pseudopterogorgia kallos, was established by X-ray analysis.⁵³⁸
Further examination of the same species from the same location also afforded the hexacyclic diterpene, bielschowskysin 578, secured by X-ray analysis.⁵³⁹ Modest biological activity towards Plasmodium falciparum and human tumour cell lines was observed. A number of new briarane-skeleton diterpenes were isolated from coelenterates in 2004. Fragilide A 579⁵⁴⁰ and junceellolide I 580⁵⁴¹ were obtained in separate studies from the same collection of Junceella fragilis (southern coast of Taiwan). Another collection of J. fragilis, this time from the South China Sea, afforded junceellonoids A 581 and B 582,⁵⁴² while extracts of J. juncea, (also South China Sea) yielded juncins O–Q 583–585.⁵⁴³
Briaexcavatolides W 586,⁵⁴⁴ and X–Z 587–589,⁵⁴⁵ were obtained from a Taiwanese Briareum excavatum. A sea whip Ellisella species (Okinawa) was the source of briaranes 590–593, of which 591 and 592 were inhibitors of cytokinesis.⁵⁴⁶ The same paper also reported 594–597 and a number of known diterpenes from a sea pen Pteroides species (Indonesia).

One of the known diterpenes, 12-O-desacetyl-12-O-benzoylpteroidine,⁵⁴⁷ demonstrated in vitro reversal of multi-drug resistance properties. The absolute stereochemistry of minabein-4 598 was established by X-ray analysis.⁵⁴⁸ From this it was concluded that the C-2/C-9 diastereomeric structure reported for nui-inoalide-D, isolated from Junceella gemmacea,⁵⁴⁹ which exhibits identical ¹³C NMR data to 598, was incorrect. Kitungolides A–C 599–601 are unusual coumarin-containing diterpenes from a new genus of Kenyan soft coral.⁵⁵⁰
Pregnanes 602 and 603, previously reported as synthetic intermediates,^551,552 were isolated from a Scleronephthya species (South China Sea).⁵²² The Δ²⁰-pregnanes 604 and 605, from an Indopacific Carijoa species, were identified as moderately potent inhibitors of the mitochondrial respiratory chain.⁵⁵³Carijoa multiflora (Panama) gave the unusual chlorinated pregnanes 606 and 607.⁵⁵⁴ Pregnane 608, previously known as a synthetic intermediate,⁵⁵⁵ and the diacetoxy-analogue 609 were isolated from a Taiwanese Subergorgia mollis.⁵⁵⁶
The pregnane saponin 610, from a Panamanian Muricea cf purpurea, is unusual because it contains L-galactose linked to the aglycone by an α-glycosidic bond.⁵⁵⁷ The sugar configuration was determined by hydrolysis, derivatisation and comparison of CD spectra with the corresponding synthetically-prepared α-D and β-D-galactose derivatives. Interestingly, a saponin bearing the same overall structure and comparable [α]_D value, but with a β-glycosidic linkage 611, was reported from Eunicea laciniata (Barbados).⁵²⁷
The natural product 612 was isolated from a Lobophytum species (Andaman and Nicobar Islands),⁵⁵⁸ while the 19-hydroxylated steroids acanthovagasteroids A–D 613–616 were reported from Acanthogorgia vagae (South China Sea).⁵⁵⁹
The 19-acetoxysterols armatinols A 617 and B 618 were isolated as mildly cytotoxic components from a Taiwanese Nephthea armata.⁵¹³ Two new, 619 and 620, and three known sterols were obtained from Sarcophyton glaucum (Taiwan).⁵⁶⁰ Whilst 619 and 620 were inactive, two of the known sterols exhibited modest cytotoxicity towards a panel of mouse and human tumour cell lines. The modestly cytotoxic steroids 621–627 were isolated from an Antarctic octocoral Dasystenella acanthina.⁵⁶¹

The absolute configuration at C-24 in 621 was established (Mosher's). Bioassay-directed fractionation of extracts of Dendronephthya gigantea (Green Is., Taiwan) yielded dendronesterones A–C 628–630 of which 628 exhibited mild cytotoxicity.⁵¹⁰
In addition to the diterpenes reported above, the cholic acid derivatives 631 and 632 were obtained from an Eleutherobia species (Pohnpei, Micronesia).⁵⁴⁸ The structure of the first A-nor-hippuristanol steroid 633, a mildly cytotoxic constituent of a Taiwanese Isis hippuris, was established by X-ray analysis.⁵¹⁴ Steroidal glycoside 634 was isolated from Junceella juncea (South China Sea).⁴⁹¹
The structure of 24-methylene-cholesta-3β,5α,6β,19-tetraol, a mildly cytotoxic sterol from Nephthea albida and N. tiexieral verseveldt,⁵⁶² has been confirmed by synthesis from stigmasterol.⁵⁶³ A number of steroids, from a range of coelenterates, exhibited significant inhibition of the 5α-reductase enzyme.⁵⁶⁴ The structures of three mildly cytotoxic biscembranoids, methyl tortuoates A 635 and B 636 from Sarcophyton tortuosum (Hainan Is.),⁵⁶⁵ and nyalolide 637, from a Kenyan Sarcophyton glaucum,⁵¹² were established by X-ray analyses of 635 and 637. The structures of all three are arbitrarily presented in this review as bearing the purported absolute configuration of the related metabolite methyl sartortuoate.⁵⁶⁶ Two unusual mixed-skeleton terpenoids were also reported from soft corals in 2004. Stolonilactone 638, putatively derived from condensation of a cembrane diterpenoid and trisnorsesquiterpene fragments, was obtained from an Okinawan Clavularia koellikeri.⁵⁶⁷ The structure of polymaxenolide 639, from a hybrid soft coral Sinularia maxima x S. polydactyla (Guam), was established by X-ray analysis,⁵⁶⁸ and represents the fusion of a cembrane diterpene with an africanane-type sesquiterpene.

9 Bryozoans

The number of new secondary metabolites reported from bryozoans in 2004 remains small. Six alkaloids, calibugulones A–F 640–645, were isolated from Calibugula intermis (Palau) with the structures of 641 and 642 being confirmed by chemical interconversion. All calibugulones displayed cytotoxicity against murine IC-2^WT tumour cells in vitro with 644 being the most potent.⁵⁶⁹ Two syntheses of calibugulones employing similar methods from an isoquinoline dione,⁵⁷⁰ or 5-aminoisoquinoline⁵⁷¹ were reported almost simultaneously. The potent and selective inhibition of the dual specificity phosphatase Cdc25B was also reported for these compounds.⁵⁷⁰ Larvae of Bugula neritina (Morehead, North Carolina) were the source of bryostatin 20 646, along with the known bryostatin 10⁵⁷² and an as yet uncharacterised bryostatin.⁵⁷³
Proof that Endobugula sertula, the bacterial symbiont of Bugula neritina, is the producer of the bryostatins was recently obtained.⁵⁷⁴ The bryostatins are concentrated in the bryozoan larvae and give protection against predation by fish, but the adults are unprotected. The bryostatins represent the first marine example of a microbial symbiont producing an antipredator defence for its host.⁵⁷⁴Flustra foliacea (“Steingrund”, North Sea) was the source of deformylflustrabromine B 647 along with a number of previously reported compounds. All compounds were tested in vitro for affinity towards the α4β2* and α7* subtype of the neuronal nicotinic acetylcholine receptor using radioligand binding assays, with deformylflustrabromine⁵⁷⁵ and deformylflustrabromine B 647 showing affinities in the lower micromolar range.⁵⁷⁶ Myriaporones are polyketide-derived compounds originally isolated from a bryozoan Myriapora truncata.^577,578 The total syntheses of myriaporones 1 648, 3 649 and 4 650 have been reported by two groups allowing determination of the previously undetermined C-5 and C-6 configurations.^579,580 The first enantioselective synthesis of the Flustra foliacea metabolite (−)-flustramine B⁵⁸¹ has been accomplished, employing a cascade addition–cyclisation strategy.⁵⁸²

10 Molluscs

There was a decrease in new chemistry identified from molluscs in 2004. Bioassay-directed fractionation of extracts from Mytilus galloprovincialis (coast of Italy) afforded the cytotoxic chlorosulfolipid 651.⁵⁸³ The relative configurations were deduced from NMR data, while the absolute configuration was based upon comparison with related compounds from the same source. Collections of Mytilus edulis and Cerastoderma edule in the presence of a Dinophysis acuta bloom (coast of Norway) afforded PTX-12 652, a new member of the pectenotoxin family that occurs as a pair of C-36 equilibrating diastereoisomers.⁵⁸⁴ A brevetoxin analogue, brevetoxin B5 653, was isolated from a New Zealand cockle Austrovenus stutchburyi and also detected in two other mollusc species, Perna canaliculus and Crassostrea gigas.⁵⁸⁵ The structure was elucidated by comparison with related toxins brevetoxin B1 and PbTx-2 and confirmed by chemical conversion from PbTx-2. A sea hare Dolabella auricularia (Japan) afforded the cytotoxic depsipeptide aurilide 654.⁵⁸⁶ The absolute stereochemistry of 654 was determined by analysis of hydrolysis products and confirmed by enantioselective synthesis. Aurilide exhibits potent in vitro cytotoxicity, toxicity in in vivo evaluation and strongly stabilises microtubules, but with a different mechanism from that exhibited by taxol.
The relative stereochemistry was established for the cytotoxic glycosidic macrolide dolastatin 19 655 from D. auricularia (Gulf of California).⁵⁸⁷ It has been demonstrated that mate attraction in sea hares of the genus Aplysia is mediated via attractin peptides that contain a conserved Ile-Glu-Glu-Cys-Lys-Thr-Ser heptapeptide sequence.⁵⁸⁸ Haterumaimides L 656 and M 657 and 3β-hydroxychlorolissoclimide 658 were obtained as cytotoxic components from Pleurobranchus albiguttatus and P. forskalii (Philippines).⁵⁸⁹
Structurally-related chlorinated diterpenes have been reported previously from Lissoclinum ascidians,^590,591 supporting the assertion that the mollusc compounds are diet-derived. The isolation of a number of scalarane-skeleton metabolites, including 659 and 660 from a nudibranch Glossodoris rufomarginata (South China Sea), was proposed to be dietary-linked as the nudibranchs were found on an unidentified sponge which contained scalaradial.⁵⁹² Tribromoimidazole 661 was reported for the first time as an antimicrobial natural product from the egg masses of Spanish and Chilean collections of Trunculariopsis trunculus, Ceratosoma erinaceum and Trophon geversianus, with the structure confirmed by synthesis.⁵⁹³ Sesquiterpenes 662–664 were isolated from a nudibranch Phyllidiella pustulosa, (Hainan Is., South China Sea).⁵⁹⁴
The absolute configuration of 662 was established by chemical conversion to a known diene. The absolute stereochemistry of oxazinin-3 665, from North Adriatic Sea mussels,⁵⁹⁵ was established by synthesis,⁵⁹⁶ while the structure and absolute stereochemistry of azaspiracid-1 666, originally obtained from Irish collections of Mytilus edulis,⁵⁹⁷ has been revised as a consequence of stereoselective total synthesis.^598,599 The structure of cyercene A, a pyrone polypropionate from a Mediterranean Cyerce cristallina,⁶⁰⁰ has been confirmed by synthesis.⁶⁰¹
Austrodoric acid 667, from an Antarctic nudibranch Austrodoris kerguelenensis,⁶⁰² has been synthesised with comparison of CD spectra being used to establish the absolute configuration of the natural product.⁶⁰³ The structure proposed for onchidin,⁶⁰⁴ a cytotoxic depsipeptide from a pulmonate Onchidium species but possibly of cyanobacterial origin, has been synthesised and exhibited different spectroscopic data to that observed for the natural product.⁶⁰⁵ A full account of the stereoselective synthesis of (+)-brasilenyne, an antifeedant haloether from a sea hare Aplysia brasiliana,²⁶⁴ has been reported.²⁶⁶ Enantioselective syntheses of (−)-tochuinyl acetate 668 and (−)-dihydrotochuinyl acetate 669⁶⁰⁶ defined the absolute configurations of the sesquiterpenes that were isolated from a nudibranch Tochuina tetraquetra and its dietary soft coral Gersemia rubiformis.⁶⁰⁷
Dolastatin 18 670, from Dolabella auricularia,⁶⁰⁸ has been synthesized, confirming the original (R) stereochemistry of the N-Me-Phe unit.⁶⁰⁹ The absolute configuration of ulapualide A 671, the renowned bioactive macrolide from egg masses of a nudibranch Hexabranchus sanguineus,⁶¹⁰ has been solved by X-ray analysis of a complex with G-actin.⁶¹¹ The sponge metabolite renieramycin M can be converted to jorumycin 672,⁶¹² a cytotoxic isoquinoline alkaloid comparable in potency to ecteinascidin 743, which was originally isolated from a nudibranch Jorunna funebris (Mandapam, India).⁶¹³ The absolute configuration of (+)-norrisolide 673, from a nudibranch Chromodoris norrisi,⁶¹⁴ has been established by stereoselective synthesis,⁶¹⁵ while the biogenetically-proposed stereoisomer of acanthodoral 674, from a nudibranch Acanthodoris nanaimoensis,⁶¹⁶ has also been synthesised.⁶¹⁷
The de novo biosynthesis of aglajnes-1 and -3, linear and 4-hydroxy-α-pyrone polypropionate metabolites previously isolated from opistobranch molluscs Aglaja depicta⁶¹⁸ and Bulla striata⁶¹⁹ respectively, has been established by [1-¹⁴C]-propionate feeding experiments.⁶²⁰ Cell-free preparations of Oxynoe olivacea can convert the dietary algal metabolite caulerpenyne⁶²¹ into oxytoxin-2,⁶²² the main defensive metabolite of the mollusc.⁶²³ The biosynthesis of 3-alkylpyridine alkaloids haminol-1 and -2, from a Mediterranean Haminoea orbignyana,⁶²⁴ has been studied using [1,2-¹³C₂]-acetate incorporation, establishing elongation with acetate of a nicotinic acid starter unit.⁶²⁵ Parguerol and isoparguerol, originally from Aplysia dactylomela,⁶²⁶ induced neurite outgrowth in PC-12 cells with modest potency.⁶²⁷ The shellfish biotoxin yessotoxin¹⁹² was a potent opener of the permeability transition pore on inner mitochondrial membranes.¹⁹³

11 Tunicates (ascidians)

While the number of new metabolites isolated from ascidians has remained essentially static for each of 2002 and 2003, a slight decrease was reported in 2004. As with previous years, the majority of the metabolites reported from ascidians are derived from amino acids. (2S,3R)-2-Aminododecan-3-ol 675 was reported as an antifungal component of Clavelina oblonga (Brazil).⁶²⁸ The absolute stereochemistry was secured by preparation of the dibenzoyl derivative and comparison of CD data with structurally-defined model compounds. The first examples of acetylenic lipids from an organism of the phylum Chordata 676–679 were isolated from an unidentified ascidian of the family Polyclinidae (Spain).⁶²⁹ Biselides A 680 and B 681 were obtained from an Okinawan ascidian from the family Didemnidae.⁶³⁰
Absolute stereochemistry was implied by comparison of NMR and CD data with those reported for the corrected absolute configuration of haterumalide NA.^631,632 A stereoselective total synthesis⁶³³ has confirmed the structure and absolute configuration of bistramide A 682 from Lissoclinum bistratum.⁶³⁴ The absolute configurations of lepadins D⁶³⁵683, E⁶³⁵684 and H⁶³⁶685, from a Didemnum species⁶³⁵ and Aplidium tabascum,⁶³⁶ have been ascertained by stereoselective total synthesis.⁶³⁷ 1,3-Dimethyl-8-oxoisoguanine 686 was isolated from an ascidian Pseudodistoma cereum (New Zealand).⁶³⁸
An Australian Atriolum robustum was the source of amino acid-derived metabolites 687–691.⁶³⁹ The absolute stereochemistries of 687 and 688 were established by degradative derivatisation studies while only the relative configurations of methylthioadenosine analogues 690 and 691 were determined.
Compound 690 was a relatively potent partial agonist of human A₃ adenosine receptors. A Palaun Botrylloides tyreum afforded the weakly cytotoxic tyrosine analogues botryllamides E–H 692–695.⁶⁴⁰Cystodytes cf. violatinctus (Kenya) gave violatinctamine 696, which in solution was proposed to exist as a rapidly interconverting mixture of imino-phenol (shown) and amino quinone-methide tautomers.⁶⁴¹ Lissoclibadin 1 697 was isolated as a mildly antibacterial component of an Indonesian Lissoclinum cf. badium.⁶⁴²
The relative orientations of the aromatic rings were based upon molecular modelling studies. Fascaplysin analogues 301 and 698–701 were obtained from a Didemnum species (Chuuk Atoll, Micronesia), while 301 was also isolated from a sponge Fascaplysinopsis reticulata (Fiji).³⁷⁶ Asymmetric syntheses of (+)-arborescidine A, (−)-arborescidine B and (−)-arborescidine C, antipodes of the natural products 702–704 from a New Caledonian Pseudodistoma arborescens,⁶⁴³ have been achieved via use of the Noyori catalytic asymmetric hydrogen transfer reaction.⁶⁴⁴
The synthetic arborescidines had opposite optical rotations to those of the natural products, establishing the absolute configurations as drawn and claimed originally,⁶⁴³ but opposite to those claimed in a subsequent revision.⁶⁴⁵ Three lamellarin alkaloids, lamellarins γ 705, α 706 and ε 707 were reported from Didemnum obscurum (Indian Ocean),⁶⁴⁶ while solid-phase syntheses of lamellarins Q and O have been reported.⁶⁴⁷ Four further ecteinascidins, ETs 731 708, 745b 709, 808 710 and 815 711 from Ecteinascidia turbinata were disclosed in a patent.⁶⁴⁸
Full accounts of the biomimetic synthesis of the dimeric prenylated quinone (−)-longithorone A⁶⁴⁹ from Aplidium longithorax,^650,651 of the corrected structure of diazonamide A,⁶⁵² and the isolation and synthesis of an endogenous sperm-activating and attracting factor from Ciona intestinalis⁶⁵³ have been reported. The structures of cyclic peptides bistratamides E, G and J,^654,655 from Lissoclinum bistratum,⁶⁵⁶ botryllazine B,⁶⁵⁷ from a Spanish Botryllus leachi,⁶⁵⁸ and subarine,⁶⁵⁹ a potentially ring-opened pyridoacridine alkaloid from an unidentified Singaporean ascidian,⁶⁶⁰ have been confirmed by syntheses. Molecular dynamics simulations have modelled the interaction of didemnins A and B^661,662 with human elongation factor eEF1A in the presence of GTP, an interaction that leads to inhibition of protein synthesis.⁶⁶³ Monomeric analogues of the heterodimeric antimicrobial peptide halocidin from Halocynthia aurantium⁶⁶⁴ have been prepared, leading to the identification of a more potent antimicrobial and less haemolytic variant.⁶⁶⁵ Further biological investigation of the meridianins, aminopyrimidineindole alkaloids originally from Aplidium meridianum,⁶⁶⁶ has revealed that they inhibit various protein kinases, prevent cell proliferation and induce apoptosis,⁶⁶⁷ while polycarpine, an alkaloid from Polycarpa clavata,⁶⁶⁸ and a dimethyl analogue both induced apoptosis via p53 and caspase-3 dependent pathways.⁶⁶⁹

12 Echinoderms

There was a slight increase in new compounds identified from echinoderms in 2004 compared to 2003. In addition to a number of known metabolites, xanthosine 712 was isolated from a starfish Asterias rollestoni (Yellow Sea, China).⁶⁷⁰ A ganglioside molecular assemblage, LMG-4, the major entity of which is represented by 713, was obtained from a Japanese starfish Luidia maculata.⁶⁷¹ The ganglioside displayed neuritogenic activity against PC12 cells in the presence of nerve growth factor. A structurally more complex ganglioside molecular entity CJP4 714, also exhibiting neuritogenic activity, was isolated from a Japanese feather star Comanthus japonica.⁶⁷²
The progesterone derivative 715 was obtained from a Russian starfish Lethasterias nanimensis chelifera,⁶⁷³ while the polyhydroxysterol 716 was isolated from a Pacific starfish Asterina pectinifera.⁶⁷⁴ Brine shrimp assay-directed fractionation of a starfish Certonardoa semiregularis, (Komun Is., Korea) extract, afforded twelve polyhydroxysterols 717–728 and two saponins 729 and 730.⁶⁷⁵
Side-chain configurations were determined either by Mosher analysis (certonardosterols Q₂718, A₃725, A₄726, B₄727 and certonardoside H₄730) or biogenetic arguments (certonardosterols Q₁717, Q₃719, Q₄720, Q₅721, Q₆722, Q₇723, D₅728 and certonardoside H₃729). All of the compounds tested exhibited modest in vitro cytotoxicity towards a panel of human tumour cell lines. In a separate study of the same organism from the same location, a further eleven sterols 731–741 and eight saponins 742–749 were identified.⁶⁷⁶
A glycoside, phrygioside A 750 and the corresponding aglycone 751, were isolated from a starfish Hippasteria phrygiana (Sea of Okhotsk).⁶⁷⁷ The steroid-taurine conjugate, triseramide 752, was a mildly bioactive component of a Fijian starfish Astropecten triseriatus.⁶⁷⁸
The Far-Eastern starfish Henricia sanguinolenta and H. leviuscula leviuscula yielded the saponins sanguinosides A 753 and B 754.⁶⁷⁹ The C-24 configuration of 754 was based on biogenetic considerations. Further investigation of the side-chain absolute stereochemistries of henriciosides H₁755, H₂756 and H₃757, originally isolated from a Far-Eastern starfish H. derjugini,⁶⁸⁰ (Mosher's) established that 755 is, in fact, identical to the previously reported steroid laevisculoside I,⁶⁸¹ and that 756 has the (24R,25S) configuration while 757 is (24R,25R).⁶⁸² Linckosides C–E 758–760, from the Okinawan starfish Linckia laevigata, induced neurite outgrowth in PC12 cells.⁶⁸³

The relative configurations of C-24 and C-28 in 759 were established, with the same configurations implied for 758. The triterpene aglycones, philinopgenins A–C 761–763, were obtained from the acid hydrolysate of the crude glycoside fraction from a sea cucumber Pentacta quadranglasis (South China Sea).⁶⁸⁴ The philinopgenins are possibly artefacts. Two saponins, thyonosides A 764 and B 765, were isolated from the sea cucumber Thyone aurea (Namibia).⁶⁸⁵

13 Miscellaneous

Two 21-residue antimicrobial peptides, arenicin-1 766 and arenicin-2 767 were obtained from a polychaete worm Arenicola marina (White Sea, Russia).⁶⁸⁶ Diatom-derived conjugated aldehydes such as (2E,4E)-decadienal continue to be of interest, exhibiting cytotoxicity towards a number of different organisms including bacteria, algae, fungi, echinoderms, molluscs and crustacea⁶⁸⁷ in addition to inhibiting fertilization success in broadcast-spawning invertebrates.⁶⁸⁸ The structure of the antipredatory chemical defence compound 2,3,4-tribromopyrrole from a hemichordate worm Saccoglossus kowalevskii,⁶⁸⁹ has been confirmed by synthesis.⁶⁹⁰ Mass spectrometric analysis of stable isotope incorporation experiments determined that Cypridina luciferin, an alkaloid utilised by the bioluminescent crustacean Cypridina (Vargula) hilgendorfii, is biosynthesised from L-tryptophan, L-arginine and L-isoleucine.⁶⁹¹ Gymnorrhizol 768, an unusual macrocyclic polydisulfide possessing an unprecedented carbon skeleton, has been isolated from a mangrove Bruguiera gymnorrhiza (Guangxi Province, China). The structure was confirmed by X-ray analysis.^692,693

14 Conclusions

In this review, the structures of 768 compounds have been reported. The biological testing on, or biological properties of, 380 compounds is included. Using numbers extracted from MarinLit,⁷⁹ the geographic origins of compounds reported in 2004 are compared with those up to 2003 (Fig. 1a). The geographical descriptors used in MarinLit are somewhat imprecise, ranging from exclusive to inclusive, but Australia, the Caribbean, the Indian Ocean, Japan, the Mediterranean and the Western Pacific clearly stand out as the sources for two-thirds of the reports on marine natural products, with Japan being the clear leader. What is most notable about the data for 2004 (Fig. 1b) is the marked increase in citations relating to the China Sea. Also shown in Fig. 1 is the relative proportion of articles for each region reporting bioactivity (“bioarticles”). These, taken collectively, suggest the possibility that greater attention is being paid to searching for, or commenting on, bioactive compounds (55% in 2004 vs. 49% up to 2003).

Fig. 1 (a) Accumulated distribution of literature citations by geographic region to 2003. (b) Distribution in 2004. For clarity Polar Regions includes Antarctic and Arctic articles, North Sea and Baltic Sea records are included with Eastern Atlantic, while the Black Sea and Caspian Sea are placed in Russian. “Articles” and “Bioarticles” do not necessarily contain structural information. “Bioarticles” refer to citations that include comment on the biological properties of extracts or isolated compounds from that region.

A second point of comparison is the type of biological activity reported which can grouped into eight areas—anticancer, antibiotic (which includes antifungal and antimalarial), antiinflammatory, antiviral, immunomodulatory, various, agricultural and methodology. Fig. 2 shows the types of the testing carried out up to, and including, 2004.

Fig. 2 Reported distribution of biological testing carried out on marine natural product extracts and isolated compounds to 2004. The MarinLit database⁷⁹ has 50 descriptors for key-wording biological testing. For convenience these have been grouped into eight, mainly disease-based, areas. Various includes neurological, blood pressure, fertility, allergy-based laxative, and enzyme activation assays, while Methodology covers bioassay methods, mechanism of action, structure–activity studies, other assays, radio immunoassays as well as the sea urchin egg and brine shrimp assay.

The actual data for 2004 did not vary significantly from that reported cumulatively, but was suggestive that the “catch-all” category of methodology was increasing. Testing with an anticancer outcome remains far and away the most used assay, but increasingly results are appearing in the literature for antimalarial, antitubercular and antiinfective assays against drug-resistant microorganisms and in time these areas will stand out against the cumulative record. There can be no doubt of the urgent need for new therapeutics in those areas, but also in agricultural areas where resistance to the standard anthelmintics is becoming a serious problem.

15 Acknowledgements

We thank Dr Sunny Hu for the collection of data and diagrams for this review, and for proof reading.

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