Marine Natural Products 2000

Marine natural products D. John Faulkner Scripps Institution of Oceanography, University of California at San Diego, La Jolla, CA 92093-0212, USA Received 1st September 1999 Covering: 1998 Previous review: 1999, 16, 155 1 Introduction 2 Marine microorganisms and phytoplankton 3 Green algae 4 Brown algae 5 Red algae 6 Sponges 7 Coelenterates 8 Bryozoans 9 Molluscs 10 Tunicates (ascidians) 11 Echinoderms 12 Miscellaneous 13 References 1 Introduction This Report is a review of the literature of marine natural product chemistry for 1998. Earlier reports published in this journal cover the period from 1977 to December 1997. Compared with the research activity reported during 1997,1 the major difference in 1998 was reflected in a shift in interest from marine bacteria to fungi of marine origins. Once again the literature is dominated by reports of sponge metabolites, but the excessive speculation regarding possible microbial origins for these metabolites is gradually being replaced by experimental studies. Interest in the synthesis of marine natural products continues to rise and there have been many studies of the pharmacological and biochemical mechanisms of action of marine metabolites. The continued interest in marine natural products chemistry from outside of the field bodes well for its continued development. The format for this review is identical to that of its immediate predecessors. The review does not provide a comprehensive coverage of all research involving chemicals from marine organisms but concentrates on reports of novel marine natural products with interesting biological and pharmaceutical proper- ties. Biochemical studies involving marine organisms, studies of the biosynthesis of marine natural products and reports of primary metabolites are specifically omitted. Wherever possi- ble, the biological and pharmacological properties of new marine natural products have been reported but, unless a new compound is highlighted, papers detailing the pharmacological studies are considered to be beyond the scope of this review. In the area of synthetic organic chemistry, the review focusses on reports of the total synthesis of marine natural products that confirm or redefine chemical structures. No attempt has been made to review the patent literature or conference abstracts, although experience has shown that these are very important sources for those seeking new structures for synthesis. A number of rather specialized reviews appeared in 1998. The most general and probably the most useful of these covers ‘Sulfated compounds from marine organisms’.2 Specific groups of compounds were reviewed in ‘The structural chemistry, reactivity, and total synthesis of dolabellane diterpenes’,3 ‘Survey of oxygenated 2,11-cyclized cembranoids of marine origin’4 and ‘Biomimetic and synthetic approaches to marine sponge alkaloids derived from bis-pyridine macrocycles’,5 while specific groups of organisms provided the focus for ‘Lithistid sponges: star performers or hosts to the stars’,6 Chemical and biological aspects of the sponge genus Dysidea’7 and ‘Advances in chemical studies on low-molecular weight metabolites of marine fungi’.8 Specialists will appreciate reviews of ‘The Fusetani Biofouling Project’,9 ‘Synthesis of marine natural products in Brazil’,10 ‘Cultivation of marine sponges for metabolite production: applications for bio- technology?’,11 ‘Chemical defense and evolution in the Saco- glossa (Mollusca: Gastropoda: Opisthobranchia)’,12 and ‘Bio- assays with marine and freshwater macroorganisms’.13 2 Marine microorganisms and phytoplankton An anticipated bloom of bioactive metabolites from marine bacteria did not occur during 1998 and in fact the number of new marine bacterial metabolites appears to be in decline. Furthermore, the ambition of culturing symbionts that produce bioactive compounds ascribed to host invertebrates has yet to be fully realised. None of the bacterial strains isolated from the sponge Suberea creba produced the brominated metabolites of the sponge and none of the metabolites, which included 2-n- heptyl-1,2,4-trihydroxyquinoline 1, from a pseudomonad iso- lated from the sponge could be detected in an extract of the sponge.14 The topoisomerase I inhibitors from a Streptomyces sp. KM86-9B, cultured from liquid expelled by squeezing an unidentified sponge, were identified as a series of iso- and anteiso-fatty acids.15 A sulfonic acid analogue 2 of ceramide was the major extractable lipid of Cyclobacterium marinus.16 This journal is © The Royal Society of Chemistry 2000 Nat. Prod. Rep., 2000, 17, 7–55 7 The anthranilamide 3, which was isolated from a marine Streptomyces sp. B7747 derived from sediment from the Gulf of Mexico, is a phytotoxic, antimicroalgal agent.17 A Streptomyces sp. BD-18T(41) isolated from a shallow water sediment on Oahu produced four new quinones, halawanones A–D 4–7,18 together with the known bacterial metabolite nanaomycin D.19 Guaymasol 8 and epiguaymasol 9 were obtained from a Bacillus sp. CNA-995 from a deep-sea sediment core.20 A strain of Micrococcus luteus that was cultured from the surface of the Indo-Pacific sponge Xestospongia sp. produced 2,4,4A-tri- chloro-2A-hydroxydiphenyl ether 10, which had previously been synthesized,21 and an acyl-1-(acyl-6A-mannobiosyl)-3-glycerol 11.22 Two marine Agrobacterium strains that were isolated from tunicates produced sesbanimide antibiotics that had previously been isolated from seeds of the leguminous plants Sesbania drummondii and S. punicea:23 strain PH-130 from Ecteinasci- dia turbinata produced sesbanamide A 12 and strain PH-A034C from a Polycitonidae sp. contained sesbanamide C 13.24 Three diketopiperazines, one of which, cyclo[l-(4-hydroxyprolinyl)- d-leucine] 14, was previously undescribed, were isolated as plant growth promotors from a marine bacterium A108 associated with a species of Palythoa.25 A Blastobacter sp. SANK 71894 isolated from seawater in Japan produced B- 90063 15, which inhibited endothelin converting enzyme.26 A strategy that employed Stille cross-coupling chemistry was used to prepare the antiviral agent (2)-macrolactin A 16, (+)-macrolactin E 17 and (2)-macrolactic acid 18,27 all of which had been isolated from an unidentified deep-sea bacterium.28,29 Macrolactin A 16 was also synthesized by a route that employed enantioselective dienolate aldol addition reactions.30 The structure and stereochemistry of (+)-pericosine B 19, which was obtained from a strain of Periconia byssoides cultured from the gastrointestinal tract of the sea hare Aplysia kurodai,31 have been confirmed by total synthesis.32 The siderophore alterobactin A 20 from Alteromonas lutoviolacea33 has been synthesized in an efficient manner.34 A highly diastereoselective asymmetric synthesis of moiramide B 21, which is a pseudopeptide from Pseudomonas fluorescens,35 has been reported.36 Pentabromopseudilin 22, which is an anti- microbial agent from Pseudomonas bromoutilis37 and other marine bacteria,38,39 was synthesized to illustrate a [3+2] cycloaddition strategy for the synthesis of nitrogen hetero- cycles.40 There has been a considerable increase in the number of metabolites reported from fungi that were isolated from the marine environment. However, the debate concerning their classification as “marine” continues. While fungal colonies have clearly been documented on the surface of marine algae and sea grasses, there is a clear need to demonstrate that fungi grow within sponges and other invertebrates. A marine isolate of the fungus Aspergillus versicolor that was isolated from the surface of the green alga Penicillus capitatus yielded four sesquiterpenoid nitrobenzoyl esters 23–26, the most abundant of which, 9a,14-dihydroxy-6b-p-nitrobenzoylcinnamolide 23, 8 Nat. Prod. Rep., 2000, 17, 7–55 showed significant cytotoxicity against the HCT-116 cell line and moderately selective cytotoxicity against a panel of renal tumor cell lines.41 Four tricyclic sesquiterpenes, hirsutanols A– C 27–29 and ent-gloeosteretriol 30, were obtained from an unidentified fungus 95-1005C cultured from an Indo-Pacific sponge of the genus Haliclona.42 Isolation of the related sesquiterpene hisutanol D 31 from the terrestrial fungus Coriolus consors shows that similar metabolites can be expected from fungi, irrespective of their origin.42 A Fusarium sp. strain CNC-477, which was isolated from a driftwood sample collected in a mangrove habitat in the Bahamas, produced the sesterterpenoids neomanginols A–C 32–34, of which 32 and 33 were cytotoxic.43 Trichodenones A–C 35–37 are cytotoxic agents that were obtained together with harzialactones A 38 and B 39 and R- mevalonolactone from the culture broth of Trichoderma harzianum OUPS-N115 that was originally isolated from the sponge Halichondria okadai.44 The fungus Corollospora pulchella, which was cultured from driftwood collected in Peleliu, yielded the simple lactam pulchellalactam 40, which inhibited CD45 protein tyrosine phosphatase.45 A strain of Penicillium waksmanii OUPS-N133 that was cultured from the brown alga Sargassum ringgoldianum produced pyrenocines D 41 and E 42, of which the latter inhibited P388 leukemia cells.46 Three additional antialgal agents, solanapyrones E–G 43–45, were isolated from an unidentified marine fungus CNC-159 that was cultured from the surface of the green alga Halimeda monile.47 Deoxynortrichoharzin 46 was obtained from a saltwater culture of Paecilomyces cf. javanica that was isolated from the sponge Jaspis cf. coriacea.48 The Penicillium sp. strain OUPS-79, which was originally isolated from the marine alga Enteromorpha intestinalis, has yielded four additional cytotoxic agents, penostatins F–I 47–50, when grown on a different culture medium.49 Epoxysorbicillinol 51 was obtained together with a known metabolite from a saltwater culture of Tricho- derma longibrachiatum that was isolated from the sponge Haliclona sp.50 The simple phthalide corollosporine 52 was obtained from Corollospora maritima, which is commonly found on rotting algae and driftwood.51 A Penicillium sp. N115501 from a Japanese marine sediment produced the antimicrobial anthrani- lamide derivative N115501A 53.52 Gymnastatins A–E 54–58, which show significant activity against P388 cells, are unusual cytotoxic agents from a strain of Gymnascella dankaliensis that Nat. Prod. Rep., 2000, 17, 7–55 9 had been cultured from the sponge Halichondria japonica.53 The same strain of G. dankaliensis contained two unusual cytotoxic sterol derivatives, gymnasterones A 59 and B 60.54 Hypoxylon oceanicum LL-15G256 contained two antifungal macrocyclic polylactones 15G256g 61 and 15G256d 62, which had previously been reported from terrestrial fungi,55 and the antifungal lipodepsipeptide 15G256e 63, which contained the rare amino acid b-ketotryptophan.56 Aspergillamides A 64 and B 65 are cytotoxic tripeptides from an Aspergillus sp. that was cultured from a saline lake sediment in the Bahamas.57 Interestingly, aspergillamide A 64 consists of a 1:1 mixture of cis and trans rotational isomers about the amide bond marked (*).57 A marine fungus of the genus Scytalidium produced two cyclic depsipeptides, exumolides A 66 and B 67, that inhibit the growth of the unicellular alga Dunaliella sp. at 20 mg mL21.58 Mactanamide 68 is a fungistatic diketopiperazine produced by an Aspergillus sp. that was obtained from a brown alga Sargassum sp. from the Philippines.59 The marine yeast Aureobasidium pullulans, which was cultured from an uni- dentified Okinawan sponge, produced two diketopiperazines 69 and 70 and orcinotriol 71.60 Tryprostatins A 72 and B 73, which 10 Nat. Prod. Rep., 2000, 17, 7–55 are cytotoxic diketopiperazines from Aspergillus fumigatus strain BM 939,61 together with their enantiomers, have been synthesized in a relatively straightforward manner.62 The macroscopic cyanobacteria (blue-green algae) Lyngbya majuscula continues to provide interesting new bioactive metabolites. A specimen from St. Croix contained an additional member of the “curacin family”, namely the antimitotic agent curacin D 74.63 An additional synthesis of curacin A 75, which is a potent antimitotic agent from a specimen of L. majuscula from Curaçao,64 has been accomplished in a concise manner.65 A collection of L. majuscula from Grenada produced the cyclopropane-containing fatty acid metabolites grenadadiene 76, which gave an interesting cytotoxicity profile, debromogre- nadadiene 77 and grenadamide 78, which showed modest cannabinoid receptor binding activity.66 Kalkipyrone 79 is a toxin from an assemblage of L. majuscula and Tolypothrix sp. collected in Curaçao.67 Carmabins A 80 and B 81 are lipopeptides from L. majuscula that was also collected in Curaçao.68 An assemblage of L. majuscula and Schizothrix calcicola from Guam contained lyngbyastatin 1 82, which is an inseparable mixture of epimers at C-15, together with an inseparable mixture of dolastatin 12 83, which had previously been isolated from the sea hare Dolabella auricularia,69 and its 15-epi derivative.70 The cyanophyte Symploca hydniodes contained symplostatin 1 84, which is a homologue of the linear peptide dolastatin 10,71 that had been isolated previously from D. auricularia.72 Louludinium chloride 85 is a moderately cytotoxic pyridinium salt from a specimen of L. gracilis collected at Palmyra atoll lagoon.73 Phormidium ectocarpi, which was isolated as an epiphyte of Udothea petiolata from Mallorca, contained hierridin B 86 and the known metabolite 2,4-dimethoxy-6-heptadecylphenol.74 (2)-Malyngolide 87, which is an antimicrobial lactone from L. majuscula,75 has been Nat. Prod. Rep., 2000, 17, 7–55 11 synthesized by four addtional routes that employ different strategies to accomplish the desired asymmetry.76–79 The epiphytic dinoflagellate Coolia monotis contained a new ceramide 88.80 The symbiotic dinoflagellate Symbiodinium sp. (strain no. Y-6), isolated from the flatworm Amphiscolops sp., produced the ceramide symbioramide-C16 89, the alkaloid zooxanthellamine 90, which closely resembles the alkaloid zoanthamine that was previously isolated from an Indian Zoanthus sp.,81 and zooxanthellabetaine A 91.82 Luteophanols B 92 and C 93 are additional polyols from an Amphidinium sp (strain no. Y-52) cultured from the Okinawan flatworm Pseudaphanostoma luteocoloris.83 Pectenotoxin-2 seco acid 94 and 7-epi-pectenotoxin-2 seco acid 95 are additional pecteno- toxin derivatives that were produced by the dinoflagellate Dinophysis acuta and concentrated by the New Zealand greenshell mussel Perna canaliculus.84 The structure of (+)-amphidinolide A 96, which is a metabolite of the dinoflagellate Amphidinium sp. isolated from the flatworm Amphiscolops sp.,85 was confirmed by total synthesis.86 A stereocontrolled synthesis of hemibrevetoxin B 97, which is a metabolite of the cultured dinoflagellate Gymnodinium breve,87 was achieved in 56 steps and 0.75% overall yield from d-mannose.88 Bacillariolide II 98, which is an eicosanoid from the diatom Pseudonitzschia multiseries,89 has been synthesized from (R)-malic acid.90 Raikovenal 99, a bicyclic sesquiterpene isolated from the marine ciliate Euplotes raikovi,91 has been synthsized by a route that involves the formation of a bicyclo[3.2.0]heptenone intermediate as the first step.92 3 Green algae Among the polar metabolites of Caulerpa taxifolia from the Mediterranean were the glycoglycerolipid 100 and the stable enols 101 and 102, which occur in both (E) and (Z) forms.93 The structure of the cyano-sym-triazine halimedin 103, which was isolated from Halimeda xishaensis collected from the Xisha Islands in the South China Sea, was determined by X-ray analysis.94 Although the sea grass Thalassia testudinum is certainly not a green alga, its chemistry is probably best reported here. It has been demonstrated that the T. testudinum metabolite luteolin 7-O-b-d-glucopyranosyl-2B-sulfate 104 inhibits the growth of the co-occurring thaustrochytrid Schizochytrium 12 Nat. Prod. Rep., 2000, 17, 7–55 aggregatum, which is considered a fouling organism on T. testudinum.95 4 Brown algae An addiotional cis-dihydroxytetrahydrofuran, (6S,7S,9S,10S)- 6,9-epoxynonadec-18-ene-7,10-diol 105, was described as part of a SAR study of the nematocidal properties of metabolites of Notheia anomala from southern Australia.96 A related metabo- lite of N. anomala, (6S,7S,9R,10R)-6,9-epoxynonadec-18-ene- 7,10-diol 106,97 has been synthesized in an enantiocontrolled manner.98 Dictyopterene CA 107, which is a metabolite of Dictyopteris spp.,99 has been synthesized using a route that features asymmetric catalytic cyclopropenation.100 A series of endothelin antagonists, the meroditerpenoids nahocols A 108, A1 109, B 110, C 111, D1 112 and D2 113, and isonahocols D1 114 and D2 115, were isolated from Sargassum autumnale from Japan.101 Two meronorsesquiterpenes, cysto- mexicones A 116 and B 117, together with 4-(5-hydroxy- 2-methoxy-3-methylphenyl)-butan-2-one 118 were isolated from Cystoseira abies marina from Tenerife.102 Two diaster- eoisomeric meroditerpenes 119 and 120 and two new steroids, (20S)-3b,20-dihydroxyergosta-5,24(28)-dien-16-one 121 and 3b-hydroxyergosta-5,24(28)-dien-16-one 122 were obtained from a South Australian specimen of Cystophora brownii.103 (+)-Zonarol 123, which is an antifungal sesquiterpene hydro- quinone from Dictyopteris zonaroides,104 has been synthesized using an enantioselective enzymatic hydrolysis reaction to obtain chiral intermediates.105 Stypodiol 124, which is an ichthyotoxic agent from Stypopodium zonale,106 has been synthesized using an efficient stereoselective route from (+)-carvone.107 Two crenulide diterpenes, 14-hydroxyacetoxy- crenulide 125 and 13-hydroxyacetoxycrenulide 126, were isolated from a Dictyota sp. from Chile.108 Five linear diterpenes eleganolone 127, eleganolone acetate 128, ele- gandiol 129, eleganonal 130 and epoxyeleganolone 131 from Nat. Prod. Rep., 2000, 17, 7–55 13 Cystoseira balearica109,110 or Bifurcaria bifurcata111 have been synthesized from farnesol in high overall yields.112 5 Red algae Four methoxylated fatty acids, 9-methoxypentadecenoic acid 132, 9-methoxyheptadecenoic acid 133, 13-methoxyheneicosa- noic acid 134 and 15-methoxytricosanoic acid 135, were isolated as their methyl esters from a Sicilian specimen of Schizymenia dubyi after treatment with 3% hydrochloric acid in methanol, but it is not clear whether the methoxylated fatty acids were present prior to methylation.113 Sulfoquinovosyldia- cylglycerol KM043 136 is a potent inhibitor of eukaryotic DNA polymerases and HIV-1 reverse transcriptase type 1 from a Japanese specimen of Gigartina tenella.114 Among the con- stituents of a specimen of Gracilaria coronopifolia collected one week after an outbreak of G. coronopifolia food poisoning in Maui were two new malyngamides M 137 and N 138 together with malyngamide I acetate 139.115 The same group also isolated anhydrodebromoaplysiatoxin 140 and the known116 metabolite manauealide C from G. coronopifolia.117 The authors conclude that the specimen of G. coronopifolia was most likely contaminated with the cyanophyte Lyngbya ma- juscula and propose that malyngamide N 138 represents a revised structure for deacetoxystylocheilamide, which had been isolated earlier from the sea hare Stylocheilus longicauda.118 The absolute configuration of constanolactone E 141, which is an eicosanoid from Constantinea simplex,119 has been deter- mined by total synthesis.120 The structure and absolute configuration of polycavernoside A 142, which is a human toxin isolated from Polycavernosa tsudai,121 have been established by total synthesis.122 An efficient synthesis of trans-kumausyne 143, which is a metabolite of Laurencia nipponica,123 involved a tandem intramolecular alkoxycarbonylation-lactonization step.124 Four sets of halogenated monoterpenes, pantopyranoids A–C 14