Marine natural products

Contents

• 1 Introduction

• 2 Reviews

• 3 Marine microorganisms and phytoplankton
  • 3.1 Marine-sourced bacteria (excluding from mangroves)
  • 3.2 Bacteria from mangroves
  • 3.3 Marine-sourced fungi (excluding from mangroves)
  • 3.4 Fungi from mangroves
  • 3.5 Cyanobacteria
  • 3.6 Dinoflagellates
  • 3.7 Microalgae
  • 3.8 Synthetic aspects
  • 3.9 Assorted bioactivities
  • 3.10 Biosynthesis

• 4 Green algae

• 5 Brown algae

• 6 Red algae

• 7 Sponges

• 8 Cnidarians

• 9 Bryozoans

• 10 Molluscs

• 11 Tunicates (ascidians)

• 12 Echinoderms

• 13 Mangroves

• 14 Miscellaneous

• 15 Conclusion

• Acknowledgements

• References

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Abstract

Covering: 2013. Previous review: Nat. Prod. Rep., 2014, 31, 160–258

This review covers the literature published in 2013 for marine natural products (MNPs), with 982 citations (644 for the period January to December 2013) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1163 for 2013), together with the relevant biological activities, source organisms and country of origin. Reviews, biosynthetic studies, first syntheses, and syntheses 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, from where he retired as an Emeritus Professor in 2008. His research interests are with natural products, the application of NMR techniques to structural problems, and the construction of databases to facilitate natural product investigations.

Brent R. Copp

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

Robert A. Keyzers

Rob Keyzers carried out his BSc(Hons) and PhD studies at Victoria University of Wellington. His thesis research, carried out under the guidance of Assoc. Prof. Peter Northcote, a former contributor to this review, focused on spectroscopy-guided isolation of sponge metabolites. He then carried out post-doctoral research with Mike Davies-Coleman (Rhodes University, South Africa) and Raymond Andersen (University of British Columbia, Canada) before a short role as a flavour and aroma chemist at CSIRO in Adelaide, Australia. He was appointed to the faculty at his alma mater in 2009 where he is currently a Senior Lecturer.

Murray H. G. Munro

Murray Munro, Emeritus Professor in Chemistry at the University of Canterbury, has worked on natural products right through his career. This started with diterpenoids (PhD; Peter Grant, University of Otago), followed by alkaloids during a postdoctoral spell with Alan Battersby at Liverpool. A sabbatical with Ken Rinehart at the University of Illinois in 1973 led to an interest in marine natural products with a particular focus on bioactive compounds which has continued to this day. In recent years his research interests have widened to include terrestrial/marine fungi and actinomycetes.

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

This review is of the literature for 2013 and describes 1163 new compounds from 379 articles, a 6% decrease in the number of compounds reported in 2012.¹ As in previous reviews, the structures are shown 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. Where the absolute configuration has been determined for all stereocentres in a compound, the identifying diagram number is distinguished by addition of the † symbol.

2 Reviews

A selection of the many reviews on various aspects of MNP studies is listed here. A comprehensive review of MNPs reported in 2011 has appeared,² as well as the highlights of compounds reported in 2012.³ Marine pharmacology papers for 2009–2011 have been collated,⁴ two reviews summarise natural products (NPs), including from marine sources, as drug leads,^5,6 while another paper describes recent advances in marine drug research.⁷ A synopsis of the project BAMMBO for the sustainable production of biologically active molecules of marine based origin has appeared.⁸ General classes of compounds have been reviewed in papers on marine triterpenoids as anticancer agents,⁹ alkaloids from corals,¹⁰ meroterpenes from marine invertebrates,¹¹ ‘head-to-sidechain’ cyclodepsipeptides,¹² marine alkaloids containing an 1-(indol-3-yl)ethane-1,2-diamine fragment,¹³ tetrahydrofuran-containing macrolides,¹⁴ terpenes from Sarcophyton sp.,^15,16 antimicrobial peptides from proteobacteria,¹⁷ diarrhetic shellfish toxins in Washington State.,¹⁸ di- and sesquiterpenes from Cystosiera sp.,¹⁹ and halogenated compounds from Rhodomelaceae.²⁰ Some general reviews on various classes of compounds include data on marine compounds – anticancer steroids,²¹ sesterterpenoids,²² NPs containing a nitrogen–nitrogen bond,²³ and muscarine, imidazole, oxazole and thiazole alkaloids.²⁴ Reviews on various aspects of specific compounds include lamellarins N and L,²⁵ STX,²⁶ lyngbouilloside and related macrolides,²⁷ thiomarinol and related dithiolopyrrolone compounds,²⁸ okadaic acid,²⁹ and the marinopyrroles.³⁰ There have been many reviews covering a variety of groups of marine organisms, including bioprospecting of plankton,³¹ actinomycetes,^32,33 S. China Sea opisthobranch molluscs,³⁴ actinobacteria,^35,36 filamentous marine cyanobacteria,³⁷ and microbes in general.^38–40 Reviews on specific organisms include Australian Dicathais orbita,⁴¹ metabolites from Osmundaria spp.,⁴²Aspergillus spp.,⁴³ and Bacillus spp.⁴⁴ A focus on bioactivities is made in reviews on anti-inflammatory compounds,^45,46 trypanocidal products,⁴⁷ neuroprotective compounds,⁴⁸ antitumour/anticancer agents,^49–52 kinase inhibitors,⁵³ anti-Herpes simplex agents,⁵⁴ anti-HIV actives,⁵⁵ angiogenesis inhibitors,⁵⁶ cardioprotective peptides,⁵⁷ antithrombotic peptides,⁵⁸ antimicrobial peptides,⁵⁹ therapeutics for Gram-negative sepsis,⁶⁰ and bioactives from Antarctic and Arctic organisms.⁶¹ The chemical ecology of plankton⁶² and the possible ecological roles of cyanotoxins⁶³ have been reviewed. The eighth in a companion series providing an overview of synthetic aspects of MNPs has appeared with coverage of publications from 2010.⁶⁴ Further reviews of syntheses of specific compounds include marine alkyl purines,⁶⁵ tetrodotoxin,⁶⁶ (+)-spirastrellolide A methyl ester,⁶⁷ and 'upenamide, the structure of which still remains elusive.⁶⁸ A number of papers which, while not necessarily being reviews, are useful to reference here as they describe advances in techniques or approaches to discovery that are relevant to MNP studies. These include papers on novel extraction technologies for bioactives from marine algae,⁶⁹ dereplication of marine actinomycetes by LCHRMS profiling,⁷⁰ X-ray analysis on the nanogram to microgram scale using porous complexes,^71,72 rapid screening of bioactive compounds by integrating 5-channel parallel chromatography coupled with on-line mass spectrometry and microplate based assays,⁷³ molecular networking as a dereplication strategy,⁷⁴ NMR-based metabolomic analysis of macroalgae,⁷⁵ biogeography and biodiscovery hotspots of macroalgal compounds,⁷⁶ and coral aquaculture to support drug discovery.⁷⁷ The MarinLit database has been updated and was used as the literature source for the preparation of this present review. This database has now been transferred to the Royal Society of Chemistry from where it is available as a web-accessible version.⁷⁸

3 Marine microorganisms and phytoplankton

MNP research effort is being increasingly directed towards marine microorganisms with 491 new compounds reported in 2013, an increase of 14% from 2012 (see 15 Conclusion). Unless otherwise stated, compounds described in this section were obtained from cultures of the named microorganisms.

3.1 Marine-sourced bacteria (excluding from mangroves)

The chlorinated pyrones halomadurone A 1 and B 2 were isolated from Actinomadura sp. (ascidian Ecteinascidia turbinata, Florida Keys, U.S.A.) and with increased concentration of potassium bromide in the growth media produced the brominated analogues halomadurone C 3 and D 4. The halomadurones A–D activated the nuclear factor E2-related antioxidant response element, an indication of potential for treatment of neurodegenerative diseases.⁷⁹ Discoipyrroles A–D 5–8 are alkaloids isolated from Bacillus hunanensis (sediment, Galveston Bay, Texas, U.S.A.) that inhibit the signaling pathway of the tyrosine kinase, discoidin domain receptor 2. They were each obtained as racemates and feeding experiments with several substituted benzaldehyde precursors indicated formation through a nonenzymic process, which led to a one-pot total synthesis of discoipyrrole A 5.⁸⁰

Three glycosylated methoxy-macrolactins 9–11 were isolated from Bacillus subtilis (B. subtilis) (sediment, Gageocho, S. Korea) and all displayed inhibition of Gram-positive and Gram-negative bacterial strains, in addition to modest antifungal activity.⁸¹ A strain of B. subtilis (sponge Haliclona simulans, Gurraig Sound, Galway, Ireland) yielded subtilomycin, a partially characterised 32-amino acid compound that was partly responsible for the observed broad spectrum antimicrobial activity of the bacterium.⁸²

Bacillus sp. (sediment, Ieodo Reef, S. Korea)⁸³ produced the 24-membered macrolactones macrolactin X–Z 12–14 and the unsaturated fatty acids linieodolide A 15 and B 16, all with modest antibacterial and antifungal activity.⁸⁴

Two separate isolates of the myxobacterium Enhygromyxa salina yielded antibiotics. Salimyxins A 17 and B 18 were obtained from one strain (sediment, Santa Barbara, California, U.S.A.) whilst the geometric isomers enhygrolide A 19 and B 20 were isolated from another strain (sediment, Prerow, Germany). Salimyxins A 17 and B 18 are structurally very similar to demethylincisterol obtained from the sponge Homaxinella sp.,⁸⁵ whilst enhygrolides A 19 and B 20 are structurally related to the nostoclides, first obtained from a Nostoc species of cyanobacterium.⁸⁶ Salimyxin B 18 and enhygrolide A 19 were moderate growth inhibitors of the Gram-positive bacterium Arthrobacter cristallopoietes.⁸⁷ The obligatory marine myxobacterium Enhygromxya salina (sediment, Prerow Is., Germany) was the source of the tetracyclic salimabromide 21 which was a moderate inhibitor of Arthrobacter cristallopoietes.⁸⁸

Kocuria palustris (sponge Xestospongia muta, Key Largo, Florida)⁸⁹ produced a thiazolyl peptide kocurin 22 with antibacterial activity including strong inhibition of methicillin-resistant Staphylococcus aureus (MRSA).⁹⁰ A molecule with the same planar structure as 22 was previously isolated from Kocuria sp. in Southeast Spain⁹¹ as baringolin and is also believed to be a correction of the structure previously assigned to PM181104,⁹² (also obtained from a Kocuria sp.) mentioned in a patent.⁹⁰ Kocurin, also produced by Kocuria marina and a Micrococcus sp. (Florida Keys),⁹³ has been synthesised by a convergent strategy in good overall yield.⁹⁴ The macrolide juvenimicin C 23 was obtained from Micromonospora sp. (sediment, Palau) and enhanced the activity of the enzymes quinone reductase I, glutathione reductase and glutathione peroxidase, suggesting potential as a cancer chemopreventive agent.⁹⁵ Levantilide C 24 is a 20-membered macrolide isolated from a Micromonospora strain (Golfo Corcovaclo, Chiloe Is., Chile) with moderate antiproliferative activity against human tumour cancer cell lines (HTCLs).⁹⁶ Two strains of Micromonospora (sediment, North Carolina coast, U.S.A.) yielded the polyene macrolactam micromonolactam 25, a constitutional isomer of salinilactam A⁹⁷ but with a different polyene pattern and a (Z)-double bond, in contrast to the all (E)-structure of salinilactam A. Genome sequencing of one of the strains determined that 25 was derived from eleven polyketide units and a modified glutamate starter unit.⁹⁸Nocardiopsis alba (deep-sea sediment, Indian Ocean) produced several diketopiperazines, including the new C-6 epimers nocazine D 26 and E 27 and the known synthetic compounds (S,Z)-3-benzylidene-6-methylpiperazine-2,5-dione and (S,Z)-3-benzylidene-6-isopropylpiperazine-2,5-dione,⁹⁹ both isolated for the first time as NPs. Methoxyneihumicin was also isolated. This is a structure that had been previously reported in a conference poster¹⁰⁰ but not in the chemical literature. Both methoxyneihumicin and the known bacterial metabolite XR334 (ref. 101) (first time marine isolate) were modestly active against HTCLs.¹⁰²

Three different groups of researchers have isolated metabolites from Nocardiopsis species and all have named them nocapyrones. To avoid confusion they are presented here in order of publication. Firstly, symbiotic Nocardiopsis alba (cone snail Conus rolani, Mactan Is., Philippines) produced the γ-pyrones nocapyrone H–Q 28–39. Of these, nocapyrone N 35/36 was isolated as a mixture of enantiomers in a 10 : 1 ratio and nocapyrone M 33/34 occurred as an inseparable mixture of diastereoisomers. Both nocapyrone H 28 and the co-isolated nocapyrone B, previously obtained from a sponge-associated Nocardiopsis strain,¹⁰³ modulated nerve cell depolarisation and were active against a wide range of dorsal root ganglion neuronal cell types. Nocapyrones B and H were moderately cytotoxic to cancer cell lines.¹⁰⁴ Secondly, three 3,6-disubstituted α-pyrones 40–42 were isolated from Nocardiopsis sp. (sediment, Ulleung Basin, Eastern sea, Korea) and named nocapyrones H–J. “Nocapyrone H” 40 inhibited pro-inflammatory factors such as nitric oxide (NO), prostaglandin E2 (PGE2) and interleukin-1β (IL-1β) (potential neuroprotective effects).¹⁰⁵ Lastly, Nocardiopsis dassonvillei subsp. dassonvillei (sediment, Lianyungang, China) also produced α-pyrones named “nocapyrones H–N”. Of these “nocapyrone H” had the same structure as 40, “nocapyrone K” was identical to 41, while the balance, 43–47, were unique. “Nocapyrone I” 43 and “M” 46 displayed inhibition of quorum sensing (QS) controlled gene expression in Chromobacterium violaceum CV026 and Pseudomonas aeruginosa QSIS-lasI biosensors.¹⁰⁶

Very clearly the naming of these metabolites needs revision. Saline culture of Nocardiopsis sp. (sediment, S. Molle Is., Queensland, Australia) previously yielded norcardioazines A and B¹⁰⁷ whilst non-saline culture of the same strain yielded nocardiopsins A and B.¹⁰⁸ Further investigation of the strain cultivated under non-saline conditions has resulted in the isolation of the prolinyl-macrolactam polyketides nocardiopsin C 48 and D 49 and the highly substituted α-pyrone polyketide, nocardiopyrone A 50.¹⁰⁹ It should be noted that the name nocardiopyrone A has coincidentally been given to a metabolite isolated from a terrestrial species, Nocardiopsis alkaliphila,¹¹⁰ and that the same CAS number appears to have been given to both compounds in error on the Scifinder database, with the terrestrial compound structure showing as corresponding to that CAS number.

The cyclic hexapeptides nocardiamide A 51 and B 52 were isolated from Nocardiopsis sp. (La Jolla Canyon, San Diego, California, U.S.A.) and then synthesised via solid-phase peptide synthetic methods.¹¹¹ A microorganism, nominally Paenibacillus profundus sp. nov., (sediment, Sea of Japan) yielded a linear glyceryl acid derived heptapeptide 53 with strong antibacterial inhibition and moderate inhibition of SK-MEL-28 cells,¹¹² while a species of Photobacterium, closely related to P. halotolerans (mussel, Solomon Is., Pacific Ocean), was the source of the cyclodepsipeptides ngercheumicin F–I 54–57 that inhibited quorum sensing in Staphylococcus aureus.¹¹³

A Pseudoalteromonas sp. (oil-contaminated surface water, Gulf of Mexico after the Deepwater Horizon oil spill) yielded the siderophores lystabactin A–C 58–60 which contained the unusual nonproteinogenic amino acid 4,8-diamino-3-hydroxyoctanoic acid (LySta). Since lystabactin C is 29-methoxy lystabactin A, it may have been an artefact of isolation.¹¹⁴

Cyanosporasides A and B are chloro- and cyano-cyclopenta[a]indene glycosides originally isolated from a Palauan Salinispora pacifica strain,¹¹⁵ while cyanosporasides C–E 61–63 came from investigation of another S. pacifica strain (sediment, Palau) and cyanosporasides D–F 62–64 from a Streptomyces sp. (sediment, Bahamas). Cloning, sequencing, and mutagenesis of cyanosporaside biosynthetic gene clusters from both bacteria demonstrated that the cyanosporasides are enediyne polyketides and a two-gene operon was identified which was implicated in the nitrile functionalisation of these metabolites.¹¹⁶ Further investigation of the strain of S. pacifica (USDA Agricultural Research Service) that produced lomaiviticins C–E¹¹⁷ resulted in the isolation of (−)-homoseongomycin 65. Synthesis of an isotopically-labelled derivative, homoseongomycin-d₅, clarified aspects of the biosynthetic pathway.¹¹⁸

The alkaloid 66 was obtained from Serinicoccus profundi sp. nov. (deep-sea sediment, Indian Ocean) (weak activity against Staphylococcus aureus (S. aureus))¹¹⁹ and Staphylococcus sp. (red alga, Corallina officinalis, Nagasaki Shitsu Coast, Japan) provided the diketopiperazine derivatives staphyloamide A 67 and B 68.¹²⁰Streptomyces antibioticus (sediment, source not given) yielded the indanomycin-related antibiotics 69–71 as moderate growth inhibitors of S. aureus.¹²¹

The alkaloids nitrosporeusine A 72 and B 73 with an unprecedented skeleton (benzenecarbothioc cyclopenta[c]pyrrole-1,3-dione) were isolated from S. nitrosporeus (sediment, Arctic Chukchi Sea). Both nitrosporeusines inhibited the H1N1 virus in infected MDCK cells.¹²² Some sesquiterpenoid naphthoquinones marfuraquinocin A–D 74–77 and the geranylated phenazines phenaziterpene A 78 and B 79 were isolated from S. niveus (sediment, S. China Sea). Marfuraquinocins A 74 and C 76 were growth inhibitors of NCI–H460 cancer cells (moderate) whilst marfuraquinocins A, C and D 77 were moderate growth inhibitors of S. aureus, with marfuraquinocins C and D also inhibitors of methicillin-resistant Staphylococcus epidermidis.¹²³

Tetroazolemycins A 80 and B 81 are oxazole/thiazole derivatives obtained from S. olivaceus (deep-sea water, southwest Indian Ocean), both of which showed binding affinity for the metal ions Fe³⁺, Cu²⁺ and Zn²⁺.¹²⁴S. seoulensis (shrimp gut Penasus orientalis, Qingdao, China) yielded the neuraminidase inhibitors streptoseolactone 82, limazepine G 83 and a known synthetic compound^125,126 isolated for the first time as an NP, and named limazepine H.¹²⁷ Endophytic S. sundarbansensis (brown alga Fucus sp., Bejaia, Algeria) provided the polyketide chromanone 84 (modest but selective activity against MRSA).¹²⁸

S. tateyamensis (sponge Haliclona sp., Tateyama City, Japan)¹²⁹ was the source of JBIR-107 85,¹³⁰ while the phenoxazine-based alkaloids venezueline A–E 86–90 and the aminophenols venezueline F 91 and G 92 were obtained from S. venezuelae (sediment, Guam) with the known analogues exfoliazone,¹³¹ chandrananimycin D¹³² and carboxyexfoliazone,¹³³ all previously obtained from terrestrial Streptomyces species but now first time marine isolates. Venezueline B 87 was moderately cytotoxic towards a panel of HTCLs.¹³⁴

Double mutation of a strain of S. xiamenensis (sediment, Eastern Pacific Ocean) led to production of two benzopyran derivatives xiamenmycin C 93 and D 94, which both inhibited proliferation of human lung fibroblasts (WI26),¹³⁵ and Streptomyces sp. (unidentified soft coral, Weizhou Is., Guangki Province, China) was the source of the chlorinated polyketides strepchloritide A 95 and B 96 cytotoxic against MCF-7 cells (modest).¹³⁶ Chlorizidine A 97, comprised of a chlorinated 2,3-dihydropyrrolizine ring attached to an unprecedented chlorinated 5H-pyrrolo[2,1-a]isoindol-5-one, was isolated from a Streptomyces strain (sediment, San Clemente, California, U.S.A.) and was moderately cytotoxic to a panel of HTCLs.¹³⁷ The biosynthetic gene cluster of chlorizidine A 97 was identified and whole pathway heterologous expression and genetic manipulations were utilised to show that it is assembled by a polyketide synthase (PKS) that uniquely incorporates a fatty acid synthase-derived dichloropyrrolyl extender unit into the pyrroloisoindolone enzymic product.¹³⁸

The diketopiperazine derivatives 98–102 were obtained from Streptomyces sp. (sediment, Huanghai Beach, Dalian, China) and 100 displayed modest activity against the influenza A (H1N1) virus, whilst the co-isolated fungal metabolites (3Z,6S)-3-benzylidene-6-isobutylpiperazine-2,5-dione¹³⁹ and albomoursin¹⁴⁰ displayed potent inhibition of the virus and were first time marine isolates.¹⁴¹

Streptomyces sp. (sediment, S. China Sea) yielded the spirotetronate lobophorin G 103, a potent inhibitor of both Mycobacterium bovis Bacillus Calmette-Guerin (BCG) and B. subtilis and a moderate inhibitor of Mycobacterium tuberculosis (M. tuberculosis).¹⁴² Sungsanpin 104 isolated from a Streptomyces sp. (deep-sea sediment, Jeju Is., S. Korea) is an example of a so-called lasso peptide, a ribosomally synthesised peptide of between 16 and 23 amino acids with an N-terminal eight- or nine-residue ring with a linear C-terminus threaded through the ring.¹⁴³ Sungsanpin inhibited A549 cells in a cell invasion assay.¹⁴⁴

Investigation of two different Streptomyces strains identified six new napyradiomycin analogues. The Streptomyces strain CNQ-329 (sediment, San Diego, California, U.S.A.) produced napyradiomycins A–E 105–109, while strain CNH-070 (sediment, San Elijo Lagoon, Encinitas, California, U.S.A.) produced napyradiomycin F 110.

Four of the napyradiomycins A, D–F were cytotoxic (moderate) to HCT-116 cells whilst napyradiomycins A and B inhibited MRSA (moderate).

Also isolated were napyradiomycins B2–B4; B3 (ref. 145) and B4 (ref. 146) as first time marine isolates.¹⁴⁷ Three napyradiomycins, 4-dehydro-4a-dechloronapyradiomycin A1 111, 3-dechloro-3-bromonapyradiomycin A1 112 and 3-chloro-6,8-dihydroxy-8-α-lapachone 113 isolated from a Streptomyces species (sediment, Xieyang Is., Beihai, Guangxi Province, China) displayed moderate inhibition of several Gram-positive bacteria while 3-dechloro-3-bromonapyradiomycin A1 112 was moderately active against several HTCLs.¹⁴⁸ A Streptomyces sp. (sediment, Santa Barbara, California, U.S.A.) yielded the antibiotic anthracimycin 114, significantly active against Bacillus anthracis. Early in vivo results indicated that 114 also provided significant protection against MRSA cell lines. The planar structure of anthracimycin 114 may have been published in a 2011 patent¹⁴⁹ but insufficient detail was given to permit a full comparison.¹⁵⁰

Surugamides A–E 115–119, cyclic octapeptides with four D-amino acid residues, were obtained from Streptomyces sp. (deep-sea sediment, Kinko Bay, Japan) and were modest inhibitors of the protease enzyme bovine cathepsin B.¹⁵¹ Three strains of S. champavatii (sediment, Gotland Deep and Kiel Bight, Baltic Sea and Urania Basin, Eastern Mediterranean) produced the octapeptide champacyclin 120, an inhibitor of the bacterium Erwinia amylovora, the causative agent of fire blight disease in certain plants. Champacyclin 120 has the same planar structure as surugamide A 115 but different configurations at two amino acid residues. Champacyclin was also prepared by solid-phase peptide synthesis.¹⁵²

Streptomyces sp. (sediment, S. China Sea) yielded the pregnene steroid 3219A 121 with a rare Δ^8,9-double bond in the skeleton,¹⁵³ and the polyketide nahuoic acid A 122 was obtained from a Streptomyces sp. (sediment, Padana Nahua, Papua New Guinea) as a selective SAM-competitive inhibitor of the histone methyltransferase enzyme SETD8.¹⁵⁴ A meroterpenoid actinoranone 123 was isolated from a bacterium, likely a Streptomyces species (sediment, San Diego, California, U.S.A.)¹⁵⁵ as a moderate cytotoxin of HCT-116¹⁵⁶ and Streptomyces sp. (sediment, Marsa Matruh city, Egypt) was the source of maroxazinone 124, moderately cytotoxic to several HTCLs.¹⁵⁷

Farnesides A 125 and B 126, linear sesquiterpenoids connected by ether linkages to a ribose dihydrouracil nucleoside, came from Streptomyces sp. (sediment, Nacula Is., Yasawa Is., Fiji) with farneside A modestly active against Plasmodium falciparum (P. falciparum).¹⁵⁸

A PCR-based genetic screening experiment targeting the dTDP-glucose-4,6-dehydratase gene was used to identify that a Streptomyces sp. (sediment, Heishijiao Bay, Dalian, China) could potentially produce glycosidic antibiotics. Further investigation of this strain yielded the 6-deoxyhexose-containing antibiotics, 11′,12′-dehydroelaiophylin 127 and 11,11′-O-dimethyl-14′-deethyl-14′-methylelaiophylin 128, of which 127 was an inhibitor of MRSA and vancomycin-resistant Enterococci pathogens. The elaiophylin derivative 128 might be an artefact resulting from methanolysis during the isolation procedure.¹⁵⁹

The cyclic peptides ohmyungsamycin A 129 and B 130 were isolated from a Streptomyces sp. (sand, Shinyang Beach, Jeju Is., S. Korea). During determination of configurations a new method to determine the absolute configuration of N,N-dimethylvaline was developed which utilises phenylglycine methyl ester derivatisation coupled with chromatographic analysis and provides a general and convenient method for determination of the configurations of amino acids with fully substituted amine groups. Ohmyungsamycins A 129 and B 130 inhibited growth of several HTCLs and of Gram-positive and Gram-negative bacteria with ohmyungsamycin A 129 being much more potent than B 130.¹⁶⁰

Separacenes A–D 131–134 are polyene polyols obtained from Streptomyces sp. (sediment, Jeju Is., S. Korea). Separacenes A 131 and B 132 are C-3 epimers whilst separacenes C 133 and D 134 are C-12 epimers. Separacene A 131 was a modest inhibitor of Candida albicans (C. albicans) isocitrate lyase and two HTCLs.¹⁶¹

Streptomyces sp. (deep-sea sediment, S. China Sea) was the source of lobophorins H 135 and I 136 of which lobophorin H 135 exhibited significant inhibition of B. subtilis and moderate inhibition of S. aureus while lobophorin I 136 was much less active.¹⁶²

The polycyclic polyketide akaeolide 137 was isolated from a Streptomyces sp. (sediment, Miyazaki Harbour, Japan) as a modest cytotoxin to 3Y1 rat fibroblasts.¹⁶³ Strepsesquitriol 138, a caged sesquiterpene isolated from Streptomyces sp. (sediment, Bay of Bengal, Indian Ocean), was a moderate inhibitor of lipopolysaccharide-induced TNFα production in RAW264.7 macrophages,¹⁶⁴ while cycloheximide acid A 139 was obtained from Streptomyces sp. (seawater, E. China Sea, Wenzhou, Zhejiang Province, China).¹⁶⁵

The immunosuppressant cyclic lipopeptides thalassospiramides A and B were originally obtained from the α-proteobacterium Thalassospira sp.¹⁶⁶ Reinvestigation of the original producer, a second strain of Thalassospira (source not given), Tistrella mobilis (Red Sea¹⁶⁷) and Tistrella bauzanensis (Pacific Ocean¹⁶⁷) led to the isolation of fourteen analogues thalassospiramides A1–A5 140–144, C 145 and C1 146, E 147 and E1 148, B1 149 and B2 150, D 151 and D1 152 and thalassospiramide F 153 that have been subdivided into six structural classes with variations in the length and composition of the acyl peptide side chain. The planar structures of 149 and 152 were described in a patent as metabolites of another α-proteobacterium, Oceanospirillum sp.¹⁶⁸ and potent inhibitors of the cysteine protease calpain 1. In the current study selected thalassospiramides (A, A1, B, C, D1 and E1) were tested and all displayed potent activity against calpain 1. Biosynthetic gene clusters for all four bacterial strains were characterised revealing some atypical NRPS biochemical features such as intrasynthetase trans A domain activation, module skipping and multimodule iteration which likely yield the structural diversity.¹⁶⁹Thalassospira sp. (brown alga Rosenvingea sp., Bahamas) yielded a further member of the thalassospiramide family of peptides, thalassospiramide G 154. The co-isolated thalassospiramides A¹⁶⁶ and D¹⁶⁹ were moderate inhibitors of NO production in lipopolysaccharide (LPS)-stimulated mouse macrophage RAW 264.7 cells.¹⁷⁰

The 18-membered macrolide macplocimine A 155 was obtained from the filamentous sulfur bacterium Thioploca sp. (benthic microbial mat, Chile).¹⁷¹Verrucosispora sp. (deep-sea sediment, S. China Sea) was the source of three further abyssomicin polyketides abyssomicin J–L 156–158. Abyssomicin C¹⁷² was also isolated and converted to abyssomicin J 156. In vitro and cell-based analytical studies were then used to show that abyssomicin J 156 can act as a prodrug which, upon oxidative activation, will be selectively transformed to atrop-abyssomicin C,¹⁷³ an anti-TB antibiotic.¹⁷⁴

Heronamide A, a polyketide macrolactam originally obtained from an Australian, sediment-derived Streptomyces sp.,¹⁷⁵ was reisolated from a Streptomyces sp. (sediment, Uranouchi Bay, Kochi Prefecture, Japan). Detailed NMR analysis of heronamide A and derivatives resulted in configurational reassignment of heronamide A to 159 and the suggestion that the configurations of heronamides B¹⁷⁵ and C¹⁷⁵ should be reinvestigated.¹⁷⁶

The configuration of the α-methylserine residue in the tetrapeptides JBIR-34 and JBIR-35 and in the trichostatin analogue JBIR-111, originally obtained from a sponge-derived Streptomyces sp.^177,178 have been corrected from (R) to (S).^179,180Tenacibaculum mesophilum (unidentified sponge, Republic of Palau) yielded a siderophore bisucaberin B. This is an open form of the known macrocyclic dimer bisucaberin^181,182 that has been reported as a degradation product of desferrioxamine B¹⁸³ but not as a product of de novo biosynthesis.¹⁸⁴

3.2 Bacteria from mangroves

Bacillus hunanensis (sediment, Trinity Bay, Galveston Texas, U.S.A.) yielded hunanamycin A 160, the first NP with a pyrido[1,2,3-de]quinoxaline-2,3-dione core, which also displayed modest inhibition of Salmonella enterica.¹⁸⁵ Hunanamycin A was subsequently synthesised via a simple and scaleable method from 6,7-dimethyl-1,4-dihydroquinoxaline-2,3-dione.¹⁸⁶ An indole alkaloid 161 was obtained from Pantoea agglomerans (mangrove Ceriops tagal, Zhanjiang, Guangdong, China) along with two phenylethylamine derivatives, 3-(p-hydroxy)benzoyl indole¹⁸⁷ and 1,2-di(1H-indol-3-yl)ethane,¹⁸⁸ both known synthetic compounds but now isolated for the first time as MNPs.¹⁸⁹

Streptomyces sp. (mangrove rhizosphere soil Heritiera globosa, Wenchang, China)¹⁹⁰ was the source of a series of azalomycin F analogues 162–168 which were all broad-spectrum antimicrobials and inhibitors of HCT-116 cells.¹⁹¹ The di-O-prenylated flavone 169 was isolated from an endophytic Streptomyces sp. (mangrove root Myoporum bontioides, Leizhou Peninsula, Guangdong Province, China) and was a moderate inhibitor of the plant pathogenic fungi, Colletotrichum musae, Gibberella zeae and Penicillium citrinum.¹⁹²

3.3 Marine-sourced fungi (excluding from mangroves)

Several acremine metabolites, 5-chloroacremine A 170, 5-chloroacremine H 171 and acremines O–R 172–175, together with the known terrestrial fungal metabolite acremine F,¹⁹³ were isolated from Acremonium persicinum (sponge Anomoianthella rubra, Gneering Reef, S. E. Queensland, Australia). The configuration of acremine F was determined as 176 and this was the first isolation as an MNP.¹⁹⁴

Alternaria sp. (sponge Callyspongia sp., Sanya, Hainan Is., China) was the source of a variety of meroterpenoids including tricycloalternarene A 177, the hydrogenated benzofurans, bicycloalternarene A–D 178–181, the hydrogenated chromans, bicycloalternarene E 182 and F 183, and the hydrogenated cyclopenta-[b]-chromans, tricycloalternarene B 184 and C 185. Four additional monocyclic meroterpenoids monocycloalternarene A¹⁹⁵186 and monocycloalternarene B–D 187–189 were obtained when the putative precursors sodium 3,4-dihydroxybenzoic acid or shikimic acid were fed to the fungus, reinforcing the proposed shikimate-isoprenoid hybrid biosynthetic pathway. All the metabolites except bicycloalternarenes E 182 and F 183 were weak to moderate inhibitors of NF-κB in RAW264.7 cells.¹⁹⁶

The sesquiterpene ascotrichic acid 190 was isolated from Ascotricha sp. (coastal mud, Fenghua County, Zhejiang, China).¹⁹⁷ The benzoquinone derivatives aculeatusquinone A–D 191–194 were isolated from Aspergillus aculeatus (sediment, Langqi Is., Fujian, China) and of these aculeatusquinones B and D were moderately cytotoxic to several HTCLs.¹⁹⁸

An oxepin-containing alkaloid 195, a quinazolinone-containing alkaloid 196 and a dihydrobenzofuran derivative 197 were obtained from A. carneus (brown alga Laminaria sachalinensis, Kunachir Is., Russia).¹⁹⁹ Clavatustides A 198 and B 199, cyclodepsipeptides with an unusual anthranilic acid dimer and a D-phenyllactic acid residue, were isolated from A. clavatus (hydrothermal vent crab Xenograpsus testudinatus, Kueishantao, Taiwan) and suppressed proliferation of HTCLs.²⁰⁰

A. elegans (soft coral Sarcophyton sp., Weizhou coral reef, S. China Sea) produced the phenylalanine derivative 4′-methoxyasperphenamate 200 and the cytochalasins aspochalasin A1 201 and cytochalasin Z24 202, in addition to a number of known cytochalasin analogues. 4′-Methoxyasperphenamate 200 was modestly active against Staphylococcus epidermidis while the known cytochalasins aspochalasin I,²⁰¹ J,²⁰¹ D^202,203 and H²⁰⁴ displayed strong antifouling activity against larval settlement of the barnacle Balanus amphitrite (B. amphitrite). Aspochalasins I, J and H, previously isolated from terrestrial Aspergillus species, are first time MNPs.²⁰⁵

Of the tris-pyrogallol ethers sydowiol A–C 203–205 from A. sydowii (sediment, E. China Sea), sydowiols A 203 and C 205 inhibited M. tuberculosis protein tyrosine phosphatase A (PTPA).²⁰⁶A. terreus, var. boedijnii (Blochwitz) (red alga Laurencia ceylanica, Arugam Bay, Sri Lanka) produced a new butyrolactone 206 which was a strong inhibitor of the enzyme β-glucuronidase.

A number of known compounds were also isolated which included (+)-asterrelenin,²⁰⁷ a moderate inhibitor of β-glucuronidase, (3R,4R)-6,7-dimethoxy-4-hydroxymellin²⁰⁸ and (+)-territonin A,²⁰⁷ all reported as first time MNPs.²⁰⁹ The cyclic tetrapeptide asperterrestide A 207, the alkaloid terremide C 208 and an aromatic butenolide aspernolide E 209 were obtained from A. terreus (gorgonian Echinogorgia aurantiaca, Sanya, Hainan Province, China). Asperterrestide A 207 inhibited influenza virus strains H1N1 and H3N2 and was cytotoxic to HTCLs.²¹⁰

Cultivation of A. unguis (unidentified sponge, Tub-La-Mu Bay, Pang-nga Province, Thailand) in media containing different halogen salts led to the production of “unnatural natural” depsidones. Growth in media containing KBr produced the brominated depsidones aspergillusidone D–F 210–212 and the orcinol derivatives aspergillusidone A 213 and B 214, whilst culture in KI produced another new depsidone 2,4-dichlorounguinol 215. Of these, aspergillusidones D–F 210–212 inhibited aromatase, a therapeutic target for breast cancer treatment.²¹¹

A large number of terpenes were sourced from A. ustus (green alga Codium fragile, Zhoushan Is., Zhejiang Province, China) and included the meroterpene 1,2-dihydroterretonin F 216, the sesterterpenes (6α)-21-deoxyophiobolin G 217, (6α)-16,17-dihydro-21-deoxyophiobolin G 218, ophiobolins U–W 219–221 and the diasteroisomeric sesquiterpenes, (6-strobilactone-B) esters of (E,E)-6,7-epoxy-2,4-octadienoic acids 222 and 223 as new compounds. Ophiobolin F²¹² was obtained from the marine environment for the first time. Ophiobolin U 219 and the co-isolated known (5α,6α)-ophiobolin H²¹³ moderately inhibited growth of E. coli.²¹⁴

Anthcolorins A–F 224–229, tetrahydropyran diterpene metabolites containing an oxoindoline moiety were isolated from A. versicolor (sea urchin Anthocidaris crassispana, Tanabe Bay, Wakayama, Japan), as three sets of epimeric pairs with moderate growth inhibition (P388) noted for anthcolorins B–D 225–227.^215,216

Aspeverin 230 isolated from A. versicolor (green alga Codium fragile, Dalian, China) was a moderate growth inhibitor of the phytoplankton Heterosima akashiwo.²¹⁷ Four prenylated diphenyl ethers diorcinol B–E 231–234 were obtained from A. versicolor (mud, Yellow Sea),²¹⁸ of which two, diorcinols D and E were toxic to HTCLs.²¹⁹

Endophytic A. wentii (brown alga Sargassum sp., no location specified) produced wentiquinone A 235, along with another secoanthraquinone derivative which was claimed as new and named wentiquinone B. A compound of this structure had already been isolated as guepinone from the terrestrial fungus Pestalotiopsis guepinii,²²⁰ but this was the first isolation from the marine environment.²²¹ The xanthone derivatives yicathin A–C 236–238 were isolated from endophytic A. wentii (red alga Gymnogongrus flabelliformis, Pingtan Is., China). Yicathins B and C had antimicrobial activities.²²²

A. westerdijkiae (deep-sea sediment, S. China Sea) was the source of the benzodiazepine alkaloids circumdatin K 239 and L 240, the prenylated indole alkaloids 5-chlorosclerotiamide 241 and 10-epi-sclerotiamide 242 and the amide aspergilliamide B 243 (ref. 223) whilst Aspergillus sp. (mussel Mytilus edulis, Toyama Bay, Japan Sea)²²⁴ produced himeic acids E–G 244–246.²²⁵

The cyclic tetrapeptides aspergillipeptide A–C 247–249 and asteltoxin B 250 were isolated from Aspergillus sp. (gorgonian Melitodes squamata, Sanya, Hainan province, China) with aspergillipeptide C 249 showing strong antifouling activity against Bugula neritina (B. neritina) larvae settlement.²²⁶

Aspergillus sp. (sponge Tethya aurantium, Limski canal, N. Adriatic Sea, Croatia) produced seven new alkaloids, tryptoquivaline K 251 and fumiquinazolines K–P 252–257, the latter group containing the rare 1-aminocyclopropane-1-carboxylic acid residue.²²⁷

The prenylated indole alkaloids 17-epi-notoamide Q 258 and M 259 and the phenyl ether derivative cordyol D 260 were obtained from Aspergillus sp. (gorgonian Dichotella gemmacea, Xisha Is., S. China Sea). A further phenyl ether was isolated and claimed as new but had already been reported from the mangrove-associated fungus Penicillium expansum.²²⁸ The synthetic compound dehydronotoamide C²²⁹ was obtained for the first time as an NP and the fungal metabolite notoamide C²³⁰ was also reisolated and the absolute configuration previously proposed²³¹ for this metabolite proven as 261.²³² As a consequence the configurations of the Aspergillus-derived notoamides J,²³³ Q²³⁴ and M,²³⁵ have been corrected from (3S) to (3R) for notoamide J^235,236 and from (3R) to (3S) for notoamides Q and M.^237,238

Aspergillide D 262, a 16-membered macrolide, was isolated from Aspergillus sp. (gorgonian Melitodes squamata, Sanya, Hainan Province, China).²³⁹ Co-isolated were two known sesquiterpenoid nitrobenzoyl esters, 9α,14-dihydroxy-6β-p-nitrobenzoylcinnamolide²⁴⁰ and 7α,14-dihydroxy-6β-p-nitrobenzoylconfertifolin,²⁴⁰ moderate inhibitors of H1N1.²³⁹ Two aspergillic acid group toxins aspergilliamide 263 and ochratoxin A butyl ester 264 were obtained from Aspergillus sp. (gorgonian Melitodes squamata, Sanya, Hainan Province, China), both modestly toxic to brine shrimp (Artemia salina). Co-isolated was the known neoaspergillic acid²⁴¹ and, surprisingly, the aluminium and zirconium salts of the acid.²⁴²

A racemic mixture of a γ-lactone derivative 265 was isolated from Aspergillus sp. (gorgonian Melitodes squamata, Sanya, Hainan Province, China) with significant toxicity to brine shrimp.²⁴³ A lactam derivative was also obtained and the structure proposed as a dehydrated pyrrolyl 1-isoquinoline alkaloid,²⁴³ a structure originally proposed for marinamide, but which was subsequently revised to that of the dehydrated quinoline alkaloid penicinoline (in section 3.4 below this same problem is addressed with respect to two unidentified microorganisms grown in co-culture).^244,245 While it might be possible that these two compounds have very similar NMR data, X-ray crystallography of this new marinamide is required to resolve the doubt.

Bartalinia robillardoides (sponge Tethya aurantium, Limsky Channel, Croatia) was the source of the chloroazaphilone helicusin E 266 and the pentaketide bartanolide 267. Isochromophilones X²⁴⁶ and XI²⁴⁶ were also isolated and claimed as new but are known terrestrial fungal metabolites. Isochromophilone XI,²⁴⁶ along with other known fungal metabolites helicusin A²⁴⁷ and deacetylsclerotiorin,²⁴⁸ had a variety of moderate to weak antimicrobial activities.²⁴⁹

Calcarisporium sp. (seawater, Wadden Sea, Germany) generated macrocyclic and linear polyesters including calcarides A–E 268–272, out of which calcarides A–C 268–270 and the co-isolated analogues 15G256α and 15G256β, previously obtained from the marine fungus Hypoxylon oceanicum,²⁵⁰ inhibited growth of Staphylococcus epidermidis and Xanthomonas campestris while the linear ester 15G256π inhibited growth of Propionibacterium acnes.²⁵¹

Two lanostanes 273 and 274, with the latter previously reported in the patent literature as a metabolite of the mushroom Fomitopsis pinicola,²⁵² were obtained from endophytic Ceriporia lacerate (starfish Acanthaster planci, Hainan Sanya National Coral Reef Reserve, China).²⁵³ Although a further lanostane, 3β-acetoxy-15α-hydroxylanosta-8,24-dien-21-oic acid was also claimed as new, it had previously been isolated from a fungal endophyte of a traditional Chinese medicinal plant Huperzia serrata.²⁵⁴

Chondrostereum sp. (soft coral Sarcophyton tortuosum, Hainan Sanya National Coral Reef Reserve, China), previously the source of chondrosterins A–E,²⁵⁵ produced further chondrosterins F–H 275–277. The terrestrial fungal metabolites incarnal²⁵⁶ and arthrosporone,²⁵⁷ and the plant metabolite (2E)-decene-4,6,8-triyn-1-ol,²⁵⁸ were also all isolated for the first time as MNPs.²⁵⁹ The benzolactone metabolites chrysoarticulin A–C 278–280 were isolated from Chrysosporium articulatum, (unidentified dictyoceratid sponge, Gagu-do, S. Korea) with chrysoarticulin C 280 active against the bacterial transpeptidase enzyme sortase A.²⁶⁰

Dendrodochium sp. (sea cucumber Holothuria nobilis, S. China Sea) produced the 12-membered macrolides dendrodolide A–M 281–293 (dendrodolides A–E, G–I, K and L had modest inhibitory activity against two HTCLs),²⁶¹ while the polyketides 294 and 295 were obtained from Eutypella scoparia (sediment, S. China Sea).²⁶²

Gymnascella dankaliensis (sponge Halichondria japonica, Osaka Bay, Japan)²⁶³ provided dankastatin C 296, a polyketide tyrosine derivative with potent growth inhibition of P388 cells.²⁶⁴Hypocreales sp. (sponge Gelliodes carnosa, S. China Sea) was the source of the cadinane-type sesquiterpenes hypocreaterpene A 297 and B 298. The known terrestrial plant metabolites, (1R,6R,7R,10S)-10-hydroxy-4(5)-cadinen-3-one²⁶⁵ and (R)-5,6-dihydro-6-pentyl-2H-pyran-2-one²⁶⁶ were also isolated for the first time as MNPs and both had moderate anti-inflammatory activity (inhibition of NO production).²⁶⁷ Oxirapentyn E 299, a highly oxidised chromene was isolated from Isaria felina (sediment, Vietnam) as a growth stimulant of corn (Zea mays L.) and barley (Hordeum vulgare L.) rootlets.²⁶⁸

Metarhizium anisopliae (unidentified sponge, Naozhou Is., Guangxi, China) generated two naphtho-γ-pyrone glycosides indigotide G 300 and H 301. The known compounds isochaetochromin B2 (ref. 269) and ustilaginoidin D²⁷⁰ were obtained for the first time from a marine source and displayed modest inhibition of Mycobacterium phlei.²⁷¹

Sartorypyrone B 302, a moderate inhibitor of HTCLs, was obtained from Neosartorya tsunodae (sponge Aka coralliphaga, Similan Is., Phagna Province, Thailand),²⁷² while tryptoquivalines R 303 and S 304 are indole alkaloids obtained from Neosartorya sp. (intertidal mud, Hainan Province, China),²⁷³ previously the producer of tryptoquivalines P and Q.²⁷⁴

Paecilomyces sp., (unspecified sponge, Tinggi Is., Malaysia) was the source of the dione 305,²⁷⁵ while the chrysotriazoles A 306 and B 307 were obtained from endophytic Penicillium chrysogenum (brown alga Sargassum palladium, Fujian, China).²⁷⁶P. oxalicum (sediment, Bohai Bay, Liaoning Province, China) produced decaturins E 308 and F 309,²⁷⁷ and 2-(4-hydroxybenzoyl) quinazolin-4(3H)-one 310 was isolated from P. oxalicum (strain 0312F1, Genbank accession no. EU926977) as a moderate inhibitor of tobacco mosaic virus (TMV) and the human gastric cancer cell line SGC-7901.²⁷⁸

The dihydrothiophene-condensed chromones oxalicumone A 311 and B 312 were obtained from P. oxalicum (gorgonian Muricella flexuosa, Sanya, China) with oxalicumone A 311 moderately cytotoxic to HTCLs.²⁷⁹ A further chromone was also claimed as new and named as oxalicumone C but while isolated from a natural source for the first time, is a known reaction product of chloromonilicin, a metabolite of the cherry rot fungus Monilinia fructicola.²⁸⁰

The anthranilic acid derivatives penipacid A–C 313–315, E 316 and G 317 were isolated from P. paneum (sediment, S. China Sea) together with a known analogue, 2-[(1-methyl-2-oxopropylidene)aminobenzoic acid,²⁸¹ previously synthesised but now isolated as an NP. Penipacids A 313 and E 316 inhibited human colon cancer RKO cells and 2-[(1-methyl-2-oxopropylidene)aminobenzoic acid was cytotoxic to HeLa cells.²⁸²

P. pinophilum (sediment, Pearl River Estuary, S. China Sea) yielded pinodiketopiperazine A 318 and 6,7-dihydroxy-3-methoxy-3-methylphthalide 319 and the known synthetic compounds, alternariol 2,4-dimethyl ether^283,284 and L-5-oxoproline methyl ester²⁸⁵ as first time NPs. The phthalide 319 displayed potent cytotoxicity to brine shrimp and pinodiketopiperazine A 318, alternariol 2,4-dimethyl ether^283,284 and the co-isolated known metabolites N-methylphenyldehydroalanyl-L-proline-anhydride²⁸⁶ and rubralide C²⁸⁷ all exhibited moderate inhibition of E. coli growth.²⁸⁸

The chlorinated sesquiterpenoid ligerin 320 came from a Penicillium strain (seawater, La Prée, Loire Atlantique, France) and strongly inhibited the osteosarcoma cell line POS1,²⁸⁹ while another Penicillium sp. (sediment, Jiaozhou Bay, China) yielded prenpenicillide 321 and prenxanthone 322.²⁹⁰

The polyaromatic metabolites herqueiazole 323, herqueioxazole 324 and herqueidiketal 325 were obtained from Penicillium sp. (sediment, Gagu-do, S. Korea). Herqueidiketal 325 was moderately cytotoxic to A549 cells and significantly inhibitory against sortase A.²⁹¹Penicillium sp. (gorgonian Dichotella gemmacea, Sanya, Hainan Province, China) produced the indolyl diketopiperazine penilloid A 326 in addition to a number of known indole alkaloids.

Aspergillus sydowii (gorgonian Verrucella umbraculum, Sanya, Hainan Province, China) also yielded additional known indole alkaloids including fumiquinazoline D,²⁹² cyclotryprostatin B²⁹³ and fumiquinazoline G,²⁹⁴ which in addition to (E)-3-(1H-imidazol-4-ylmethylene)-6-(1H-indol-3-ylmethyl)-2,5-piperazinedione,²⁹⁵ meleagrin,²⁹⁶ roquefortine C,²⁹⁷ and 11α-methoxy roquefortine C²⁹⁸ from the Penicillium sp. exhibited significant antifouling activity towards B. amphitrite and/or B. neritina larvae. Meleagrin also exhibited moderate activity against the larvae settlement-inducing bacterium Micrococcus luteus.²⁹⁹ Penstyrylpyrone 327 and the known terrestrial fungal metabolite anhydrofulvic acid (first time MNP)³⁰⁰ were obtained from Penicillium sp. (unidentified sponge. Jeju Is., S. Korea) as inhibitors of protein tyrosine phosphatase 1B (PTP1B) activity. Furthermore, penstyrylpyrone 327 suppressed production of pro-inflammatory mediators via the NF-κB pathway through expression of the anti-inflammatory enzyme, heme oxygenase.³⁰¹

Penicillium sp. (gorgonian coral Dichotella gemmacea, Sanya, Hainan, China) was the source of the polyketides 328 and paecilin C 329, and some known analogues. 6,8,5′,6′-Tetrahydroxy-3′-methylflavone 328, emodin,³⁰² citreorosein³⁰² and isorhodoptilometrin³⁰³ exhibited significant antifouling activity against B. amphitrite larvae settlement while penicillixanthone A³⁰⁴ was moderately antibacterial.³⁰⁵

Endophytic Penicillium sp. (unidentified sponge, Weizhou, S. China Sea) was the source of the hydroisocoumarins penicimarin A–C 330–332, the isocoumarins penicimarin D–F 333–335 and the benzofurans penicifuran A–D 336–339, out of which only penicifuran A 336 was cytotoxic to Staphylococcus albus (moderate).³⁰⁶

Co-cultivation of Penicillium sp. (sponge Mycale angulosa, Toque-Toque Is., Brazil)³⁰⁷ and Trichoderma sp. (sponge Geodia corticostylifera, same location)³⁰⁷ led to the unusual polyketides, (Z)-2-ethylhex-2-enedioic acid 340 and (E)-4-oxo-2-propylideneoct-7-enoic acid 341.³⁰⁸ A chloro-trinoreremophilane sesquiterpene 342 and three chlorinated eremophilane sesquiterpenes 343–345 were isolated from Penicillium sp. (deep-sea sediment, Prydz Bay, Antarctica). Just 342 was cytotoxic to HTCLs (moderate).³⁰⁹

The isoaustamide alkaloid 346 was obtained from Penicillium sp. (unidentified sponge, Jeju Is., S. Korea). Also isolated for the first time as an NP was deoxydihydroisoaustamide, previously reported as an intermediate in the total synthesis of (+)-deoxyisoaustamide.^310,311Pestalotiopsis sp. (soft coral Sarcophyton sp., Yongxing Is., S. China Sea) was the source of the chlorinated benzophenone derivative (±)-pestalachloride D 347 (moderate antibacterial activity against several Gram-positive strains). Co-isolated was (±)-pestalachloride C, known as a metabolite of terrestrial endophytic Pestalotiopsis adusta³¹² but now a first time MNP.³¹³

The eudesmane sesquiterpenes 348 and 349 were produced by Pestalotiopsis sp. (brown alga Sargassum horneri, Wenzhou, China) in response to abiotic stress elicitation by addition of CuCl₂ to the growth media and both were both potent inhibitors of tyrosinase.³¹⁴ Endophytic Phaeosphaeria spartinae (red alga Ceramium sp., North Sea, Büsum, Germany) was the source of spartopregnenolone 350.³¹⁵

Polyporapyranones A–H 351–358 were isolated from two Polyporales species (seagrass Thalassia hemprichii, location unspecified, presumably Thailand). Polyporapyranones A 351 and D 354 exhibited moderate and weak inhibition of the Vero cell line respectively.³¹⁶Scopulariopsis sp. (gorgonian Carijoa sp., Weizhou, S. China Sea) was the source of fumiquinazoline L 359, an alkaloid with a heptacyclic skeleton.³¹⁷

Stachybotrys chartarum (sponge Xestospongia testudinaris, Xisha Is., China) yielded new phenylspirodrimanes stachybotrin D–F 360–362, stachybocin E 363 and F 364 and stachyboside A 365 and B 366, of which stachybotrin D 360 inhibited replication of HIV-1 by targeting reverse transcriptase and blocked non-nucleoside reverse transcriptase inhibitors-resistant strains as well. The absolute configuration of a co-isolated known terrestrial sesquiterpenoid 367 (S. chortarum³¹⁸) was determined.³¹⁹

Several polyketides were obtained from Stachylidium sp. (sponge, Callyspongia sp. cf. C. flammea, Bear Is., Sydney, Australia) including cyclomarinone 368, maristachone A–E 369–373 and marilactone.³²⁰ Due to rotation values being close to zero, racemic mixtures were assumed for cyclomarinone 368, maristachone A 369 and the epimers 372 and 373. Marilactone³²⁰ is a known synthetic compound but now a first time NP. From a biosynthetic perspective, all of the isolated compounds are unusual due to the presence of an additional carbon atom over the basic polyketide skeleton.³²¹

Stagonosporopsis cucurbitacearum (unidentified sponge, Atami-shi, Shizuoka Prefecture, Japan) yielded the alkaloids didymellamides A–D 374–377. Didymellamide A 374 inhibited growth of several pathogenic fungi including azole-resistant C. albicans.³²²

The peptaibols aspereline G 378 and H 379 were obtained from Trichoderma asperellum (sediment, Langqi Is., Fujian, China),³²³ while asperelines G-Z₁₃ are thirty-two new short peptaibols detected from T. asperellum (sediment, Penguin Is., Antarctica) by ultrahigh pressure liquid chromatography in combination with electrospray-ionisation tandem mass spectrometry (UHPLC-ESIMS/MS).³²⁴ Several strains of marine-derived T. atroviride (University of Nantes culture collection) produced two series of 17-residue peptaibiotics with a common C-terminus³²⁵ and eight new peptaibols 380–387, trichorzianine 1938, 1909, 1895, 1896, 1924, 1910, 1924A and 1909A, linear 19-residue hydrophobic peptides were obtained from T. atroviride (Axinellid sponge, Akhziv, Mediterranean coast, Israel).³²⁶

The diterpenoid lactone trichodermaerin 388 was isolated from endophytic T. erinaceum (sea star Acanthaster planci, Hainan Sanya National Coral Reef Reserve, China).³²⁷ A Xylariaceae sp. (gorgonian coral Melitodes squamata, S. China Sea) produced a number of polyketides including penicitrinol F 389, 7-carboxypenicitrinol C 390 and 391–393. Several known polyketides were also isolated and of these, dihydrocitrinin³²⁸ and phenol acid A³²⁸ strongly inhibited settlement of B. neritina larvae with dihydrocitrinin³²⁸ also an inhibitor of the enzymes SHP2 and IMPDH. Phenol acid A³²⁸ and dihydrocitrinone³²⁹ inhibited cathepsin B and (3R,4S)-(+)-4-hydroxy-6-deoxyscytalone³³⁰ inhibited the enzymes SHP2, PTP1B and IMPDH and is a first time MNP.³³¹ There is considerable confusion surrounding this report: the name penicitrinol F has been given previously to a citrinin derivative obtained from a Penicllium sp.³³² so 389 should be renamed. Also, for 7-carboxypenicitrinol C 390 there is a discrepancy between the configuration in the diagram and in the text. The text gives (1R) but the diagram gives (1S). If the diagram is correct, this is a known compound from both terrestrial³³³ and marine^334,335 fungi. The configuration of cochliomycin C, a resorcylic acid lactone obtained from the gorgonian-derived fungus Cochliobolus lunatus³³⁶ has been corrected to 394.³³⁷

Addition of sodium bromide to a culture of Aspergillus ochraceus (red alga Chondria crassicualis, Yokji Is., Kyeongnam Province, S. Korea) resulted in medium-induced production of (R)-(−)-5-bromomellein as a modest radical scavenger (against 1,1-diphenyl-2-picrylhydrazyl (DPPH)). Both the racemate³³⁸ and antipode³³⁹ have been previously synthesised but this is the first report of their isolation as NPs.³⁴⁰ The sesquiterpene helminthosporic acid has been reported previously as a semi-synthetic derivative of the fungal metabolite helminthosporol aldehyde³⁴¹ but has been isolated for the first time as an NP from Drechslera sp. (green alga Ulva sp., Tönning, North Sea).³⁴² Also as a first time MNP was the terrestrial fungal metabolite epiepoformin³⁴³ isolated from an endophytic Penicillium sp. (brown alga Fucus spiralis, Bridge End, Shetland Is., U.K.).³⁴⁴

3.4 Fungi from mangroves

Aspergillus effuses (rhizosphere soil, unidentified mangrove, Fujian Province, China) produced the prenylated indole diketopiperazine alkaloid dihydroneochinulin B 395 and the enantiomeric spiro-polyketide-diketopiperazine hybrids cryptoechinuline D 396 and 397. The latter compound has been isolated previously from terrestrial³⁴⁵ and marine³⁴⁶ fungi but in this study was resolved into enantiomers and absolute configurations assigned.³⁴⁷ The benzyl derivatives aspergentisyl A 398 and aspergentisyl B 399 and a naphthoquinone derivative aspergiodiquinone 400 were isolated from A. glaucus (mangrove sediment, unspecified species, Fujian Province, China). Aspergentisyls A 398 and B 399 were strong radical-scavengers (DPPH).³⁴⁸

Some 4-phenyl-3,4-dihydroquinolone derivatives were obtained from A. nidulans (mangrove leaves Rhizophora stylosa, source not given, presumably China), namely aniduquinolone A–C 401–403, 6-deoxyaflaquinolone E 404, isoaflaquinolone E 405 and 14-hydroxyaflaquinolone F 406. Of these, aniduquinolones B 402 and C 403 and the co-isolated aflaquinolone A³⁴⁹ were moderately toxic to brine shrimp. Aflaquinolone A, previously obtained from a terrestrial Aspergillus sp., was obtained for the first time as an MNP.³⁵⁰

Aniquinazolines A–D 407–410 are quinazolinone alkaloids from the endophytic A. nidulans (mangrove leaves Rhizophora stylosa, unspecified location, presumably China) and were all strongly cytotoxic to brine shrimp.³⁵¹ The nigerasterols A 411 and B 412 were obtained from endophytic A. niger (mangrove Avicennia marina, Hainan, China) as relatively potent inhibitors of the HTCLs HL60 and A549.³⁵² The butenolide isoaspulvinone E 413 came from A. terreus (mangrove rhizospehere soil, Fujian Province, China) along with the known butenolides aspulvinone E³⁵³ and pulvic acid.³⁵⁴ All exhibited significant H1N1 virus inhibition but only isoaspulvinone E inhibited H1N1 viral neuraminidase. Pulvic acid was a first time MNP.³⁵⁵

A. taichungensis (mangrove root soil Acrostichum aureum, no location given)³⁵⁶ was the source of the prenylated indole alkaloids 6-epi-stephacidin A 414, N-hydroxy-6-epi-stephacidin A 415 and 6-epi-avrainillanide 416, and of these 415 and 416 were cytotoxic to two HTCLs. On exposure to light and air 415 converted to a complex mixture of analogues, including (+)-versicolamide B,³⁵⁷ a mixture of two compounds (here named versicolamide C) and 416, which suggested that 416 may be an artefact. 6-Epi-stephacidin A 414 was stable under the same conditions.³⁵⁸

Botryosphaerin F 417 was obtained from endophytic A. terreus (mangrove branch Bruguiera gymnorhiza, Guangxi, China) and inhibited growth of HTCLs.³⁵⁹ Several known compounds were also isolated including LL-Z1271β,³⁶⁰ which although reported as active against the HL60 cell line used here, had previously been reported as being inactive against a number of other HTCLs.^361,362 Endophytic A. terreus (mangrove branch Bruguiera gymnorhiza, Guangxi province, China) was the source of a thiophene compound 418. The co-isolated 6-ethyl-5-hydroxy-3,7-dimethoxynaphthoquinone,³⁶³ a known synthetic compound, was a first time NP.³⁶⁴ Asperterpenoid A 419, a sesterterpenoid with a new carbon skeleton, was isolated from endophytic Aspergillus sp. (mangrove species not specified, no location given) and displayed inhibitory activity against M. tuberculosis protein tyrosine phosphatase B (mPTPB).³⁶⁵ Asperterpenols A 420 and B 421 are sesterterpenoids with an unusual 5/8/6/6 tetracyclic ring skeleton. Both were acetylcholinesterase inhibitors and were obtained from endophytic Aspergillus sp. (mangrove, S. China Sea).³⁶⁶

Cladosporium sp. (mangrove soil, Guangzhou, China) was the source of a number of indole alkaloids including five glyantrypine derivatives; 3-hydroxyglyantrypine 422, oxoglyantrypine 423, 424, cladoquinazoline 425 and epi-cladoquinazoline 426 and a pyrazinoquinazoline derivative norquinadoline A 427. Of these alkaloids, oxoglyantrypine 424 and norquinadoline A 427, together with the co-isolated known terrestrial Aspergillus alkaloid metabolites, deoxynortryptoquivaline,³⁶⁷ deoxytryptoquivaline,³⁶⁷ tryptoquivaline³⁶⁸ and quinadoline B³⁶⁹ had significant activities against H1N1. The latter four were also obtained for the first time as MNPs. Over time, a solution of oxoglyantrypine 423 partially converted into 424, leading to the proposal that 424 was an artefact.³⁷⁰

Further investigation of endophytic Corynespora cassiicola (mangrove leaf Laguncularia racemosa, Hainan Is., China), which originally yielded some decalactone derivatives,³⁷¹ yielded some minor metabolites coryoctalactone A–E 428–432, of which coryoctalactones A 428 and B 429 were assumed to be C-9 epimers.³⁷²

As part of a screening programme for new antimalarial compounds, four metabolites were obtained from several species of Chinese mangrove endophytic fungi from either Mai Po Nature Reserve, Hong Kong or Hainan Is., Taiwan. Despite lack of a tight correlation between location and source microorganism, this study described the isolation of a dimeric tetrahydroxanthone dicerandrol D 433 from a Diaporthe sp., diaporthochromes A 434 and B 435 from another Diaporthe sp. and the lipid 436 was obtained from Xylaria sp. Dicerandrol D 433 exhibited potent activity against P. falciparum with relatively low toxicity to A549 cells.³⁷³

Endophytic Fusarium proliferatum (mangrove Bruguiera sexangula, Hainan Is., China) produced the tricyclic sesterterpenes fusaprolifin A 437 and B 438 and the 2H-pyran-2-one derivatives prolipyrone A–C 439–441. Fusaprolifins A and B had modest activity against brine shrimp.³⁷⁴

Penicillium camemberti (mangrove soil Rhizophora apiculata, Wenchang, Hainan Province, China) produced the indole diterpenoids 442–447, as well as some known analogues. Of these, emindole SB,³⁷⁵ 21-isopentenylpaxilline,³⁷⁶ paspaline,^377,378 and paxilline³⁷⁹ displayed significant activity against H1N1 as did indole diterpenoids 442–444, 446 and 447. 21-Isopentenylpaxilline³⁷⁶ and dehydroxypaxilline³⁸⁰ were obtained for the first time as MNPs.³⁸¹

Penicillium sumatrense (mangrove rhizosphere Lumnitzera racemosa, WenChang, Hainan Is., China) yielded sumalarins A–C 448–450, sulfur-containing curvularin derivatives which were cytotoxic to several HTCLs.³⁸² The planar structure of sumalarin C 450 had previously been reported as part of several compound libraries.^383–385 The citrinin dimers penicitrinone E 451 and penicitrinol J 452 and the citrinin monomers penicitrinol K 453 and citrinolactone D 454 were isolated from Penicillium sp. (mangrove sediment, Fu Gong, Long Hai, Taiwan Strait, China).³⁸⁶

Arisugacin I 455, an α-pyrone meroterpene, was obtained from endophytic Penicillium sp. (mangrove leaves Kandelia candel, Shankou, Guangxi Province, China) as an inhibitor of acetylcholinesterase.³⁸⁷ The known fungal metabolite arisugacin F³⁸⁸ was also obtained for the first time from the marine environment.³⁸⁷ Endophytic Penicillium sp. (mangrove leaves Avicennia sp., Dong Sai, Hainan, China) yielded the isobenzofuranone 456 which was moderately cytotoxic to KB and KB_V200 cells.³⁸⁹

Pestaliopens A 457 and B 458, hybrid sesquiterpene–cyclopaldic acid metabolites with an unusual carbon skeleton, were isolated from endophytic Pestalotiopsis sp. (mangrove leaves Rhizophora mucronata, Hainan Is. China). Pestaliopen A 457 exhibited modest inhibition of E. faecalis.³⁹⁰

P. virgatula (mangrove leaf Sonneratia caseolaris, Dong Zhai Gang mangrove garden, Hainan Is., China) yielded the α-pyrone derivatives pestalotiopyrone I–L 459–462 as well as (6S,1′S,2′S)-hydroxypestalotin 463,³⁹¹ a diastereoisomer of a metabolite isolated from a plant associated Penicillium sp.³⁹²

The xanthones O-glycoside 464 isolated from endophytic Phomopsis sp. (mangrove stem Excoecaria agallocha, Dong Zai, Hainan, China)³⁹³ and 465 and 466 isolated from Phomopsis sp. (mangrove sediment, Shankou, Hainan, China)^394,395 were moderate inhibitors of HEp-2 and HepG2 cells.

Three new phomoxanthone compounds phomolactonexanthone A 467, B 468 and deacetyl-phomoxanthone C 469 were obtained from Phomopsis sp. (mangrove branch Acanthus ilicifolius, Hainan, S. China Sea) along with five phomoxanthones known as endophytic metabolites of terrestrial fungi, namely dicerandrol A,³⁹⁶ dicerandrol B,³⁹⁶ dicerandrol C,³⁹⁶ deacetylphomoxanthone B³⁹⁷ and penexanthone A,³⁹⁸ all isolated as first time MNPs.³⁹⁹

Phomopsis sp. (mangrove plant Rhizhopora mucronata, Muara Angke, Jakarta, Indonesia) was the producer of the dimeric tetrahydroxanthone 12-O-deacetyl-phomoxanthone A 470 which exhibited moderate inhibition of several Gram-positive bacteria.⁴⁰⁰ A polysubstituted benzaldehyde derivative 471 was isolated from co-culture of two unidentified mangrove fungi (S. China Sea coast).⁴⁰¹

Marinamide and the methyl ester, methyl-marinamide were originally isolated from a co-culture of two mangrove endophytic fungi from the S. China Sea Coast and assigned as pyrrolyl 1-isoquinolone alkaloids.⁴⁰² Subsequently, the fungus Auxarthron reticulatum (sponge Ircinia variabilis) yielded the quinolinone methyl-penicinoline, shown to be identical to methyl-marinamide requiring structural revision.²⁴⁴ The revised structure of marinamide is identical to that of penicinoline, previously obtained from a mangrove endophytic fungus.⁴⁰³ This problem has already been addressed above in Section 3.3. Both marinamide/penicinoline⁴⁰³ and its methyl ester²⁴⁵ displayed potent cytotoxicity to several HTCLs.

3.5 Cyanobacteria

There has been a marked drop in the number of new metabolites reported from cyanobacteria, continuing the downward trend from 2012. The lipopeptide malyngamide 4 472 was isolated from Moorea producens (Red Sea, Jeddah, Saudi Arabia) as a moderate inhibitor of several HTCLs.⁴⁰⁴

M. producens (La Parguera, Puerto Rico) was the source of the lipopeptides parguerene 473 and precarriebowmide 474. Studies of the stability of precarriebowmide 474 to atmospheric oxygen indicated that carriebowmide⁴⁰⁵ and carriebowmide sulfone,⁴⁰⁶ previously isolated from Lyngbya polychroa and Lyngbya majuscula respectively, may in fact be isolation artefacts of precarriebowmide 474.⁴⁰⁷

Two new aprataoxin analogues, apratoxin H 475 and apratoxin A sulfoxide 476, were obtained from M. producens, (Nabq Mangroves, Gulf of Aqaba, Red Sea) and both exhibited cytotoxicity to NCI-H460 lung cancer cells, but apratoxin H 475 was much more potent than apratoxin A sulfoxide 476.⁴⁰⁸

M. bouillonii (New Britain, Papua New Guinea) was the source of bouillonamide 477, a cyclic depsipeptide which contained two unique polyketide-derived moieties, a 2-methyl-6-methylamino-hex-5-enoic acid residue and a unit of 3-methyl-5-hydroxy-heptanoic acid. Bouillonamide 477 displayed moderate toxicity to neuron 2a mouse neuroblastoma cells.⁴⁰⁹

A cyanobacterium of similar morphology to Lyngbya sp. (Piti Bay, Guam) produced the lipids pitinoic acid A 478 and B 479. Pitinoic acid A 478 inhibited quorum sensing in Pseudomonas aeruginosa and pitinoic acid B 479 exhibited anti-inflammatory activity, inhibiting production of pro-inflammatory cytokine expression. Pitinoic acid B 479 has been synthesised.⁴¹⁰ A species resembling the genus Symploca (Santa Cruz Is., Coiba National Park, Panama) yielded santacruzamate A 480, a potent and specific inhibitor of histone deacetylase 4 and cytotoxic to several HTCLs. Santacruzamate A 480 was synthesised from γ-aminobutyric acid.⁴¹¹

3.6 Dinoflagellates

An Amphidinium sp. (sediment, Iriomote Is., Japan) was the producer of iriomoteolides-4a 481 and -5a 482, which displayed moderate cytotoxicity against human B lymphocyte DG-75 cells.⁴¹²

An epoxy polyether with twelve contiguous trans-fused ether rings, gambieroxide 483 was obtained from Gambierdiscus toxicus (Papeete, Tahiti, French Polynesia).⁴¹³ Gymnocin-A2 484 was isolated from Karenia (formerly Gymnodinium) mikimotoi (Kushimoto Bay, Wakayama, Japan) as a moderate cytotoxin to P388 cells, along with the known synthetic analogue, gymnocin-A carboxylic acid⁴¹⁴ (first isolation from a natural source).⁴¹⁵

The epiphytic, benthic dinoflagellate Ostreopsis cf. ovata (Jeju Is., S. Korea) was the source of ostreol A 485, significantly cytotoxic to brine shrimp,⁴¹⁶ whilst the IK2 strain of O. ovata (Ikei Is., Okinawa, Japan) produced ovatoxins-a, -d and -e, each tentatively assigned by negative fast-atom bombardment collision-induced tandem mass spectrometry (FAB CID MS/MS).⁴¹⁷

Pyrocystis lunula (University of Texas Culture Collection) yielded three polyunsaturated C27 hydrocarbons; n-heptacosa-3,6,9,12,15,18-hexaene (C27:6) 486, (approx. 0.7 ng per sheathed cell), n-heptacosa-3,6,9,12,15,18,21-heptaene (C27:7) 487 and n-heptacosa-3,6,9,12,15,18,21,24-octaene (C27:8) 488.⁴¹⁸ The benthic dinoflagellate Vulcanodinium rugosum (Northland, New Zealand) yielded portimine 489, a polycyclic ether toxin containing a five-membered imine ring, which exhibited potent toxicity to P388 cells, in addition to activation of caspases, as an indication of apoptotic activity.⁴¹⁹ The structure of amphidinolide N, the most potent cytotoxic macrolide isolated from Amphidinium sp. to date⁴²⁰ has been revised to 490 (and the relative configuration has been assigned).⁴²¹

3.7 Microalgae

The microalga Nannochloropsis granulata (Provasoli-Guillard National Centre for Culture of Marine Phytoplankton, West Boothbay Harbour, Maine) was the source of the digalactosyldiacylglycerols 491, 492 and the known 493 (ref. 422) and 494,⁴²² whose configurations were determined. Also isolated were the monogalactosyl analogues 495,⁴²²496 (ref. 423) (first time as an NP) and 497.⁴²³ All of the isolated metabolites exhibited strong NO inhibitory activity against LPS-induced NO production in RAW264.7 macrophage cells suggesting potential as anti-inflammatory agents.⁴²⁴ The green microalga Tetraselmis sp. (National Institute of Technology and Evaluation Biological Resource Centre, Chiba, Japan) was a producer of the glycosylceramides GT1 498 and GT2 499.⁴²⁵

3.8 Synthetic aspects

Synthesis of acremolin, originally isolated from sponge-associated Acremonium strictum and assigned as containing a 1H-aziridine moiety⁴²⁶ proved that the alternative structure independently proposed (an isomeric, substituted N²,3-ethenoguanine)⁴²⁷ was indeed correct.⁴²⁸ Total synthesis of ent-(−)-azonazine utilising a hypervalent iodine-mediated biomimetic oxidative cyclisation to construct the core, has resulted in revision of the absolute configuration of natural (+)-azonazine, originally obtained from Hawaiian Aspergillus insulicola⁴²⁹ to 500,⁴³⁰ while syntheses of versicolactones A and B, lactones originally isolated from coral-associated Aspergillus versicolor,⁴³¹ have resulted in revision of the absolute configurations of the NPs to (4Z,6R,7S)-501 and (4E,6R,7S)-502 respectively.⁴³² It should be noted that the names versicolactones A and B have also been used to refer to unrelated sesquiterpene lactones isolated from the plant Aristolochia versicolor.^433,434

Citrinadins A and B are pentacyclic alkaloids, originally obtained from a red alga-associated strain of Penicillium citrinum.^435,436 An enantioselective total synthesis of (−)-citrinadin A has been achieved in twenty steps from commercially available materials which featured an asymmetric vinylogous Mannich addition of a dienolate to a chiral pyridinium salt to set the initial chiral centre. The synthesis led to revision of the core stereochemistry of the citrinadins and thus of citrinadin A to 503.⁴³⁷ An enantioselective total synthesis of (+)-citrinadin B featuring a stereoselective intermolecular nitrone cycloaddition reaction as a key step, similarly led to revision of the configuration of citrinadin B to (+)-504.⁴³⁸

Trichodermatide A, a polyketide isolated from the fungus Trichoderma reesei,⁴³⁹ has been synthesised from L-tartaric acid utilising an intramolecular ketal formation reaction to construct the core of the molecule.⁴⁴⁰ The total syntheses of the putative structures of (±)-trichodermatides B and C featuring the oxa-[3 + 3] annulation strategy have also been accomplished but mismatch of spectroscopic data between the synthetic and NP samples has indicated that the structural assignments of these metabolites may need revision.⁴⁴¹ Syntheses of two diastereoisomers of penicillenol C1, originally obtained from an endophytic, mangrove-associated Penicillium species,⁴⁴² have led to reassignment of the absolute configuration as 505 (5S,6R,9S).⁴⁴³ The absolute configurations of the endophytic mangrove Pestalotiopsis sp. metabolites, pestalotiopsones D and E⁴⁴⁴ were determined through total syntheses as 506 and 507 respectively.⁴⁴⁵

Synthesis of the reported structure of xylopyridine A, a DNA-binding agent originally obtained from a mangrove-associated Xylaria sp.,⁴⁴⁶ has indicated that the reported structure is incorrect and requires revision.⁴⁴⁷ Total synthesis of laxaphycin B, a metabolite of terrestrial Anabaena laxa⁴⁴⁸ and of marine L. majuscula,⁴⁴⁹ was achieved through stepwise automated solid-phase peptide synthesis, which led to revision of configuration to 508. The related L. majuscula metabolite lyngbyacyclamide A⁴⁵⁰ was also synthesised by a similar procedure.⁴⁵¹

The dolastatin 14 analogue, malevamide E, was originally obtained from the cyanobacterium Symploca laete-viridis and the stereochemistry of the peptidic portion assigned.⁴⁵² Convergent synthesis of (29S,37S)-malevamide E involving Julia-Kocienski olefination, Urpi acetal aldol and Shiina macrolactonisation reactions has been achieved but a mismatch of the NMR data between the synthetic and natural samples indicated that the originally assigned configurations of some of the amino acids need revision.⁴⁵³ A stereoselective synthesis of the C-43–C-67 fragment of amphidinol 3, originally obtained from the dinoflagellate Amphidinium klebsii,⁴⁵⁴ revised the originally assigned configuration at C-51 from (R) to (S).⁴⁵⁵ Ieodomycins A and B are antimicrobial fatty acids originally obtained from a Bacillus sp.⁴⁵⁶ The first⁴⁵⁷ of several total syntheses of these published in 2013,^458–460 has been achieved in fifteen steps via the chiral pool approach from D-glucose.⁴⁵⁷ Syntheses of the glycolipopeptides ieodoglucomide A and B, originally obtained from Bacillus licheniformis,⁴⁶¹ have been accomplished via a method involving β-glycosylation and Grubbs olefin cross-metathesis as key steps. The syntheses highlighted that the optical rotation values were originally misreported as being of opposite sign to their actual values and the authors of the isolation paper had noted this also.^462,463 Syntheses of marinacarbolines A–D, antimalarial β-carboline alkaloids originally obtained from Marinactinospora thermotolerans⁴⁶⁴ were achieved in four steps from methyl 1-chloro-β-carboline-3-carboxylate⁴⁶⁵ and the cyclic peptide urukthapelstatin A, originally isolated from the bacterium Mechercharimyces asporophorigenens^466,467 has been synthesised via a convergent strategy.⁴⁶⁸ Trioxacarcin A, a structurally complex glycosidic metabolite of terrestrial⁴⁶⁹ and marine⁴⁷⁰Streptomyces species, has been synthesised via a method which utilised late-stage stereoselective glycosylation reactions of aglycon substrates.⁴⁷¹ Indoxamycins A, C, and F, cytotoxic tricyclic polypropionates originally obtained from a Streptomyces sp.⁴⁷² and whose stereochemistry has also been revised as a result of a synthesis of indoxamycin B,⁴⁷³ have been synthesised via a divergent approach with an Ireland-Claisen rearrangement, a stereodivergent reductive 1,6-enyne cyclisation and a tandem 1,2-addition/oxa-Michael/methylenation reaction sequence as key steps.⁴⁷⁴ Cytosporin D, an epoxyquinone metabolite of Eutypella scoparia,⁴⁷⁵ has been prepared from the Diels–Alder adduct of cyclopentadiene and 2-prenyl-p-benzoquinone,⁴⁷⁶ while helicascolide B, a lactone originally obtained from the fungus Helicascus kanaloanus,⁴⁷⁷ has been synthesised in seven steps from commercially available tiglic aldehyde.⁴⁷⁸ Leptosin D, originally obtained from a Leptosphaeria sp. associated with a brown alga⁴⁷⁹ has been synthesised via a strategy which first prepared the known terrestrial⁴⁸⁰ and marine⁴⁸¹ fungal metabolite gliocladine C, which was then manipulated to access various tryptophan-derived epidithiodioxopiperazine NPs.⁴⁸² Enantioselective total synthesis of (−)-penicipyrone, a polycyclic 4-hydroxy-2-pyrone metabolite of a Penicillium species associated with a Thai sea fan Annella sp.,⁴⁸³ was achieved in twelve steps by a biomimetic bimolecular cascade cyclisation featuring an intermolecular Michael addition/cyclo-(spiro-) ketalisation sequence⁴⁸⁴ and total syntheses of plectosphaeroic acids A–C (indoleamine 2,3-dioxygenase inhibitors from the fungus Plectosphaerella cucumerina⁴⁸⁵) have been accomplished.^486,487 The quinoline alkaloid, 4,8-dimethyl-6-O-(2′,4′-di-O-methyl-β-D-xylopyranosyl)hydroxyquinoline, originally obtained from a Caribbean collection of Lyngbya majuscula,⁴⁸⁸ has been synthesised by a method which utilises unusual silyl group migrations⁴⁸⁹ and synthesis of nhatrangin A, an aplysiatoxin-related metabolite isolated from Vietnamese Lyngbya majuscula,⁴⁹⁰ has been accomplished and confirmed the absolute configuration originally proposed.⁴⁹¹ (+)-Serinolamide A, a cannabinomimetic lipid metabolite of Panamanian Lyngbya majuscula⁴⁹² has been synthesised from L-serine in nine steps with 30% overall yield⁴⁹³ and total synthesis of viequeamide A, a cyclic depsipeptide metabolite of the Puerto Rican “button” cyanobacterium Rivularia sp.,⁴⁹⁴ was achieved in ten linear steps based on three retrosynthetic fragments.⁴⁹⁵ Amphidinolide C, a macrocyclic lactone metabolite of the dinoflagellate Amphidinium sp.,⁴⁹⁶ has been synthesised through the use of a common intermediate to access both the C-1–C-8 and the C-18–C-25 sections.⁴⁹⁷

3.9 Assorted bioactivities

The sesterterpenes ophiobolin K,^498,499 6-epi-ophiobolin K^498,499 and 6-epi-ophiobolin G,⁴⁹⁹ known metabolites of both terrestrial⁴⁹⁸ and marine⁴⁹⁹ fungi were isolated from Emericella variecolor (sediment, Gokasyo Gulf, Mie Prefecture, Japan) as inhibitors of biofilm formation of Mycobacterium smegmatis and of M. bovis BCG at concentrations below those required for antimicrobial activity.⁵⁰⁰ Toluquinol, a methylhydroquinone known as a metabolite of the soil fungus Nectria erubescens⁵⁰¹ was isolated from a Penicillium sp. (Instituto Biomar, León, Spain) as an antiangiogenesis agent, inhibiting the growth of endothelial and tumour cells via apoptosis after a cell cycle block and caspase activation.⁵⁰² Several known fungal metabolites were isolated as selective inhibitors of PTP1B, a potential target for the treatment of type 2 diabetes and obesity.⁵⁰³Penicillium sp. (sediment, Wan Is., S. Korea) yielded fructigenine A⁵⁰⁴ and cyclopenol,⁵⁰⁵Eurotium sp. (sediment, Wan Is., Korea) yielded echinulin⁵⁰⁶ and flavoglaucin⁵⁰⁷ and a further Penicillium sp. (unidentified sponge, Jeju Is., S. Korea) was the source of viridicatol.⁵⁰⁵ Bis-N-norgliovictin, a known terrestrial⁵⁰⁸ and marine^509,510 metabolite was isolated from a marine-derived endophytic fungus (no other details given), as an anti-inflammatory agent that inhibited LPS-induced TNF-α production in RAW264.7 cells.⁵¹¹

3.10 Biosynthesis

The gene cluster responsible for the biosynthesis of the glycosylated diazofluorene polyketides lomaiviticins A–E,^512,117 originally isolated from Salinispora pacifica (formerly Micromonospora lomaivitiensis), was identified in wild-type Salinispora tropica and several mutant strains through bioactivity-guided genome mining.⁵¹³ An investigation of 163 strains of actinomycetes isolated from mangrove sediments via homologous screening of the biosynthetic genes and bioassay identified 16% of the strains as possessing the potential to produce halogenated NPs.⁵¹⁴ The stephacidin and notoamide families of NPs occur in various Aspergillus species, both terrestrial⁵¹⁵ and marine.⁵¹⁶ In a further elaboration of the biosynthesis of these metabolites, notoamide T was identified as the likely precursor to stephacidin A and synthesised along with the C-6-epimer, 6-epi-notoamide T. Stephacidin A was chemically converted to notoamide T by reductive ring opening while notoamide T also underwent oxidative conversion to stephacidin A. [¹³C]₂-Notoamide T was synthesised and fed to two Aspergillus strains resulting in significant incorporation into the advanced metabolite notoamide B.⁵¹⁷ Analysis of transcriptome data of a number of saxitoxin (STX)-producing dinoflagellates, especially Alexandrium tamarense strains, identified 265 putative homologues of 13 cyanobacterial STX synthesis genes, including all of the genes directly involved in toxin synthesis. Putative homologues of four proteins group closely in phylogenies with cyanobacteria but the phylogenies do not support transfer of these genes directly between toxic cyanobacteria and dinoflagellates, suggesting that the STX synthesis pathway was likely to have been assembled independently in cyanobacteria and dinoflagellates, but using some evolutionarily related proteins.⁵¹⁸

4 Green algae

Interest in green alga chemistry continued at a low ebb in 2013. Further work on Caulerpa racemosa (Zhanjiang coastline, China), previously the source of caulerpin and two related caulerpin derivatives,⁵¹⁹ led to the discovery of two prenylated para-xylenes caulerprenylol A 509 and B 510 that were each weakly antifungal.⁵²⁰

Interesting results were uncovered from the screening and careful bioassay-guided analysis of a collection of Floridian marine eukaryotic algae using an ARE-luciferase reporter gene assay that led to the detection and isolation of three mono-unsaturated fatty acids 511–513 from Ulva lactuca as activators of the ARE response. Each contained the identical Δ⁷,9-keto motif.⁵²¹

A stereoselective synthesis of the C-8′–O–C-6′′ ether of the antimitotic agent nigricanoside A⁵²² was successfully applied in model systems.⁵²³ Included in the green algal literature for 2013 were reports on the cytotoxic effects of clerosterol from Codium fragile⁵²⁴ on HTCLs⁵²⁵ and the spasmolytic effects of caulerpine⁵²⁶ on guinea pig ileum.⁵²⁷

5 Brown algae

The number of new compounds characterised in 2013 from the Ochrophyta was again relatively low and was dominated by terpenoid chemistry. Based on the in vitro cytotoxicity of a crude Dictyota dichotoma (Abu-Bakr, Red Sea, Egypt) extract an investigation was mounted and three new diterpenoids (Z)-pachydictyol B 514, (E)-pachydictyol B 515 and pachydictyol C 516 were characterised along with the known pachydictyol A⁵²⁸ and several other well-known brown algal metabolites.⁵²⁹

Re-investigation of Dilophus spiralis (Elafonissos Is., Greece) resulted in the isolation of three new dolastanes 517–519 and five previously reported perhydroazulenes. The relative configurations were established for all three dolastanes and the absolute configuration of 518 established by conversion to a compound of known absolute configuration. The absolute configurations of 517 and 519 were assumed on the basis of biogenetic considerations.⁵³⁰

The cytotoxic meronorsesquiterpenoids cystoazorone A 520 and B 521 and meroditerpenoids cystoazorol A 522 and B 523 were isolated from Cystoseira abies-marina (Mosteiros, Sao Miguel Is., Azores)⁵³¹ while a series of meroditerpenoids cystodione A–F 524–529, all with strong antioxidant properties in the ABTS assay, were isolated from Cystoseira usneoides (Gibraltar Strait).⁵³²

The mildly antiproliferative meroditerpenoid zonaquinone acetate 530 was obtained from a Jamaican Stypopodium zonale.⁵³³ Other known brown algal metabolites were co-isolated and these included flabellinone,⁵³⁴ not previously identified in S. zonale, stypoldione,⁵³⁵ and sargaol.⁵³⁶ The absolute configuration of 530 was determined by vibrational circular dichroism (VCD) calculations at several levels of theory.⁵³³

The synthesis of the core framework of the proposed structure of sargafuran⁵³⁷ was achieved but the ¹H and ¹³C NMR spectral data of the synthetic analogue did not match suggesting that the originally proposed structure of sargafuran is incorrect.⁵³⁸ The data matched better with the known sargachromenol.⁵³⁹ Another total synthesis of (−)-ecklonialactone B,⁵⁴⁰ as well as the non-natural (+)-9,10-dihydro-ecklonialactone B, was reported.⁵⁴¹ In papers covering biological properties of brown algal metabolites, four papers were published on the eckol group of phlorotannins describing anti-inflammatory properties,^542,543 induction of apoptosis in carcinoma cells⁵⁴⁴ and potential as SARS inhibitors.⁵⁴⁵ Two surveys were published on the antioxidant potential of brown algal extracts which included an excellent summary from species across the phylum as well as the properties of individual brown algal metabolites.^546,547 The antiviral properties of sulfoquinovosyldiacylglycerols from Sargassum vulgare (Ilha de Itacuruçá, S.E. Brazil) were evaluated⁵⁴⁸ and the antiviral activity of Dictyota diterpenes assessed in docking studies against HIV-1 reverse transcriptases.⁵⁴⁹ A putative inhibitory mechanism for RANK-induced osteoclast formation by sargachromanol G from Sargassum siliquastrum⁵⁵⁰ has been proposed⁵⁵¹ and the antiplatelet and antithrombotic effects of sargahydroquinoic and sargaquinoic acids determined.⁵⁵² In other reports of biological testing, the strong antimelanogenic properties of an extract from Dictyota coriacea (Jeju Is., S. Korea) were attributed to 1,9-dihydroxycrenulide⁵⁵³ and epiloliolide,⁵⁵⁴ known compounds.⁵⁵⁵ Seven known meroditerpenoids were isolated from Sargassum siliquastrum (Jeju Is., S. Korea) and evaluated for cytotoxicity against a range of HTCLs,⁵⁵⁶ while the cytotoxic sterol (24R)-hydroperoxy-24-vinylcholesterol⁵⁵⁷ was reported for the first time from Nizamuddinia zanardinii (Oman Sea).⁵⁵⁸ In a comprehensive study the anticancer effects of fucoxanthin were examined from a mechanistic perspective.⁵⁵⁹ In another wide-ranging study, 20 green and brown algal extracts from the French coast were evaluated against Trypanosoma brucei rhodesiense (T. b. rhodesiense).⁵⁶⁰ The Bifurcaria bifurcata extract showed the strongest trypanocidal activity which was tracked to eleganolone.⁵⁶¹ The potential of the HPLC/NMR technique for chemical profiling and dereplication was illustrated with the characterisation of nine known compounds from Cystophora torulosa (Pt. Lonsdale, Victoria, Australia).⁵⁶²

6 Red algae

The nine new compounds reported from red algae in 2013 is a marked reduction in the number reported from the previous year (47). The relative configurations of the 30 stereogenic centres in the macrodiolide luminaolide 531 (Hydrolithon reinbodii)⁵⁶³ were assigned from NMR data, although the relationships of the two side chains to the macrolide ring are still to be established.⁵⁶⁴

The structures of laurefurenynes A 532 and B 533 (Laurencia sp.)⁵⁶⁵ were reassigned following syntheses of 532⁵⁶⁶ and 533,⁵⁶⁷ respectively, and density functional theory (DFT) calculations of NMR chemical shift data.⁵⁶⁷ There is still doubt about the configuration of the closely related elatenyne (L. elata).⁵⁶⁸ Computational⁵⁶⁹ and synthetic⁵⁷⁰ efforts suggested a revised structure. However, recent more extensive NMR and chemical derivatisation studies proposed a further revision 534 but were unable to establish the absolute configuration.⁵⁷¹

Various aspects of the configurations of armatols A–F (Chondria armata)⁵⁷² have now been clarified through the total synthesis of armatol A 535 and hence by analogy to the structures for armatols B–F 536–540.⁵⁷³ This paper also reported the first total synthesis of dioxepandehydrothyrsiferol (Laurencia viridis)⁵⁷⁴ as the enantiomer.

The chamigrane sesquiterpenes yicterpene A 541 and B 542 were isolated from L. composita (Pingtan Is., China).⁵⁷⁵ Of the 7 compounds isolated from L. similis (Sepanggar Is., Kota Kinabalu, Sabah), ent-1(10)-aristolen-9β-ol 543 was claimed as an enantiomer of a known compound.^576,577 Two bromophenols 544 and 545 with radical scavenging activity were obtained from Symphyocladia latiuscula (Qingdao, Shandong Province, China).⁵⁷⁸ This same collection of S. latiuscula also provided the weakly antifungal bromophenol sulfoxide 546.⁵⁷⁹

One new (547) and three known bromophenols isolated from Vertebrata lanosa (Oldervik, Ullsfjorden, Norway) had cellular antioxidant activities, the first time this activity has been reported for this class of compounds.⁵⁸⁰ The unprecedented polybrominated spiro-trisindole similisine A 548 and its enantiomer similisine B were obtained from Laurencia similis (S. China Sea).⁵⁸¹

Synthesis of the two proposed diastereomers of prevezol C (L. obtusa)⁵⁸² showed that neither is the structure of the NP.⁵⁸³ Parguerenes (L. filiformis)⁵⁸⁴ were identified as inhibitors of P-glycoprotein (ABCB1) in multidrug resistant human cancer cells.⁵⁸⁵ Five known bromophenols from a variety of red algae had inhibitory activity against glucose 6-phosphate dehydrogenase, this being the first report of such inhibitors from red algae.⁵⁸⁶ Analysis of the metabolite compositions of seasonal collections of Graciliaria gracilis (Lesina Lagoon, S. Adriatic Sea, Italy) led to the proposition for using G. gracilis as a multi products source for biotechnological, nutraceutical and pharmaceutical applications.⁵⁸⁷ Bioactive metabolites isolated from Asparagopsis taxiformis were found to have little potential for therapy services to fish infected with Streptococcus iniae.⁵⁸⁸

7 Sponges

Even with only 243 new compounds reported in 2013, a significant decrease in relation to previous years (19% and 33% down on 2011 and 2012, respectively),^589,2 sponges remain the dominant phylum for the discovery of new marine-derived bioactives (see section 15 Conclusion). The modified sphingoid base halisphingosine B 549 was isolated from Haliclona tubifera (Santa Catarina, Brazil)⁵⁹⁰ while taurinated fatty acid 550 was isolated from Axinella sp. (Hainan Is., S. China Sea).⁵⁹¹

The asymmetric total synthesis of the “two-headed” sphingoid base rhizochalin C (Rhizochalina incrustata)⁵⁹² has been completed.⁵⁹³ An Axinyssa djiferi found attached to mangrove tree roots (Djifer, Senegal) yielded axidjiferosides A–C 551–553, a mixture of which inhibited chloroquine-resistant P. falciparum.⁵⁹⁴

An acetylated nitrogenous glycolipid 554 was isolated from Plakinastrella clathrata (Gneerings Reef, Queensland, Australia), with the absolute configuration confirmed by synthesis of lipid-chain analogues. The compound was claimed to be a moderate anti-inflammatory by inhibition of PGE₂ but no data was provided.⁵⁹⁵

Mycalol 555 is a glycerol ether isolated from Mycale acerata (Terra Nova Bay, Antarctica). A combination of chiroptical and Mosher's methods were used to assign the absolute configuration of this specific inhibitor of human anaplastic thyroid carcinomas, the most aggressive and currently untreatable thyroid gland malignancies, but inactive against other solid tumours.⁵⁹⁶ The absolute configuration of topsentolide C₂556 (Topsentia sp.)⁵⁹⁷ was established by total synthesis of four possible diastereomers.⁵⁹⁸ The moderately antimicrobial fatty acid trimer manzamenone O 557 was isolated from Plakortis sp. (Manzamo, Okinawa).⁵⁹⁹

Sponges from the genus Petrosia continue to be a rich source of new polyacetylenes. The report of petrosiols A–E 558–562 from Petrosia strongylata (Ishigakijima Is., Okinawa) as inducers of nerve growth factor-like neuronal differentiation in PC12 cells was followed rapidly by reports of the total synthesis and absolute configuration of petrosiol D 560,^600,601 and the discovery that 558 inhibits proliferation and migration of platelet derived growth factor-induced vascular smooth muscle cells and hence could be used as a lead for vascular disorders.⁶⁰²

The absolute configuration of the isolated methyl group of miyakosyne A 563 (Petrosia sp.)⁶⁰³ was established by chemical degradation and subsequent esterification with Ohrui's acid,⁶⁰⁴ thus correcting an earlier tentative assignment made from an analysis by X-ray crystallography of miyakosyne absorbed in a porous metal complex.^71,605 A racemic mixture of C20 bisacetylenic alcohols 564 and 565 has been isolated from Callyspongia sp. (Iriomote Is., Okinawa), and separated by chiral HPLC. Total synthesis of both enantiomers and detailed biological evaluation showed 564 was more active than its enantiomer against HeLa and temperature sensitive rat lymphatic endothelial cells, thus defining the 1-yne-3-ol moiety as an essential pharmacophore.⁶⁰⁶ Petrosiacetylene E 566 (Petrosia sp. Dokdo Is., S. Korea) was a low μM inhibitor of multiple HTCLs.⁶⁰⁷

Petrosynic acids A–D 567–570 (Petrosia sp., Tutuila, American Samoa) all displayed similar activity versus various HTCLs and non-proliferative human fibroblasts and hence no therapeutic window is available.⁶⁰⁸

A New Caledonian Niphates sp. was the source of nepheliosyne B 571.⁶⁰⁹ Examination of Petrosia solida (Amami-Oshima, Japan) yielded petroacetylene 572 that inhibited starfish embryo blastulation.⁶¹⁰

Bromoacetylene testafuran A 573 was isolated from Xestospongia testudinaria (Iwo Is., Kagoshima, Japan) along with four other polyacetylenes 574–577, all five of which induced apidogenesis (stimulation of the differentiation of preadipocytes to adipocytes), and hence may act as leads for treatment of cardiovascular disorders.⁶¹¹

An inhibitor of starfish egg maturation, bromotheoynic acid 578, was reported from Theonella swinhoei (Tanegashima, Kagoshima, Japan),⁶¹² while two further bromopolyacetylenes 579 and 580 were obtained from Haliclona sp. (Sharm Obhur, Jeddah, Saudi Arabia).⁶¹³

Phosphoiodyns A 581 and B 582 are iodinated and phosphate containing alkynes from Placospongia sp. (Tong-Young City, S. Korea). Phosphoiodyn B was inactive, but 581 was a potent inhibitor of human peroxisome proliferator-activated receptor delta (hPPARδ) with 200-fold selectivity over other PPARs, and therefore a potent regulator of lipid and glucose metabolism, and potentially a lead for treating type 2 diabetes or metabolic disorders.^614,615

Four mono- or di-iodinated polyacetylene acids were isolated from Suberites mammilaris (583 and 584) and S. japonicus (585 and 586) (Gageo Is., S. Korea). Anti-inflammatory bioactivity profiling of the methyl esters indicated that pre-treatment with the S. mammilaris metabolites inhibited nitrite production in LPS-stimulated RAW 267.4 macrophages while the S. japonicus metabolites inhibited NO production in BV2 microglial cells, with each pair being inactive in the other assay.⁶¹⁶

A mixed extract from Smenospongia aurea, S. cerebriformis and Verongula rigida (Key Largo, Florida) yielded a linear phenyl alkene 587 with activity against HL-60 cells. Molecular modelling docking studies suggested that 587 had a pharmacophore similar to that of eribulin and hence potential to interfere with microtubule dynamics.⁶¹⁷ Dysideolides A 588 and B 589 are methyl-branched lactones from Dysidea cinerea (Lang Co Beach, Vietnam),⁶¹⁸ while 12-manadoperoxide B 590, manadoperoxidic acid B 591 and monoester 592 were reported from Plakortis lita (Bunaken Is., Manado, Indonesia). Both 591 and the likely oxidative breakdown product 592 showed potent antitrypanocidal activity against T. b. rhodesiense.⁶¹⁹

Six new methylated peroxidic acids 593–598 were isolated from Plakortis simplex (Keomun Is., West Sea, S. Korea). All showed low moderate cytotoxic activity against RAW264.7 cells.⁶²⁰

A chemical ecological study of Discodermia dissoluta held in Santa Marta, Colombia has shown that <40 kg of sponge could be sufficient to sustainably produce 1 g of discodermolide⁶²¹ over six months for clinical trials.⁶²² A comprehensive study combining computation, chemical derivatisation and NMR studies was used to assign both the relative and absolute configurations of plakilactones G 599 and H 600 from a Fijian Plakinastrella mamillaris.⁶²³

Plakortoxides A 601 and B 602, simplextones C 603 and D 604 and plakorsin D 605 were all isolated from Plakortis simplex (Yongxing Is., S. China Sea) although only 603 showed activity.⁶²⁴

A two-sponge association between Plakortis communis and Agelas mauritiana (Mooloolaba, Queensland, Australia) yielded a new peroxy acid 606.⁶²⁵Plakinastrella mamillaris (Fiji Is.) produced plakortides R–U 607–610. Congener 610 was a potent antimalarial agent against chloroquine-resistant P. falciparum. The remaining compounds were less active and none of the compounds were cytotoxic against Vero cells at much higher concentrations.⁶²⁶

Gracilioether K 611 is a Pregnane X-Receptor (PXR) agonist with no activity against the Farnesoid X-Receptor isolated from Plakinastrella mamillaris (Fiji Is.). In silico docking studies suggested a similar binding motif to other gracilioether congeners.⁶²⁷ The sponge Hippospongia lachne (Xisha Is., S. China Sea) provided hippolachnin A 612, a compound with an unprecedented carbon skeleton, that was potently antifungal, but had no activity against three cancer cell lines. The absolute configuration of 612 was determined from comparison of calculated and experimental electronic circular dichroism (ECD) spectra.⁶²⁸

Manzamenones L–N 613–615 were isolated from Plakortis sp. (Manzamo, Okinawa). Manzamenones M and N showed some antimicrobial activity against E. coli, S. aureus and Cryptococcus neoformans (C. neoformans), while manzamenone L (isolated as a racemate) was inactive.⁶²⁹

Callylactam A 616 was isolated from Callyspongia sp. (Hainan Is., China),⁶³⁰ while allos-hemicalyculin 617 was reported from Discodermia calyx (Shikine-Jima Is., Japan). Photo-oxidative cleavage of the oxazole moiety of calyculin A was suggested as a route to the formation of 617.⁶³¹ The lipopeptide ciliatamide D 618 was found from a dredged Stelletta sp. (170 m, Oshimashinsone seamount, Japan).⁶³² This study also reaffirmed the absolute configuration of ciliatamide A (Aaptos ciliata) as that assigned during the original isolation,⁶³³ and subsequently incorrectly reassigned by synthesis.⁶³⁴

The sponge Lithoplocamia lithistoides (Madagascar) produced PM050489 619 and PM060184 620, polyketide amides that differ only in the presence of a chlorine atom. Both are active at sub-nanomolar levels against several cancer cell lines. The gram-scale total syntheses of each compound were also reported. PM060184 620 has undergone a remarkably rapid development from the source sponge collection in 2005 through isolation, characterisation and synthesis in 2006, to the commencement of phase I clinical trials in 2011.⁶³⁵

A detailed study of the terrestrial myxobacterial genera Sorangium and Jahnella has delineated the biosynthesis of the microsclerodermins, unusual peptides isolated from Microscleroderma and Theonella sponges,^636,637 hence suggesting the likely microbial origin of these NPs.⁶³⁸ Gombamide A 621, a disulfide linked hexapeptide, was isolated from Clathria gombawuiensis (Gageo-Do, S. Korea).⁶³⁹ Stylissatin A 622, a cyclic heptapeptide from Stylissa massa (Loloata Is., Papua New Guinea), inhibited NO production in LPS-stimulated macrophages,⁶⁴⁰ while euryjanicins E–G 623–625 are phenylalanine- and proline-rich heptapeptides from Prosuberites laughlini (Puerto Rico).⁶⁴¹

Although the structure of the NP is yet to be reported, the proline-rich octapeptide phakellistatin-19 626 has been synthesised. Interestingly, the bioactivity of the natural (GI₅₀ = 440–515 nM vs. three cell lines) and synthetic (not active) versions differ significantly, a puzzling discrepancy that has been noted previously.^642,643

The antifungal activity of the theonellamides (Theonella sp.)⁶⁴⁴ has been linked to their ability to bind to the 3β-OH of sterols in lipid bilayers. This was established using solid state ²H-NMR and surface plasmon resonance spectroscopies.⁶⁴⁵ Sulfinyltheonellapeptolide 627 and theonellapeptolide If 628 were isolated from Theonella swinhoei (N. Sulawesi, Indonesia), both with similar activities against HepG2 hepatic carcinoma cells.⁶⁴⁶

The total synthesis of yaku'amide A 629 (Ceratopsion sp.)⁶⁴⁷ established the configuration of the C-terminal methyl. Altering the configuration of the methyl had no significant effect on bioactivity.⁶⁴⁸ Asteropsin A 630 (Asteropus sp., Geoje Is., S. Korea) is a cysteine-knot peptide with an unusual N-terminal pyroglutamate residue that enhanced neuronal Ca²⁺ influx in murine cerebrocortical neuron cells and therefore may be useful for the treatment of topical pain or hypertension.⁶⁴⁹

The total syntheses of 18-epi-latrunculol A (Negombata magnifica)⁶⁵⁰ and haliclamide (Haliclona sp.)⁶⁵¹ have been achieved, with the latter study determining the absolute configuration 631 of the NP.^652,653 Two separate collections of Pachastrissa nux (Koh Tao, Surat Thani Province, and Chumphon Is. National Park, Thailand) yielded the antimalarial trioxazole macrolide kabiramide L 632.⁶⁵⁴

A comprehensive study using J-based conformational analysis, the universal NMR database and chemical derivatisations, established the absolute configurations of theonezolide A–C 633–635, originally isolated from a Theonella sponge.^655–657

Theonella swinhoei (Bunaken Marine Park, Manado, Indonesia) provided isoswinholide B 636 and swinholide K 637. Interestingly 636 was completely inactive while 637 showed significant potency against HepG2 cells consistent with other swinholide congeners.⁶⁵⁸

The absolute configuration of (−)-dysibetaine CPa 638 (Dysidea herbacea)⁶⁵⁹ was established by total synthesis, although the current study incorrectly mentions Lendenfeldia chondrodes as the original source.⁶⁶⁰

The synthesis of nakinadine C (Amphimedon sp.)⁶⁶¹ confirmed the absolute structure.⁶⁶² Synthesis also confirmed the structures of batzellasides A and C (Batzella sp.).^663,664 Manzamine A (Haliclona sp.)⁶⁶⁵ inhibited autophagy, and hence could prevent pancreatic cancer, by uncoupling vacuolar ATPases,⁶⁶⁶ as well as suppressing hyperlipidaemia and hence atherosclerosis in apoE-deficient mice.⁶⁶⁷ Zamamiphidin A 639 is a moderately antibacterial (S. aureus) manzamine-type alkaloid isolated along with ircinic acid 2 640 from Amphimedon sp. (Zamami, Okinawa).⁶⁶⁸

The synthesis of two unstable stereoisomers of 'upenamide (Echinochalina sp.)⁶⁶⁹ has shown that the putative structure was incorrect, although the constitution of the NP could not be established and given the paucity of remaining compound, structural revision will be difficult.⁶⁷⁰ The sponge Haliclona sp. (d'Urville Is., New Zealand) yielded dehydrohaliclocyclins C 641 and F 642 but lack of material prevented bioactivity profiling.⁶⁷¹Plakortis simplex (Keomun Is., West Sea, S. Korea) provided two regioisomeric alkylpyridinium carboxylates 643 and 644.⁶²⁰ The pyridinium diamine callyimine A 645 was obtained from Callyspongia sp. (Hainan Is., China).⁶³⁰

Synthesis confirmed the structures of amphimedosides A–C (Amphimedon sp.).^672,673 Pyrinodemins G–I 646–648 are bis-3-alkylpyridinium alkaloids from Amphimedon sp. (Okinawa), although the exact positioning of the alkyne functionalities is uncertain and hence the compounds are likely a mixture of related congeners.⁶⁷⁴

High-level DFT calculations helped confirm the unusually deshielded ¹³C chemical shifts found in trikentramides A–D 649–652, isolated using an NMR-guided approach from Trikentrion flabelliforme (East Point Bommies, Northern Territory, Australia).⁶⁷⁵ The synthesis of igzamide (Plocamissa igzo)⁶⁷⁶ was achieved.⁶⁷⁷ Three 5-hydroxyindole compounds 653–655 were reported from Scalarispongia sp. (Dokdo, S. Korea).⁶⁷⁸

Hyrtioreticulin F 656 was obtained from Hyrtios reticulatus (N. Sulawesi, Indonesia) and is the likely product of a Pictet–Spengler reaction between tryptophan, alanine and glycine.⁶⁷⁹ The bis-indole 6′'-debromohamacanthin A (Spongosorites sp.)⁶⁸⁰ inhibited angiogenesis by suppressing vascular endothelial growth factor VEGFR2-mediated PI3K/ALT/mTOR signalling in human umbilical vascular endothelial cells and mouse embryonic stem cells.⁶⁸¹

Hyrtioerectines D–F 657–659 are indolo-β-carboline alkaloids from a Red Sea Hyrtios species, with all three showing antimicrobial and radical scavenging activity.⁶⁸² Two brominated indolo-carbazoles 660 and 661 were isolated from a deep water Asteropus sp. (offshore from Bimini, Ocean Cay, Bahamas). While catechol 660 showed antimicrobial activity (C. albicans and MRSA), sulfonate 661 was completely inactive.⁶⁸³

Hyrtimomines A–C 662–664 are 5-hydroxyindole alkaloids from Hyrtios sp. (Kerama Is., Okinawa), although only 662 showed activity against tumour cells.⁶⁸⁴ Hyrtimomines D 665 and E 666 from the same collection are bisindole dimers with some activity against C. albicans, C. neoformans, S. aureus and Trichophyton mentagrophytes.⁶⁸⁵

The Australian sponge Plakortis lita (Tydeman Reef, Queensland) yielded thiaplakortones A–D 667–670 following HTS of a library of 202 983 fractions from 18 453 extracts. All were potent inhibitors of P. falciparum with 667 showing greater than 60-fold selectivity for Plasmodium over human embryonic kidney cells.⁶⁸⁶ The total syntheses of zyzzyanones A–D (Zyzzya fuliginosa)^687,688 have been achieved.⁶⁸⁹ Atkamine A 671 is a new pyrroloiminoquinone isolated from a deep water Latrunculia sp. (Aleutian Is., Alaska). Olefin metathesis was used to identify the location of the side-chain alkene of this surprisingly inactive metabolite.⁶⁹⁰

Of four new aaptamine-derivatives 672–675 (Aaptos suberitoides, Ambon, Indonesia) only 674 showed any activity against murine lymphoma.⁶⁹¹ The total synthesis of 2-deoxy-2-aminokealiiquinone (Leucetta chagosensis)⁶⁹² confirmed the structure of the NP.⁶⁹³

Pulchranins A–C 676–678, isolated from two dredged Monachora pulchra samples (Kuril Is. Chain, Russia), were moderately active inhibitors of the transient receptor potential cationic channel subfamily V (capsaicin receptor), and hence are pain and thermal reception modulators.^694,695 The same sponge that yielded pulchranins B and C also yielded monanchomycalin C 679, a modest inhibitor of MDA-MB-231 breast cancer cells.⁶⁹⁶

Spongiacidin C (Stylissa massa, Indonesia)⁶⁹⁷ is the first selective inhibitor of USP-7 over other ubiquitin-specific-processing proteases to be isolated from a natural source, and hence is a new lead as an oncological therapeutic.⁶⁹⁸ Nagelamides U–Z 680–685 are bromopyrrole alkaloids from Agelas sp. (Kerama Is., Okinawa) with a variety of biological activities, especially the inhibition of the growth of C. albicans. Congeners 683 and 684 were isolated as racemates.^699,700

Three new bromotyrosine compounds 686–688 were isolated from Aplysina sp. (Ladda Reef, S. China Sea),⁷⁰¹ while the structures of ma'edamines A and B (Suberea sp.)⁷⁰² have been confirmed by synthesis.⁷⁰³

Pseudoceratina verrucosa (Hook Reef Lagoon, Queensland, Australia) yielded pseudoceralidinone A 689 and aplysamine 7 690, with the absolute configurations established by Mosher's method and by total synthesis, respectively. The latter compound inhibited the growth of PC3 prostate adenocarcinoma cells while the former was inactive.⁷⁰⁴

Eight new bromotyrosine derivatives of the psammaplysin 691–693, ceratinamide 694 and subereamide 695–698 classes were isolated from Suberea sp. (Chuuk, Federated States of Micronesia). Only psammaplysin X 691 and the 19-hydroxy derivative 692 showed activity against six HTCLs.⁷⁰⁵

Sesquibastadin 699 (Ianthella basta, Ambon, Indonesia) is a trimer of hemibastadin that inhibited a variety of protein kinases from a panel of 24 enzymes, but had no effect on the proliferation of murine lymphoma cells (L5178Y).⁷⁰⁶

The Verongid sponges Ianthella basta and Aplysina cavernicola were examined for the presence of brominated skeletal components within their organic and siliceous matrices. The conclusions drawn from this work were that the bastadin and aerothionin compounds found are likely of microbial origin and that the known secondary metabolites are not associated with the sponge skeletons. However, a considerable quantity of brominated mass was found within the skeleton and it is possible that this represents tightly bound sponge-derived secondary metabolites with a defensive role.⁷⁰⁷ Reticulatins A 700 and B 701 are dimethylimidazolium cations isolated from Hyrtios reticulatus (N. Sulawesi, Indonesia). Surprisingly, they differ in absolute configuration of the side chain carbinol.⁶⁷⁹

Bis-uracil 702 was isolated from Agelas clathrodes (Yongxing Is., S. China Sea).⁷⁰⁸ A Fasciospongia sp. (Weizhou Is., Guangxi, China) gave the sesquiterpene alkaloid fasciospyrinadine 703,⁷⁰⁹ while Dysidea avara (Fethiye, Turkey) yielded the merosesquiterpenoid N-methylmelemeleone-A 704.⁷¹⁰

Samples of Dactylospongia elegans collected in both Malaysia and Palau contained the related 5,8-di-epi-ilimaquinone 705, 4,5-di-epi-dactylospongiaquinone 706, 8-epi-dactyloquinone 707, 10,17-O-cyano,4,5-di-epi-dactylospongiaquinone 708 and cyclospongiacatechol 709. All five compounds showed antiproliferative effects at high concentrations while 706 and 707 also activated Hypoxia Inducible Factor-1 (HIF-1), with the 1,4-benzoquinone moiety demonstrated as essential for activity.⁷¹¹

The asymmetric total synthesis of strongylin A (Strongylophora hartmani)⁷¹² confirmed the absolute configuration,⁷¹³ while synthesis of dysideavarone A (Dysidea avara)⁷¹⁴ confirmed the structure and also provided material to demonstrate the compound's potent antimicrobial activity, especially against Gram-positive bacteria, in particular various Staphylococci spp.⁷¹⁵ The bisabolane sesquiterpenoids 3-oxobolene 710 and 1-oxocurcuphenol 711 were isolated from Myrmekioderma sp. (Phi-Phi Is., Thailand) and were potent inhibitors of HT-29 cancer cells.⁷¹⁶

Ianthellalactams A 712 and B 713 (Ianthella flabelliformis, Port Philip Heads, Victoria, Australia) did not inhibit Glycine-gated chloride channel receptors (GlyR) like other related glycinal lactams.⁷¹⁷ Euryspongins A–C 714–716 (Euryspongia sp., Iriomote Is., Okinawa) have rare six- or eight-membered skeletons with either fused furan or γ-lactone rings. The presence of the C-4 hydroxyl group in all three compounds was thought to totally abrogate activity compared with other active analogues.⁷¹⁸

Phorbasin H, originally isolated from Phorbas gukulensis⁷¹⁹ but differing from another structure with the same name from Phorbas sp.,⁷²⁰ inhibits the hypha-specific HWP1 and ALS3 mRNAs of C. albicans, preventing the yeast-to-hyphae transition and therefore inhibits virulence of the pathogen.⁷²¹ Axistatins 1–3 717–719 are pyrimidine diterpenoids from Agelas axifera (Koror, Republic of Palau). All three were low μM inhibitors of various human and murine cancer cell lines, as well as being potent broad-spectrum antibiotics against several Gram-positive and negative bacteria.⁷²²

Phenotypic screening using zebra fish as a genome-wide eukaryote assay identified kalihinol F (Acanthella sp.)⁷²³ as a copper chelator, resulting in abnormal development as indicated by an undulating notochord, and both pigmentation and neural defects. This study exemplifies the use of zebra fish as a viable chemical genetic tool for assessing bioactives in a complex eukaryotic organism.⁷²⁴ The total syntheses of cyanthiwigins A, C (Epipolasis reiswigi)⁷²⁵ and H (Myrmekioderma styx)⁷²⁶ have been achieved, confirming the absolute structures.⁷²⁷Hamigera tarangaensis (Cape Karikari, North Is., New Zealand) provided hamigerans F–K 720–725, 10-epi-hamigeran K 726, 4-bromohamigeran K 727, hamigeran L 728 and the methyl ester 729, hamigeran A ethyl ester 730 and an unrelated congener of epi-verrucosane 731. All but the latter compound inhibited the growth of HL-60 cells while chemical genetic screening using yeast as a model organism showed that the mode of action of the antifungal hamigeran G 721 was via influence of Golgi function and Golgi vesicle formation.⁷²⁸

Two new isoneoamphilectane diterpenes 732 and 733 were isolated from Svenzea flava (previously described as Pseudoaxinella flava) (Great Inagua Is., Bahamas). The absolute configurations of these compounds were secured by comparison of experimental and calculated VCD data. Both compounds inhibited the growth of Mycobacterium, but had no effect on mammalian cell lines.⁷²⁹ Petronigrione 734 is a cembranoid dimer from Petrosia nigricans (Haivan, Danang, Vietnam) with moderate activity against HTCLs,⁷³⁰ while Phorbas gukhulensis (Gagu-Do Is., S. Korea) yielded the diterpene pseudo-dimers gukulenin C–F 735–738. All four were cytotoxic against K562 and A549 cancer cell lines but none showed any activity against various microbes.⁷³¹

The norsesterterpene cyclic peroxides 13,14-epoxymuqublin A 739 and the 9,10-epoxy isomer 740 were isolated from Diacarnus erythraeanus (Elfanadir, Hurghada coast, Egypt). Both were low micromolar inhibitors of various HTCLs.⁷³²

Collections of the Homoscleromorpha sponge Oscarella balibaloi at two sites near Marseilles (Mediterranean Sea) yielded the glucosidated sesterterpenes balibaloside 741, 6′′-O-acetylbalibaloside 742, 6′′′-O-acetylbalibaloside 743 and 6′′,6′′′-O-diacetylbalibaloside 744. These metabolites are the first glycosidated sesterterpenes reported and although tested in a wide variety of assays, proved to be inactive.⁷³³

Hyrtios communis (Northern Reef region, Palau) yielded thorectidaeolide A 745, the 4-acetoxy congener 746, and thorectidaeolides B–E 747–750. Compounds 745–747 inhibited HIF-1 yet did not show any antiproliferative effects against the parent T47D or NDA-MB-231 breast cancer cell lines.⁷³⁴

A Canadian Phorbas sp. (Ansell Point, Howe Sound, British Columbia), provided four distinct sesterterpenes ansellone B 751, phorbadione 752, secoepoxyansellone A 753 and alotaketal C 754. The latter compound showed similar levels of activation of cAMP signalling to the standard probe, forskolin.⁷³⁵

Five new sesterterpenes were reported from three different Psammocinia sp. (various locations in New South Wales and Victoria, Australia). Ircinianin lactam A 755, the sulfate derivative 756, oxoircinianin 757, oxoircinianin lactam A 758 and ircinianin lactone A 759 were all assessed for GlyR modulating activity with 755 and 758 being selective and potent potentiators of α3-GlyR and α1-GlyR, respectively, having potential as leads for treatment of inflammatory pain, epilepsy and both breathing or movement disorders.⁷³⁶

Phorbaketals D–K 760–767 and phorbin A 768 were reported from Monachora sp. (Gageo Is., Korea), with 764 and 765 weakly active against A498 cancer cells. The absolute configurations of all the new compounds were established by Mosher's method and comparison of CD-curves with known congeners.⁷³⁷

The scalarane sesterterpenoid hippospongide C 769 (Hippospongia sp., Tai-Tung, Taiwan) had moderate activity against four HTCLs,⁷³⁸ while 12-deacetoxy-23-hydroxyscalardial 770, 12-deacetoxy-23-hydroxyhyrtiolide 771 and 12-O-acetyl-16-deacetoxy-23-acetoxyscalarafuran 772 from Psammocinia sp. (S. Korea) were inactive in all assays used.⁷³⁹

Four new scalaranes 773–776 were reported from Carteriospongia sp. (Nosy Be, Madagascar) with 773 and 774 being significantly more active than the other two congeners, indicating the importance of the aldehyde pharmacophore.⁷⁴⁰

Cholic acid-3,7-diacetate 777 was isolated as an MNP for the first time from Siphonochalina fortis (Bahia Bustamante, Chubat, Argentina),⁷⁴¹ while the 5α,8α-epidioxy sterol 3-acetylaxinysterol 778 was isolated from Axinyssa sp. (Pingtung, Taiwan).⁷⁴²Haliclona crassiloba (Dongshan Is., Guangdong, China) yielded halicrasterols A–D 779–782 with moderate activity against various microbial pathogens.⁷⁴³

Cyclopropanated sterols aragusterol I 783, 21-O-octadecanoyl-xestokerol A 784 and 7β-hydroxypetrosterol 785 were isolated from Xestospongia testudinaria (Truong Sa Archipelago, Khanh Hoa, Vietnam). Both 783 and 784 had antifouling potential (growth inhibition of Pseudoalteromonas and Polaribacter bacterial species) at similar levels of activity to the now-banned antifoulant marine pollutant tributyltin oxide.⁷⁴⁴

The structure of the unusual autophagy-modulating aminosterol clionamine B (Cliona celata)⁷⁴⁵ was confirmed by synthesis, which also confirmed the assumed absolute configuration.⁷⁴⁶ A Corticium sp. (New Britain, Papua New Guinea) yielded the steroidal alkaloid plakinamine M 786, which displayed antitubercular activity.⁷⁴⁷ Stellettin N 787 is an isomalabaricane triterpene acid from Stelletta sp. (Lingshui Bay, Hainan, China), which along with the other isolated congeners presented a chemotaxonomic link between three genera within the sponge order Astrophorida.⁷⁴⁸

A dredged Penares sp. (Vietnam) provided six new lanosterol congeners 788–793. Only 793 showed any significant activity against HL-60 cells. A combination of CD and X-ray data allowed the assignment of absolute configuration for 789 and also permitted reassignment of the aglycone of eryloside U 794 from 7α,8α to 7β,8β.^749,750

Finally, ulososide F 795, urabosides A 796 and B 797 are triterpene saponins from Ectyoplasia ferox (Caribbean Sea, Colombia), with 797 being the first reported compound with both C-4 methyls elevated to the carboxylic acid oxidation state.⁷⁵¹

8 Cnidarians

The number of new compounds reported from cnidarians in 2013 (281) has increased by 38% over the average for each of the previous 10 years. In addition to an epidioxysterol (see later), three ceramides 798–800 were isolated from Sinularia candidula (Safaga, Egyptian Red Sea).⁷⁵² Of the three ceramides, 798 was the most potent anti-H5N1 virus agent.

Pyrimidinedione 801 was reported from Verrucella umbraculum (Hainan Is., S. China Sea),⁷⁵³ while Mediterranean specimens of the scleractinian coral Astroides calycularis afforded the new aplysinopsin analogue 802.⁷⁵⁴ The highly strained cyclo-1,3-carbazole structure originally proposed for antipathine A (Antipathes dichotoma)^755,756 has been corrected to the 2,3-carbazole 803 by total synthesis.⁷⁵⁷ Polyacetylenic montiporic acid D 804 (Montipora digitata, Sesoko Is., Okinawa, Japan) exhibited only mild antibacterial and antioxidant properties.⁷⁵⁸

New clovane-type sesquiterpenes rumphellclovane C–E 805–807 and four unnamed variants 808–811 were reported from the same collection of Rumphella antipathies (Southern Taiwan).^759,760 The latter four compounds are reported as NPs for the first time. Clovane 808 inhibited superoxide generation and elastase release by stimulated human neutrophils.

Sesquiterpenes capillosanane A–N 812–825 and seco-variants capillosanane O–R 826–829 were isolated from Sinularia capillosa (Sanya Bay, Hainan Province, China).⁷⁶¹ Absolute configurations were established by combinations of chemical conversions, Mosher's method, CD analysis and biogenetic reasoning. Capillosanane A exhibited antifouling activity against B. amphitrite.

Further examples of tricyclic sesquiterpenes were reported from Lemnalia philippinensis (philippinlins A 830 and B 831) collected at Lanyu, Taiwan⁷⁶² and Paralemnalia thyrsoides (parathyrsoidins A–D 832–835) collected at Sansiantai, Taitong County also in Taiwan.⁷⁶³

Spiro-butenolides sinularianins C 836 and D 837 and potential biosynthetically-related precursors sinularianins E 838 and F 839 were isolated as mild inhibitors of NF-κB activation from Sinularia sp. (Dongluo Is., Hainan Province, China).⁷⁶⁴

Perezoperezone 840 and curcuperezone 841 (Pseudopterogorgia rigida, Caribbean Sea) are envisaged to arise, in the case of 840, from non-symmetrical dimerisation of known co-metabolite perezone⁷⁶⁵ and in the case of 841, through coupling of perezone and α-curcumene.⁷⁶⁶ Flexibilisquinone 842 (cultured specimen of Sinularia flexibilis)⁷⁶⁷ was claimed to be the enantiomer of sarcophytonone (Sarcophyton crassocaule)⁷⁶⁸ based upon optical rotation data (842 [α]_D −19.6, sarcophytonone [α]_D +5.8).

Of two new C₁₉-norditerpenes 12-hydroxy-scabrolide A 843 and 13-epi-scabrolide C 844 (Sinularia maxima, Nha Trang Bay, Vietnam) the latter was identified as an inhibitor of the production of IL-6 and IL-12 by LPS-stimulated bone marrow-derived dendritic cells.⁷⁶⁹ In addition to five sterols (see later), δ-lactone 845 was isolated from Scleronephthya gracillimum (Green Is., Taiwan) as a modest inhibitor of expression of iNOS and COX-2 in stimulated macrophages.⁷⁷⁰ The weakly cytotoxic spatane diterpene leptoclalin A 846 was reported from cultured specimens of Sinularia leptoclados.⁷⁷¹

As with most years, a diverse array of cembranoid diterpenes were reported from soft corals in 2013. Arbolides A 847 and B 848, epoxy-alcohols with the former also containing a hydroperoxide functional group, were obtained from Sinularia arborea (southern Taiwan).⁷⁷² Similarly functionalised cembranes flexibilins A 849 and B 850 in addition to ε-lactone-containing flexibilin C 851 were reported from S. flexibilis also collected from southern Taiwan.⁷⁷³

The absolute configuration of co-metabolite (−)-sandensolide (Dendronephthya sp.)⁷⁷⁴ was confirmed by X-ray crystal analysis. Of the δ-lactones 11-acetylsinuflexolide 852 and dihydro analogue 853 (S. flexibilis, Pingtung county, Taiwan), only the former exhibited cytotoxicity as anticipated for an exomethylene-conjugated lactone.⁷⁷⁵Sinularia flexibilis (southern Taiwan) was also the source of flexibilin D 854 and of known congener 5-dehydrosinulariolide⁷⁷⁶ the absolute configuration of which was determined by X-ray crystal analysis.⁷⁷⁷ The same publication and a second one⁷⁷⁸ also described sinulanorcembranolide A 855 and the 1-epi-diastereomer 856 from the same collection of S. gaweli (Sansiantai, Taitung county, Taiwan).

While cembranoid cugibberosene A 857 (S. gibberosa, Pingtung, Taiwan)⁷⁷⁹ was found to be devoid of cytotoxic or antibacterial properties, one of sinulariols T–Z₅858–869 (S. rigida, Sanya Bay, Hainan Is., S. China Sea), specifically 864, exhibited effects against the model fouling organisms B. amphitrite and B. neritina.⁷⁸⁰

The casbane family of cembranoid diterpenes is characterised by the presence of a fused dimethyl-cyclopropyl ring. Of new examples sinularcasbanes A–F 870–875 (Sinularia sp., Ximao Is., Hainan, S. China Sea), 871 and 874 exhibited modest ability to inhibit NO production by stimulated macrophages.⁷⁸¹

Two separate collections of Lobophytum sp. yielded epoxycembranes 876–880 (Ximao Is., Sanya Bay, Hainan, China)⁷⁸² and α-methylene-γ-lactones 881–883 (Sanya Bay, Hainan, China).⁷⁸³ This is the first report 880 as an NP. Epoxycembrane 878 was a modest inhibitor of NO production by stimulated macrophages, while 881–883 were each found to be moderately cytotoxic towards a range of human and murine tumour cell lines.

Hydroxycembrane sarcophytol W 884 was isolated from Sarcophyton sp. (Xuwen coral reef area, Guangdong Province, China) – absolute configuration was assigned based upon that determined for a previously reported (Sinularia ovispiculata)⁷⁸⁴ co-metabolite.⁷⁸⁵Sarcophyton ehrenbergi (San-hsian-tai, Taitong county, Taiwan) was the source of diterpenes ehrenbergol C 885 and acetylehrenberoxide B 886 which both exhibited mild cytotoxicity (P388) but 886 was more potent as an anti-human cytomegalovirus agent.⁷⁸⁶

Of the sarcophyolides B–E 887–890 isolated from S. elegans (Xidao Is., Hainan, China), the structures and absolute configurations of 887 and 888 were established by X-ray crystal studies.⁷⁸⁷

Sarcophyolide B exhibited modest cytotoxicity. Red Sea collections of S. glaucum afforded 891–893 with 893 being reported as an NP for the first time.⁷⁸⁸ While 891 and 892 were equally cytotoxic towards a melanoma and a mouse kidney cell line, 892 exhibited selectivity towards the tumour cell line. Due to the presence of the conjugated triene functionality in sarglaucol 894 (S. glaucum, Sanya Bay, Hainan, China), it can be considered a diene-precursor to biscembranoids typically isolated from soft corals of the genus Sarcophyton.⁷⁸⁹

The same collection of S. elegans that afforded sarcophyolides B–E (see earlier) also yielded new examples of an isobiscembranoid and biscembranoids, the sarcophytolides G–L 895–900.⁷⁹⁰ These structures represent minor modifications to previously reported biscembranoids, being a dihydroxylated analogue of lobophytone F,⁷⁹¹ a positional isomer of lobophytone S,⁷⁹² a methoxylated analogue of lobophytone H,⁷⁹³ a dehydrated analogue of methyl tortuoate A,⁷⁹⁴ an oxidised analogue of lobophytone U⁷⁹⁵ and a 31-epimer also of lobophytone U, respectively.

Further investigation of S. latum (Sanya, Hainan Province), that had previously afforded, amongst other metabolites, biscembranoids bislatumlides A and B,⁷⁹⁶ has now yielded four more congeners bislatumlides C–F 901–904.⁷⁹⁷ Detailed examination of the absolute configuration of 901 and 903 by time dependent DFT (TDDFT) calculations of ECD data necessitated reassignment of the C-21 configuration of bislatumlides A 905 and B 906.

Re-isolation of methyl tortuoate D⁷⁹⁸ (Sarcophyton tortuosum, Yalong Bay, Hainan, China) has led to its structural revision to 907, with absolute configuration assigned by comparison of ECD data with that of co-metabolite ximaolide A.⁷⁹⁹ The study also concluded that the structure previously attributed to lobophytone K (Lobophytum pauciflorum)⁸⁰⁰ should also be corrected to 907.

A Red Sea (Hurghada) collection of S. trocheliophorum provided trochelioids A 908 and B 909 and 16-oxosarcophytonin E 910, the latter reported for the first time as an NP.⁸⁰¹

In three separate accounts, sixteen new cembranoids were reported from S. trocheliophorum (Yalong Bay, Hainan, China). Of methyl sarcotroates A 911 and B 912, and sarcophytonolides M–R 913–918, only hydroperoxide-containing 912 and sarcophytonolide N 914 were found to inhibit human PTP1B.^802,803

Also isolated were ε-lactone-containing cembranolides sartrolide A–G 919–925 and dimer bissartrolide 926.⁸⁰⁴ The unusual (1E,3Z)-diene configuration of 925 was supported by X-ray crystal analysis of isomeric co-metabolites sarcrassin D⁸⁰⁵ and emblide.⁸⁰⁶ Bissartrolide represents a dimer of sartrolide A and a free carboxylic acid analogue of sarcophytonolide B.⁸⁰⁷

A total of 34 new briarane diterpenes were reported from two collections of Dichotella gemmacea: gemmacolides AA–AR 927–944 (S. China Sea)⁸⁰⁸ and dichotellides F–U 945–960 (Meishan Is., Hainan, China).⁸⁰⁹ The absolute configurations of 927–944 were assigned by comparison of ECD data with those of dichotellide T 941, the absolute configuration of which was established by X-ray crystal analysis. Modest to moderate levels of cytotoxicity were observed for the gemmacolides while the dichotellides were all poorly cytotoxic with some examples exhibiting strong antifouling activity.

Junceella fragilis (Tai-Tong county, Taiwan) was the source of four more briaranes, frajunolide P–S 961–964.⁸¹⁰ Hirsutalins I–M 965–969 are eunicellin diterpenes isolated from Cladiella hirsuta (Sianglu Islet, Penghu Is., Taiwan).⁸¹¹ Moderate inhibition of NO production by stimulated macrophages for 967 was shown.

In addition to a number of related metabolites, C. krempfi (Weizhou Is., S. China Sea) yielded oxylitophynol 970, litophynol A acetate 971, litophynol C 972 and krempfenin 973.⁸¹² Reduction of 970 gave a product identical to known co-metabolite litophynol A,⁸¹³ subsequent acetylation of which afforded a product identical to 971.

Also isolated from C. krempfi (Penghu Is., Taiwan) were krempfielins E–M 974–982.^814,815 Although 974–977 were inactive in antitumour and anti-inflammatory assays, structurally related co-metabolites did exhibit activity.

Of four new eunicellins reported from Cladiella sp. (Penghu Is., Taiwan), cladieunicellins I 983, K 984, and L 985 and litophynin I diacetate 986, the latter has been previously reported⁸¹⁶ as a semi-synthetic derivative.^817,818 Cladieunicellins I and L exhibited moderate activity towards an HTCL.

An unusual member of the klymollins I–S 987–997 (Klyxum molle, Penghu Is., Taiwan) is the phenylacetate-bearing klymollin M 991.⁸¹⁹ This same metabolite was the most potent of the set, exhibiting cytotoxicity and the ability to inhibit superoxide generation and elastase release from stimulated human neutrophils.

In addition to two eunicellin diterpenes sibogin A 998 and B 999, investigation of the NPs from Muricella sibogae (Weizhou Is., China) also afforded three new seco-sterols sibogol A–C 1000–1002.⁸²⁰ A further two seco-sterols 1003 and 1004 were reported from Sinularia nanolobata (Xiao-Liuqiu Is., Pingtung county, Taiwan)⁸²¹ and eleven, subergorgol A–J 1005–1014 and 1015, from Subergorgia suberosa (Meishan coast, S. China Sea).⁸²² The latter unnamed seco-sterol is reported as an NP for the first time. Subergorgols C 1007 and D 1008, and F 1010 and G 1011 were isolated as their respective epimeric pairs but with unassigned configuration. The latter two were considered artefacts of isolation. While 1013 was found to be the most cytotoxic (moderate), 1015 was devoid of activity.

As well as a modestly bioactive δ-lactone noted earlier, an extract of Scleronephthya gracillimum (Green Is., Taiwan) also afforded pregnanes sclerosteroid J–N 1016–1020.⁷⁷⁰ Sclerosteroids K and M were more active than the other metabolites at inhibiting expression of iNOS and COX-2 in stimulated macrophages. Pregnane 1021 (Carijoa sp., Weizou Is., S. China Sea) exhibited potent antimicrobial properties.⁸²³

In addition to a number of known congeners, three new mildly cytotoxic polyhydroxylated steroids 1022–1024 were isolated from Sarcophyton sp. (Weizhou Is., S. China Sea).⁸²⁴ The possible artefactual origin of methylether 1022 was noted.

A collection of Anthogorgia caerulea from the same general location afforded caerulsteroid A 1025.⁸²⁵ Three studies of Red Sea (Hurghada) cnidarians afforded steroids – hurgadacin 1026 was isolated from Sinularia polydactyla,⁸²⁶ gorgostane 1027 (= 11-acetyl-sarcoaldosterol A⁸²⁷) from Heteroxenia ghardaqensis⁸²⁸ and zahramycins A 1028 and B 1029 from Sarcophyton trocheliophorum.⁸²⁹ Zahramycin B exhibited modest antibacterial activity.

Fourteen new sterols 1030–1043, plus one 1044 reported as an NP for the first time, were isolated as mildly cytotoxic constituents of Menella kanisa (coast of Beihai, Guangxi province, China).⁸³⁰

In addition to a number of co-metabolites, muriflasteroids A–C 1045–1047 were identified as weak to moderate cytotoxins (Muriceopsis flavida, Beihai, Guangxi province, China).⁸³¹ Sterols containing 24(28)-unsaturation were reported from Sinularia depressa (1048 and 1049, Lingshui Bay, Hainan, S. China Sea)⁸³² and Nephthea chabrolii (nebrosteroids Q–S, 1050–1052, San-Hsian-Tai coast, Taitong county, Taiwan).⁸³³ The latter three sterols exhibited mild cytotoxicity.

While sterols 1053–1059 (Sarcophyton sp., Weizhou Is., S. China Sea)⁸³⁴ exhibited variable levels of antimicrobial activity, dissesterol 1060 (Sinularia dissecta, Hai Van-Son Cha, Hue, Vietnam) was a strong inhibitor of IL-12 p40 cytokine production by stimulated bone marrow-derived dendritic cells.⁸³⁵ One new 18-acetoxy sterol 1061 was isolated from a South China Sea (Xuwen coral reef area) collection of Sarcophyton sp.⁸³⁶

Two 5α,8α-epidioxysterols were reported: mildly cytotoxic 1062 from Sinularia gaweli (Sansiantai, Taitung county, Taiwan)⁸³⁷ and antiviral (H5N1) 1063 from S. candidula (Safaga, Egyptian Red Sea).⁷⁵²

A range of ring-A cross-conjugated steroids, including lactone side-chained withanolides, were reported from cnidarians. All five cholestadienones 1064–1068 (Nepthea sp., Naozhou Is., S. China Sea)⁸³⁸ exhibited cytotoxicity towards a panel of HTCLs, while of three carboxylic acid-containing examples, paraminabic acid A–C 1069–1071 (Paraminabea acronocephala, Pingtung county, Taiwan), 1071 exhibited the most potent cytotoxicity.⁸³⁹

Sinubrasolides A–G 1072–1078 are withanolide-type steroids isolated from cultured specimens of Sinularia brassica (Taiwan) – the structure of 1075 is notable for containing an unusual spiroketal moiety.⁸⁴⁰ Mild cytotoxicity was observed for 1072, 1073 and 1076.

Acetylation of hemiacetal-containing nephthoacetal 1079 (Nephthea sp., Naozhou Is., S. China Sea) yielded two acetates.⁸⁴¹ The NP inhibited the settlement of B. neritina larvae, an activity not observed for the acetate derivatives, while all three compounds were mildly cytotoxic to HeLa cells.

Finally, new steroidal glycosides junceelloside E–G 1080–1082 were reported from Dichotella gemmacea (Beihai, China).⁸⁴² Detailed analysis of the nature of the arabinopyranose subunits (thiocarbamoyl-thiazolidine derivative) identified junceelloside E to contain the β-L anomer while junceellosides F and G contained the more standard β-D anomer. The arabinopyranose unit present in co-metabolite junceelloside C (Junceella juncea)⁸⁴³ was corrected from β-D to β-L (1083).

The structure of (−)-sinularianin B (Sinularia sp.)⁸⁴⁴ has been confirmed and absolute configuration established via synthesis which made use of sulfone-mediated tandem intramolecular-intermolecular alkylation.⁸⁴⁵ Comparison of NMR and chiroptical data for two diastereomers of (+)-sarcophytonolide C (Sarcophyton sp.)⁸⁰⁷ synthesised via a route including macrolactonisation and transannular RCM steps has confirmed the structure and established the absolute configuration of the NP.⁸⁴⁶ A general strategy for the synthesis of cladiellin diterpenoid NPs has been exemplified with the synthesis of ten examples.⁸⁴⁷ Efforts to mimic the putative carbon-centred radical reactions proposed for the biosynthesis of selected norcembranoids in Sinularia sp. were unsuccessful – a new model pathway was proposed, acting via a (3 + 2) transannular cyclisation reaction.⁸⁴⁸ In a related study, the 5,5,6- and 5,5,7-tricyclic ring systems found in the cnidarian metabolites plumarellide and rameswaralide were constructed from linear furanbutenolide precursors under acidic conditions, suggesting a potential biosynthetic mechanism involving two-step carbocation cyclisation sequences.⁸⁴⁹ Further investigation of the previously reported anti-inflammatory activity of the sesquiterpene lemnalol (Lemnalia sp.)⁸⁵⁰ has revealed that intramuscular injection leads to attenuation of inflammation in a monosodium urate model of human gouty arthritis, and that the NP also suppressed neutrophil infiltration and expression of related pro-inflammatory cytokines.⁸⁵¹ While the mechanisms of cytotoxicity of the cembranoid 5-episinuleptolide acetate⁸⁵² appear to include inhibition of levels of Hsp90 and induction of apoptosis,⁸⁵³ 11-episinulariolide acetate⁸⁵⁴ targets EGF-mediated cytoplasmic calcium levels and inhibits COX-2 and IL-8 expression.⁸⁵⁵ Of a range of exo-methylene lactone-containing cembranoids tested for immunomodulatory effects, lobocrassin B (Lobophytum crassum)⁸⁵⁶ was the most effective at blocking TNF-α production and attenuating LPS-stimulated dendritic cell maturation and endocytosis.⁸⁵⁷ A hydroxypropyl-β-cyclodextrin formulation of pseudopterosin A (Pseudopterogorgia elisabethae)⁸⁵⁸ was more effective at inducing HUVEC cell proliferation than a DMSO solution of the NP – the change in formulation allowed observation of the decoupling of proliferative and cytotoxic effects.⁸⁵⁹ The previously reported ability of hippuristanol (Isis hippuris)⁸⁶⁰ to inhibit RNA helicase and eukaryotic initiation factor 4A, has prompted further investigation of the biological properties of the spiroacetal-containing steroid, identifying it as an inhibitor of primary effusion lymphoma cells, inducing G₁ phase arrest, caspase activation and apoptosis.⁸⁶¹ Activity was also observed in an in vivo model. Further investigation of anti-inflammatory (15R)-prostaglandins from Plexaura homomalla⁸⁶² has identified the metabolites (15R)-PGE₂ and (15R)-OAc-PGA₂ as topically active inhibitors of oedema formation, leucocyte degranulation and elastase enzyme activity.⁸⁶³ As noted in the previous review in this series, simplexin Q (Klyxum simplex)⁸⁶⁴ is a duplicate of klysimplexin C⁸⁶⁵ and simplexin S⁸⁶⁴ is identical to cladieunicellin G (Cladiella sp.).^866,867

9 Bryozoans

Only one new metabolite was reported from bryozoans in the last year, continuing the trend of minimal NP research efforts on this phylum. A new alkaloid, 7-bromo-1-ethyl-β-carboline 1084 was isolated from Pterocella vesiculosa (Aldermen Islands, New Zealand).⁸⁶⁸

Wilsoniamines A and B, tribrominated alkaloids originally obtained from an Australian collection of Amathia wilsoni,⁸⁶⁹ have been synthesised in two steps featuring a condensation reaction between (2,4,6-tribromo-3-methoxyphenyl)acetaldehyde and (S)-N-methylpyrrolidine-2-carboxamide as a key step.⁸⁷⁰ Convolutamydine A, a dibrominated oxindole originally obtained from Amathia convoluta,⁸⁷¹ (along with two synthetic analogues) has/have been shown to possess antinociceptive effects comparable to those of morphine.⁸⁷²

10 Molluscs

The number of new metabolites reported from molluscs (15) is just over half the yearly average number reported over the past decade. The previously noted ability of molluscs to acylate dinoflagellate-produced toxin okadaic acid has been confirmed with acylating activity located in the digestive gland of various molluscs.⁸⁷³ A range of unusual Δ⁸ unsaturated 4-methyl and 4,4-dimethyl sterols was identified in extracts of the gonads of the Japanese limpet Cellana grata and C. toreuma.⁸⁷⁴ Matrix solid-phase dispersion combined with GC-MS was demonstrated as a useful technique to detect the presence of brominated diphenyl ethers and newer halogenated flame retardants in mussel, cockle and clam extracts.⁸⁷⁵ New onchidione analogues 1085–1088 and ilikonapyrone esters 1089–1094 were reported from different Onchidium sp. molluscs.⁸⁷⁶ Acylation of 1086 gave 1087 and 1088, while reduction of co-metabolite onchidione afforded two diastereomers, one of which was identical to onchidionol 1086. The configurational relationships between 1089–1094 were identified by methanolysis of each, affording a product identical to co-metabolite ilikonapyrone.⁸⁷⁷ Mild cytotoxicity was observed for some of the compounds.

Two formamide-containing pupukeanane sesquiterpenoid congeners 1095 and 1096, the latter previously known as a synthetic derivative, were reported from the tubercle nudibranch Phyllidia coelestis (Koh-Ha Islet, Krabi province, Thailand).⁸⁷⁸ Moderate to strong cytotoxicity towards tumour cell lines was observed.

The absolute configuration of the mildly cytotoxic cyclic dodecapeptide cycloforskamide 1097 (Pleurobranchus forskalii, Ishigaki Is., Okinawa) was established by combinations of ozonolysis and acid hydrolysis.⁸⁷⁹ In addition to this peptide, the ergot alkaloid ergosinine⁸⁸⁰ was also isolated, an unusual finding as ergot alkaloids are usually only isolated from terrestrial higher plants and fungi.⁸⁸¹

A potentially artefactual hydroperoxide, phototridachiapyrone J 1098 was isolated from the sacoglossan mollusc Elysia patagonica (San Jorge Gulf, Patagonia, Argentina).⁸⁸² The search for new leads for the treatment of leishmaniasis has identified the known 5α,8α-epidioxycholest-6-en-3β-ol (Dolabrifera dolabrifera) as mildly active against the amastigote form with nearly sixty-fold selectivity versus Vero cells.⁸⁸³ The structure of furan 1099 (Hypselodoris jacksoni, S. E. Queensland) was confirmed and absolute configuration established by a thorough study using combinations of synthesis, chiral HPLC and MPA derivatisation.⁸⁸⁴

A new enantioselective route to oxazinin alkaloids (Mytilus galloprovincialis)^885,886 has helped confirm the absolute configuration of amongst others, oxazinin-1 and -2.⁸⁸⁷ Synthesis of a library of analogues of cytotoxic depsipeptide kulokekahilide-2 (Philinopsis speciosa)^888,889 has revealed requirements of conformation, ring formation and ring size for biological potency.⁸⁹⁰ Aplysiatoxin (Stylocheilus longicauda)⁸⁹¹ is a potent PKC binding tumour promoter – synthesis and evaluation of simplified debromo analogues suggest that activation of PKCδ might play a role in the observed antiproliferative activity.⁸⁹² Following the synthesis of sanguinamide B (Hexabranchus sanguineus),⁸⁹³ the same group has reported that the use of biotinylated analogues of two cytotoxic D-Phe analogues in combination with pull-down assays have identified cellular targets that include eukaryotic ribosomal subunits.⁸⁹⁴ Close investigation of the mechanisms of cell death induced by the compounds indicates that the exact mechanism depends on the position of the D-Phe group. The results of a dose-escalating phase I study of kahalalide F (originally mollusc Elysia rufescens and green alga Bryopsis pennata)⁸⁹⁵ have been reported,⁸⁹⁶ while evaluation of a kahalalide F analogue, elisidepsin, against a panel of tumour cell lines suggests that cell lines that exhibit high E-cadherin, ErbB3 and Muc1 gene expression can be regarded as being sensitive to the clinical candidate.⁸⁹⁷ Drug resistance was associated with the presence of KRAS activating mutations. Using constrained NOESY NMR data, a conformational search has helped assign the configuration (3S) in the 9-methyl-3-decanol subunit of kahalalide Y (Elysia rufescens):⁸⁹⁸ unfortunately the study made use of the enantiomer of the NP and so the configuration should in fact be (3R).^899,900 Investigation of the mechanism of cytotoxic action of aplyronine A (Aplysia kurodai)⁹⁰¹ using photoaffinity biotinylated derivatives has identified aplyronine A to synergistically bind to tubulin in association with actin in a 1 : 1 : 1 ratio, leading to inhibition of tubulin polymerisation, and ultimately prevention of spindle formation and mitosis.⁹⁰² Similar experiments using aplyronine C⁹⁰² (lacks the trimethylserine sidechain of aplyronine A;⁹⁰³ three orders of magnitude less cytotoxic) showed it to bind to actin, as previously reported, but it did not bind to tubulin in this present study. Model compounds of the N-methylformamide sidechain of aplyronine A exhibit cytotoxicity towards tumour cell lines which is strongly correlated with their ability to induce the disruption of actin filaments.⁹⁰⁴

11 Tunicates (ascidians)

The 35 new tunicate-derived NPs presented in this review is average for the number reported per annum over the last decade. The sulfonated serinol lipids siladenoserinol A–L 1100–1111 (Didemnidae, North Sulawesi, Indonesia) inhibited the interaction of tumour suppressor p53 with Hdm2, potentially leading to reactivation of p53 and induction of apoptosis in cancer cells.⁹⁰⁵ The absolute configuration of 1100 was established by a combination of degradation, modified Mosher's analysis and comparison with similar fragments of defined configuration.

Two new examples of the rare 1,2,4-thiadiazole ring system, polycarpathiamine A 1112 and B 1113, were isolated from Polycarpa aurata (Ambon, Indonesia). While 1112 exhibited sub-micromolar cytotoxicity (L5178Y), 1113 was inactive.⁹⁰⁶ The regiochemistry of the 1,2,4-thiadiazole ring was established by analysis of ¹H–¹⁵N HMBC data and by synthesis of a model compound.

A diverse range of pteridine (duramidines A–D 1114–1117), thymidine (leptoclinidines A 1118 and B 1119), choline (durabetaines A 1120 and B 1121) and imidazole (leptoclinidamines D–F 1122–1124) analogues was isolated from Leptoclinides durus (Swains Reef, Great Barrier Reef).⁹⁰⁷

Four methylsulfinyladenosine derivatives, momusine A–D 1125–1128, isolated as pairs of interconverting isomers, were reported from extracts of Herdmania momus (Jeju Is., S. Korea).⁹⁰⁸

The structures of the modestly cytotoxic dioxothiazinomeroterpenes conthiaquinone A 1129 and B 1130 (Aplidium conicum, Porto Cesareo, Lecce, Italy) were established by interpretation of NMR data in combination with DP4 calculated chemical shifts.⁹⁰⁹ The absolute configuration of 1129 was proposed from TDDFT calculated ECD data.

Four new examples of pyridoacridine alkaloids, shermilamine F 1131, dehydrokuanoniamine F 1132 arnoamine C 1133 and D 1134 (Cystodytes violatinctus, Solomon Is.) exhibited modest cytotoxicity towards a panel of HTCLs.⁹¹⁰ A variant biosynthetic pathway to address the formation of arnoamines C and D was proposed. New analogues of the structurally related styelsamines⁹¹¹ were prepared and assessed for DNA binding ability and cytotoxicity.⁹¹²

A sperm activation and attractant 1135 was isolated from egg seawater of Ascidia sydneiensis; structure elucidation by NMR and MS was performed on 2.6 μg (4 nmol) of material.⁹¹³ The proposed planar and stereo structure of 1135 was supported by the synthesis of model compounds. The structure of this sperm attractant is very similar to that previously reported from Ciona intestinalis and C. savignyi.⁹¹⁴

Synthesis and cytotoxic evaluation of aminol lipids clavaminol G⁹¹⁵ (Clavelina phlegrea)⁹¹⁶ and crucigasterins A, B and D^917,918 (Pseudodistoma crucigaster)⁹¹⁹ have been reported; mild activity was observed. First syntheses of kottamide E⁹²⁰ (Pycnoclavella kottae),⁹²¹ lukianol B⁹²² (unidentified tunicate)⁹²³ and eudistomin Y₇^924–926 (Eudistoma sp.)⁹²⁷ have been published. Syntheses of an isomer of didemnaketal A⁹²⁸ and the proposed structure of didemnaketal B⁹²⁹ (Didemnum sp.)⁹³⁰ provide further evidence that the NPs require revision of configurational assignments. Synthesis and structure–activity relationship studies on orthidine F⁹³¹ (antimalarial),⁹³² ascidiathiazone⁹³³ (antimalarial),⁹³⁴ meridianin G⁹³⁵ (antimalarial),⁹³⁶ perspicamide A⁹³⁷ (antileishmanial),⁹³⁸ rigidin⁹³⁹ (antitumour),⁹⁴⁰ and ningalin B⁹⁴¹ (P-glycoprotein modulator)⁹⁴² have been reported. Further investigation of recently reported ascidian metabolites of the cadiolide and synoilide families of furanones (Synoicum sp.)⁹⁴³ has identified cadiolides E, H and I as being potent inhibitors of C. albicans isocitrate lyase, an enzyme associated with microorganism virulence.⁹⁴⁴ Semi-synthetic N-acyl derivatives of ecteinascidin 770 (Ecteinascidia thurstoni)⁹⁴⁵ has identified quinoline- and fluorocinnamoyl-containing examples that exhibit 50–70 fold increased cytotoxicity towards the HCT-116 cell line versus the parent NP.⁹⁴⁶ Minor corrections to manuscripts describing the mandelalides (Lissoclinum sp.)⁹⁴⁷ and herdmanine K (Herdmania momus)⁹⁴⁸ have been noted.

12 Echinoderms

The 33 new metabolites reported from echinoderms in this review is lower than the average number reported per annum over the last decade. A commercially available specimen of the starfish Asterias rollestoni (Xiamen food market, China) afforded the tetraosides 1136 and 1137 (ref. 949) while Astropecten polyacanthus (Cat Ba, Haiphong, Vietnam) contained the inactive or mildly cytotoxic sterols astropectenol A–D 1138–1141.⁹⁵⁰ The latter set of compounds was also reported to inhibit the expression of pro-inflammatory cytokines in bone marrow-derived dendritic cells.⁹⁵¹

Aphelasteroside E 1142, which contains the rare sulfation at C-26, was isolated from Aphelasterias japonica (Poset Bay, Sea of Japan)⁹⁵² and the C-24-arabinosides pectinioside H–J 1143–1145 were identified in extracts of Asterina pectinifera (Dalian coast, Yellow Sea, China).⁹⁵³

Tetraosides typicoside A₁1146 (the 24E isomer of previously reported intercedenside A (Mensamaria intercedens)⁹⁵⁴), A₂, B₁, C₁ and C₂1147–1150 are minor metabolites isolated from the sea cucumber Actinocucumis typica (Vizhinjam coast, Arabian Sea, India).⁹⁵⁵ Antifungal, haemolytic and cytotoxic evaluations of the five NPs identified widespread activity, with typicoside C₁ being markedly less active in all assays. The presence of disulfated tetraoside turquetoside A 1151, which contains the rare 3-O-methyl-D-quinovose sugar unit, in both Staurocucumis turqueti and S. liouvillei suggests the sugar is a taxonomic character of this particular genus of Antarctic sea cucumber.⁹⁵⁶

Of the disulfated pentaosides cucumarioside I₁, I₃ and I₄1152–1154 (Eupentacta fraudatrix, Peter the Great Gulf, Sea of Japan), only 1152 exhibited biological activity including cytotoxicity (weak) and haemolytic activity (strong).⁹⁵⁷ Pentaosides cladoloside B₁1155 and B₂1156 and hexaosides cladoloside C, C₁, C₂ and D 1157–1160 (Cladolabes schmeltzii, Nha Trang Gulf, S. China Sea) all exhibited similar levels of strong cytotoxicity and haemolytic activity.⁹⁵⁸

Extracts of the starfish Astropecten monacanthus (Cat Ba, Haiphong, Vietnam) afforded the hexaosides astrosterioside A–C 1161–1163 and pentaoside astrosterioside D 1164.⁹⁵⁹ While 1161 and 1163 exhibited mild inhibition of IL-6 production by stimulated bone marrow-derived dendritic cells, diketo-containing 1164 exhibited potent inhibition of production of IL-6, IL-12 p40 and TNF-α.

The pyrrole and furan oligoglycosides astebatherioside A–D 1165–1168 were reported from the starfish Asterina batheri (Catba, Haiphong, Vietnam).⁹⁶⁰ While 1165 was either inactive or weakly active, 1166–1168 demonstrated inhibition of IL-12 p40 production, and to a lesser extent of IL-6 production, in LPS-stimulated bone marrow-derived dendritic cells.

The synthesis of goniopectenoside B (starfish Goniopecten demonstrans)⁹⁶¹ has been reported.⁹⁶² Purified polar steroids previously reported from the starfish Patiria pectinifera and Distolasterias nipon are potent enhancers of neurite outgrowth and acted as neuroprotectors against damage caused by oxygen-glucose deprivation.⁹⁶³ Crude preparations of cerebrosides from the sea cucumber Acaudina molpadioides and the starfish Asterias amurensis were found to protect PC12 cells from oxidative damage due to exposure to H₂O₂ or tert-butyl hydroperoxide.⁹⁶⁴ In both cases the neuroprotection appeared to be conferred by upregulation of superoxide dismutase activity and modulation of components of the mitochondrial apoptotic pathway. High-energy CID tandem mass analysis has been used to determine the structures of ceramides and cerebrosides isolated from Distolasterias nipon.⁹⁶⁵ Stable isotope biosynthesis feeding experiments have determined that dietary cholesterol and cholesterol 3-sulfate are elaborated into polyhydroxylated sterols in the starfish Patiria (= Asterina) pectinifera.⁹⁶⁶

13 Mangroves

Aerial parts of the mangrove plant Kandelia obovata (Ximen Is., Zhejiang Province, China) afforded two new furofuran lignans kandelisesquilignan A 1169 and B 1170.⁹⁶⁷ Similar levels of antioxidant activity (DPPH assay) were observed for 1169 and 1170versus ascorbic acid.

Ethanolic extracts of the bark of Ceriops decandra (Godavari estuary, Andhra Pradesh, India) afforded diterpenes decandrin A–K 1171–1181, the structures of which encompass abietane and podocarpane skeletons,⁹⁶⁸ while the wood of Excoecaria agallocha (Corangi forest, Godavari estuary) afforded ent-isopimarane diterpenoids agallochaexcoerin D–F 1182–1184.⁹⁶⁹

Two triterpenes tiliacol A 1185 and B 1186 were isolated from the semi-mangrove plant Hibiscus tiliaceus (Hainan Is., China).⁹⁷⁰

A diverse range of liminoids were reported from extracts of Xylocarpus granatum: granatumins H–K 1187–1190 (seeds, Krishna estuary, Andhra Pradesh),⁹⁷¹ xylomexicanins C 1191 and D 1192 (seeds, Hainan Province, China),⁹⁷² and xylogranins A 1193 and B 1194 (leaves, Sundarbans Mangrove Forest, Bangladesh).⁹⁷³ Xylomexicanin C 1191 exhibited modest cytotoxicity towards a breast tumour cell line, while xylogranin B 1194 and co-metabolite swietephragmin were potent inhibitors of the Wnt signalling pathway and exhibited sub-micromolar cytotoxicity towards two human colorectal tumour cell lines.

Extracts of the seeds of X. moluccensis (Trang province, Thailand) afforded thaixylomolins A–F 1195–1200.^974,975 The structure of 1195 was secured by X-ray diffraction analysis and TDDFT calculations were used to establish the absolute configurations of 1196 and 1197, while 1198 was assigned by comparison of ECD data. The 4-hydro-dithiosulfonate, bruguiesulfurol (Bruguiera gymnorhiza)⁹⁷⁶ was detected as a modest inhibitor of PTP1B, prompting its synthesis and preparation of a library of analogues, some of which exhibited more potent activity.⁹⁷⁷

14 Miscellaneous

Investigation of water conditioned with sea lamprey (Petromyzon marinus) larvae afforded the hexahydrophenanthrene sulfate petromyzonin 1201.⁹⁷⁸ Absolute configuration was assigned by ECD analysis. Petromyzonin elicited potent (10⁻¹¹ M) response in electro-olfactogram recordings using olfactory epithelia of adult male sea lamprey, indicating a likely ecological role as an odorant.

The detection of 5,11-dideoxytetrodotoxin,⁹⁷⁹ isolated as an NP for the first time, in the pufferfish Takifugu poecilonotus and the flatworm Planocerid sp. 1 (Guam) prompted speculation on the putative biosynthetic pathways for the biosynthesis and metabolism of tetrodotoxins.⁹⁸⁰ A new method involving sonication, SPE and LC-MS/MS has been reported to allow simultaneous quantification of Pacific ciguatoxins-1, -2 and -3 in the whole blood of fish.⁹⁸¹

15 Conclusion

Fifty years ago in 1963 just four papers were published on MNPs with only one paper containing new compounds. At that time MNPs was becoming established as a field of interest. In this Conclusion the phylum-preferences of the MNP community across the subsequent 50 years period are examined. These preferences are presented (Fig. 1) as the annual number of publications reporting the isolation of new compounds for each phylum that has been sampled over this period. The most aggressively selected phylum has been the Porifera, but the popularity of this target has diminished somewhat since the mid 1990s coinciding with the very rapid rise in popularity of the Ascomycota, Actinobacteria and the Cyanobacteria. The Cnidaria have steadily increased in popularity across the years and while the phyla Rhodophyta, Ochrophyta, Echinodermata and Mollusca were as popular as the Porifera in the early years, interest waned in later years. The popularity of these phyla in earlier years may have been a reflection of the relative ease of collection by snorkeling and shore-wading as in the 1960s and 1970s SCUBA diving was more of a specialist technique. The numeric totals for the 50 years of collection are given in Table 1 along with the percentage contribution of each phylum to the marine literature. For the 50 years period from 1963 9220 papers have reported the isolation of 24 662 new compounds. These 9220 papers constitute 37% of the total papers in MarinLit.⁷⁷ The other 17 284 papers are associated with topics such as reviews, syntheses, stereochemistry, corrections of structure or stereochemistry, bioactivities, and ecological surveys. Other data shown in Table 1 include the numbers of compounds reported/phylum over the 50 years period as well as the % contributions each phylum has made to the number of papers reporting new compounds or the number of compounds. These relative proportions are comparable as the number of isolated compounds reported/paper is 2–3 across most of the phyla. Also included are the recognised totals of species/phylum from the World Register of Marine Species (WORMS),⁹⁸² allowing comparison of the numbers of samples of each phylum collected with the actual number of recognised species. This comparison should be used carefully as multiple collections of the same species have been made, or the sample may have only been identified to the genus level. However the comparison does offer insights into the coverage of each phylum. This point is emphasised by considering the various contributions the most studied genus for each phylum has made. For example, for the Rhodophyta the most studied genus has been Laurencia. Even though Laurencia is only one of 84 genera studied, this one genus contributed 369 out of the total 672 papers from the Rhodophyta describing new MNPs and was the source of 824 of the 1668 new compounds from this phylum. The important consideration is that even though multiple collections of the same genus/species may have been made, the same genus or species at different locations is giving rise to a different suite of metabolites. Apart from Porifera and Cyanobacteria, the coverage of most phyla is very limited, although the credibility of the numbers of species recognised by WORMS⁹⁸² for the Ascomycota and Actinobacteria is probably suspect as much of the micro-world has yet to be fully recognised. Over the past 50 years MNP chemists have studied samples collected from 1300 genera across 28 phyla. These 28 phyla represent an estimated (WORMS) 210 892 marine species out of an estimated total of 224 070 for all marine phyla.⁹⁸² In other words MNP chemists have collected widely, but perhaps thinly across the Kingdoms. The Kingdom Virus (119 representatives) has not been sampled at all by MNP chemists and so has been excluded from consideration. As chemists we have published 9220 papers over the past 50 years describing new compounds from these 28 phyla. But, in fact, the 9220 papers describe compounds elicited from just 2657 named species with another 2485 occurrences across 484 genera that are only described as sp. So, the number of distinct species studied is a long way short of 9220. This nicely emphasises the point that there is still an enormous MNP resource waiting to be explored; probably in excess of 200 000 species still to be evaluated.

Fig. 1 The phylum-preferences of the marine natural product research community across a 50-year period from 1963.

Table 1 The numeric totals and percentage contribution of each phylum to the marine literature over a 50 years period from 1963. Also included are the numbers of compounds reported/phylum, the % contributions each phylum has made and the recognised totals of species/phylum from the World Register of Marine Species^a

	Kingdom	Number of genera	Most studied genus	Number of papers and compounds from the most studied genus	Papers/phylum	% MLit papers with new compounds	Compounds/phylum	% of MLit	Compounds	Compounds/paper	Number of recognised species
a In the 28 phyla sampled by MNP chemists WORMS lists 210 892 species. Across all Kingdoms WORMS lists 226 070 marine species.
Animalia	Annelida	13	Odontosyllis	5	12	24	0.3%	46	0.2%	1.9	2640
	Arthropoda	8	Megabalanus	2	2	9	0.1%	10	0.0%	1.1	6216
	Bryozoa	24	Bugula	19	33	86	0.9%	199	0.8%	2.3	6036
	Chordata	66	Didemnum	54	144	434	4.7%	1102	4.5%	2.5	1898
	Cnidaria	161	Sinularia	234	678	1589	17.2%	4949	20.1%	3.1	10 839
	Echinodermata	136	Asterias	35	69	493	5.3%	1335	5.4%	2.7	295
	Hemichordata	3	Cephalodiscus	9	19	11	0.1%	27	0.1%	2.5	30
	Mollusca	116	Aplysia	87	184	468	5.1%	1095	4.4%	2.3	44 233
	Nematoda	2	Amphiporus	1	1	2	0.0%	2	0.0%	1.0	6997
	Platyhelminthes	3	Amphiscolops	2	2	3	0.0%	6	0.0%	2.0	11 836
	Porifera	285	Dysidea	163	418	2991	32.4%	8152	33.1%	2.7	8320
Archaea	Euryarchaeota	1	Thermococcus	2	24	2	0.0%	24	0.1%	12.0	98
Bacteria	Actinobacteria	28	Streptomyces	201	465	322	3.5%	778	3.2%	2.4	72
	Bacteroidetes	9	Rapidithrix	3	4	12	0.1%	24	0.1%	2.0	235
	Cyanobacteria	28	Lyngbya	140	283	234	2.5%	484	2.0%	2.1	436
	Firmicutes	5	Bacillus	43	94	47	0.5%	101	0.4%	2.1	96
	Proteobacteria	38	Pseudomonas	16	33	110	1.2%	225	0.9%	2.0	772
Chromista	Bacillariophyta	7	Rhizosolenia	2	7	10	0.1%	24	0.1%	2.4	2675
	Ciliophora	4	Euplotes	8	24	12	0.1%	37	0.2%	3.1	2676
	Cryptophyta	1	Chrysophaeum	2	9	2	0.0%	9	0.0%	4.5	91
	Dinophyta	26	Prorocentrum	20	27	194	2.1%	297	1.2%	1.5	2194
	Haptophyta	6	Coccolithus	2	3	8	0.1%	11	0.0%	1.4	260
	Ochrophyta	57	Dictyota	94	249	460	5.0%	1247	5.1%	2.7	5009
Fungi	Ascomycota	129	Aspergillus	187	545	783	8.5%	2165	8.8%	2.8	966
Plantae	Chlorophyta	29	Caulerpa	30	90	116	1.3%	272	1.1%	2.3	1810
	Rhodophyta	84	Laurencia	369	824	672	7.3%	1668	6.8%	2.5	6399
	Tracheophyta	23	Xylocarpus	27	119	75	0.8%	253	1.0%	3.4	432
Protozoa	Euglenozoa	1	Euglena	1	3	1	0.0%	3	0.0%	3.0	231
	Totals/Averages	1300		1758	4361	9220	100%	24 662	100%	2.7

---

16 Acknowledgements

We thank Dr Anthea Lees for assistance with the collection of data for this review.

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