Marine natural products

John W. Blunt,*a Brent R. Copp,b Robert A. Keyzers,c Murray H. G. Munroa and

Michèle R. Prinsepd

a Department of Chemistry, University of Canterbury, Christchurch, New Zealand. E-mail:

john.blunt@canterbury.ac.nz

b School of Chemical Sciences, University of Auckland, Auckland, New Zealand

c Centre for Biodiscovery, and School of Chemical and Physical Sciences, Victoria

University of Wellington, Wellington, New Zealand

d Department of Chemistry, University of Waikato, Hamilton, New Zealand

Received (in Cambridge, UK)

First published as an Advance Article on the web

Covering: 2011. Previous review: Nat. Prod. Rep., 2012, 29, 144–222.

This review covers the literature published in 2011 for marine natural products, with 870

citations (558 for the period January to December 2011) 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 (1152 for 2011), together with the

relevant biological activities, source organisms and country of origin. Biosynthetic studies,

first syntheses, and syntheses that lead to the revision of structures or stereochemistries, have

been included.

1 Introduction

2 Reviews

3 Marine microorganisms and phytoplankton

4 Green algae

5 Brown algae

6 Red algae

7 Sponges

8 Cnidarians

9 Bryozoans

10 Molluscs

11 Tunicates (ascidians)

12 Echinoderms

13 Mangroves and the intertidal zone

14 Miscellaneous

15 Conclusion

16 References

1 Introduction

This review is of the literature for 2011 and describes 1152 new compounds from 352

articles, a 15% increase in the number of compounds reported for 2010, but from the same

number of articles.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.

It is with deep regret that we record the untimely passing in 2012 of Professor Ernesto

Fattorusso. His death was a great loss for all marine natural products communities around the

world. The impact that his personality and his work had on us is perhaps best summed up in

the words inviting his colleagues to a Commemorative Event that was held in Naples, 9

November, 2012:2

His critical intelligence

Generosity of spirit and

The warm twinkle in his eyes

Will bring us together

To cherish his enthusiasm for science

And pass it on …

2 Reviews

A selection of the many reviews on various aspects of marine natural product studies is listed

here. A comprehensive review of marine natural products reported in 2009 has appeared,3 as

well as the highlights of compounds reported in 2010.4 The distribution and temporal trends

within the biological source and chemical structure classes of compounds reported between

1985 and 2008 have been analysed.5 The numbers reported in this survey appear to be

significantly less than those reported in previous reviews in this series of annual reviews, and

in the database MarinLit that continues to be used as the literature source for the preparation

of these reviews.6 A number of reviews describing pharmacological development and

potential for biomedical application of marine natural products have appeared.7–13 Many

classes of marine-sourced compounds have been reviewed to varying extents, including

briarane-type diterpenoids,14 cyclic polypeptides containing β-amino acid fragments,15

pyrroloiminoquinone alkaloids,16 antitumour peptides,17 cyclic imines including spirolides

and gymnodimines,18 kahalalides,19 guanidine-containing alkaloids,20 ascidian-derived

alkaloids,21 2-aminoimidazole alkaloids,22,23 other assorted alkaloids,24 carotenoids,25,26 algal

bromophenols,27 volatile algal halogenated compounds,28 brominated compounds from

Aplysina sponges,29 furanocembranoids30 and norcembranoids (from Sinularia sp.),31 α-

conotoxins,32 cladiellins, asbestinins and briarellins,33 and eleutherobins, fuscosides and

pseudopterosins.34 There were several reviews of general classes of compounds that included

reference to marine compounds – sesquiterpenoids,35 triterpenoids,36 disesquiterpenoids37 and

alkaloids containing five-membered heterocycles.38 Reviews of natural products from various

sources include those from Lithistida sponges,39 gorgonian Junceella spp.,40 sea cucumbers,41

bacterial symbionts,42 starfish,43 mangrove-associated microbes,44 Arctic region sponges,45

cnidarians,46 cyanobacteria47 and fungi from marine habitats.48 An on-line database of a

selection of compounds from macroalgae, predominantly from red algae, has appeared.49,50

Particular types of bioactivity have been reviewed in papers on kinase inhibitors from

sponges,51 anti-inflammatory compounds from macroalgae,52 anticancer compounds and their

derivatives reported in 2010,53 compounds as therapeutics for Herpes simplex virus,54

conopeptides for pain management,55 pectenotoxin-2 as a potential anticancer agent56 and

various other anticancer candidates.57,58 Several aspects of biosynthesis have been reviewed,

including studies on cyanobacteria,59 steroids in mollucs,60 and the emerging role of genomics

in these studies.61,62 Three papers have reviewed topics in chemical ecology of marine

compounds.63,64,65 The sixth in a companion series providing an overview of synthetic aspects

of marine natural products, covering publications in 2009, has appeared,66 while more specific

reviews published in 2010 relating to the synthesis of marine natural products will be

referenced in the eighth of that broad review series. Of particular note is a paper that surveys

the synergy of spectroscopy and chemical synthesis in marine natural product structure

revisions,67 as referenced in the Conclusion to the last review in this series.1

3 Marine microorganisms and phytoplankton

Marine microorganisms are increasingly a major focus of natural products research efforts

and are a rich source of novel and bioactive compounds. Unless otherwise stated, compounds

described in this section were obtained from cultures of the named microorganisms.

Marine-sourced Bacteria (excluding from mangroves)

The actinomycete Actinoalloteichus cyanogriseus (sediment, Weihai, China) produced the

bipyridine alkaloids caerulomycin F–J 1–5 and the phenylpyridine alkaloid caerulomycin K 6.

The terrestrial bacterial metabolites caerulomycins A68 and C,69 were also isolated (first time

from marine source), along with two synthetic derivatives, caerulomycinamide70 and

caerulomycinonitrile70 (first isolation as natural products). Caerulomycins F–J 1–5 and

caerulomycins A68 and C69 were cytotoxic to four human tumour cell lines (HTCLs).71

Cyanogrisides A–D 7–10 are glycosidic bipyridines also from A. cyanogriseus (sediment,

Weihai, China). Cyanogrisides A–C 7–9 were moderately cytotoxic to three HTCLs and

cyanogriside B 8 displayed multidrug resistance (MDR) reversing activity in MDR cell lines.

Cyanogriside D 10 was proposed as a possible artefact of isolation via photoreaction of

cyanogriside A 7.72 Bendigoles D–F (E 11) are 3-keto sterols obtained from Actinomadura sp.

(sponge Suberites japonicus, source unspecified), of which bendigole D was cytotoxic to the

L929 (mouse fibroblast) cell line, and all were active against NF-κB and glucocorticoid

receptors.73 Bendigoles D and F had previously been reported as products of bile acid

syntheses74 and as theoretical products of aerobic bile acid degradation.75,73 Two epimeric

quinazolinone alkaloids, (R)-2-(heptan-3-yl)quinazolin-4(3H)-one 12 and a mixture of

(2R,3'R) and (2S,3'R)-2-(heptan-3-yl)-2,3-dihydroquinazolin-4(1H)-one, 13 and 14 were

isolated from Bacillus cereus (sea mud, Baimajin, Hainan, China). Both were synthesised and

moderate activity against Candida albicans (C. albicans) was noted.76 Bacillus sp. (sediment,

Ieodo, South Korea) yielded the 24-membered antibacterial macrolactones macrolactin I–III

15–17.77 From the Bacillus sp. (sea urchin Anthocidaris crassispina, Nagasaki Shitsu coast,

Japan) the diketopiperazine derivatives bacillusamide A 18 and B 19 were characterised.

Bacillusamide A 18 was a modest inhibitor of Aspergillus niger (A. niger).78 The fatty acids

ieodomycin A–D 20–23 from Bacillus sp. (sediment, Ieodo, South Korea) had broad spectrum

antimicrobial activity.79 The epimeric cyclic peptides turnagainolides A 24 and B 25 were

obtained from Bacillus sp. (sediment, Turnagain Is., British Columbia, Canada) and then

synthesised. Turnagainolide B 25 activated the inositol 5-phosphatase SHIP1, a negative

regulator of the phosphatidylinositol-3-kinase (PI3K) pathway, aberrant functioning of which

is implicated in inflammatory diseases and some cancers.80 The constitution of turnagainolide

A 24 is identical to that of EGM-556 from the marine fungus Microascus sp. (sediment,

Florida, U.S.A.),81 but the reported structure of EGM-556 had a different configuration at a

valine residue. Direct comparison of authentic samples of each indicated that they were

identical leading to revision of the structure of EGM-556 to that of turnagainolide A 24.80 A

glycosylated macrolide, macrolactin W 26, isolated from Bacillus sp. (sediment, Ieodo, South

Korea), had potent activity against both Gram-positive and Gram-negative bacteria.82 The

glucose unit in 26 was shown to have the D- configuration but was drawn with the L-

configuration – the correct representation is shown here. Four β-carbolines, marinacarboline

A–D 27–30 and two indolactams, 13-N-demethyl-methylpendolmycin 31 and

methylpendolmycin-14-O-α-glucoside 32, originated from Marinactinospora thermotolerans

(sediment, South China Sea, China) and were active against Plasmodium falciparum (P.

falciparum) lines 3D7 and Dd2.83 Of the three γ-pyrones marinactinone A, B 33 and C 34,

from Marinactinospora thermotolerans (sediment, South China Sea), marinactinone A was

claimed as new but was previously isolated from a sponge-associated Nocardiopsis strain as

nocapyrone B.84 All were moderately cytotoxic to some HTCLs while marinactinone B 33

was a weak inhibitor of topoisomerase II.85 Micromonospora strain (deep sea sediment,

Levantine Sea, Eastern Mediterranean) was the source of two 20-membered macrolides

levantilide A 35 and B 36. Levantilide A 35 was moderately antiproliferative against several

tumour cell lines.86 The α-pyrones nocapyrone E–G 37–39, the diketopiperazine derivatives

nocazine A–C 40–42 and an oxazoline, nocazoline A 43, were isolated from the actinomycete

Nocardiopsis dassonvillei (sediment, Yellow River estuary, Dongying, China). Only

nocapyrones E–G 37–39 had modest activity against Bacillus subtilis (B. subtilis).87 The

constitution of nocazine C 42 had previously been proposed88 but was unsupported by

experimental data.87 3,6,7-Tri-epi-invictolide 44 along with the isoprenyl analogue 45 were

obtained from Nocardiopsis tangguensis (sediment, Uranouchi Bay, Kochi, Japan).

Accompanying biosynthetic feeding experiments indicated that 44 and 45 may be assembled

from propionate or methylmalonate.89 44 is an epimer of invictolide, a queen recognition

pheromone in red imported fire ants.90 Nocardiopsis sp. (sediment, South Molle, Is., Brisbane,

Australia) yielded the prenylated diketopiperazines norcardioazine A 46 and B 47, of which

norcardioazine A 46 was a noncytotoxic MDR reversing agent.91 Chemical investigation of a

bacterial strain (mussel, tropical Pacific Ocean) identified as being closely related to

Photobacterium halotolerans, led to isolation of the cyclic peptides solonamide A 48 and B

49, which interfered with the agr quorum sensing system that controls virulence gene

expression in Staphylococcus aureus (S. aureus).92 Of the pseudonocardians A–C 50–52,

diazaanthraquinones from a Pseudonocardia species (deep sea sediment, South China Sea),

two (50 and 51) were potent cytotoxins to three HTCLs and all three were inhibitors of S.

aureus, Enterococcus faecalis (E. faecalis) and Bacillus thuringensis.93 The synthetic

compound deoxynyboquinone94 was obtained for the first time from a natural source.93

Genome analysis of a strain of Salinispora pacifica (Fiji) and subsequent chemical analysis

resulted in isolation of salinosporamide K 53, which displayed 20S proteasome

(chymotrypsin-like) inhibition.95 Of the four pyranones 54–57 isolated from Streptomyces

albus (sediment, Punta Sagres, Portugal) 54 and 57 exhibited strong cytotoxicity against three

HTCLs, while 55 was sub-nanomolar active as an inhibitor of mitogenic signalling. The

(9R,10R) configuration was established for 55.96 The antibiotics antimycin A19 58 and A20

59 were isolated from Streptomyces antibioticus (sediment, Guangdong province, South

China Sea) and exhibited potent activity against C. albicans.97 The tetromycins 1–4 60–63

and the previously reported tetromycin B98 from Streptomyces axinellae (sponge Axinella

polypoides, Banyuls-sur-Mer, France) were active against Trypanosoma brucei but only

tetromycin 3 62 was active against Leishmania major while tetromycins 3 62, 4 63 and

tetromycin B displayed time-dependent inhibition of cathepsin L-like proteases.99 Tetromycin

4 63 is isomeric with the known tetromycin C2100 and this is the first report of tetromycin B

as a marine metabolite. Lobophorins C 64 and D 65 were obtained from Streptomyces

carnosus (sponge Hymeniacidon sp., Qingbang Is., East China Sea) as selective inhibitors of

HTCLs, but the evidence for the assigned structures and configurations is not convincing.101

Streptomyces microflavus (sponge Hymeniacidon perlevis, Dalian, Yellow Sea, China)

produced 3-acetyl-5-methyl-2'-deoxyuridine 66 and the known uridines 3,5-dimethyl-2'-

deoxyuridine and 3-methyl-2'-deoxyuridine. 3-Methyl-2'-deoxyuridine had previously been

obtained from the Swedish sponge Geodia baretti,102 but the isolation here from a

microorganism suggests that the sponge may not have been the actual source.103 A family of

peptidic metabolites was obtained from two bacterial strains separated from molluscs.

Nobilamides A–E 67–71 were obtained from one Streptomyces strain (Chicoreus nobilis,

Cebu, Philippines) and nobilamides A 67 and F–H 72–74 were isolated from another

Streptomyces species (Conus tribblei, Cebu, Philippines). Related peptides A-3302-A and A-

3302-B,104 previously obtained from terrestrial B. subtilis, were isolated for the first time from

a marine source and the known synthetic peptide, N-acetyl-L-phenylalanyl-L-leucinamide105

was obtained for the first time from a natural source. Nobilamide B 68 and A-3302-B were

potent and long-acting antagonists of mouse and human transient receptor potential vanilloid-

1 (TRPV1) channels (pain and inflammation mediators).106 Actinoramides A–C 75–77 are

modified peptides composed of the unusual amino acids, 2-amino-4-ureidobutanoic acid and

4-amino-3-hydroxy-2-methyl-5-phenylpentanoic acid, that were isolated from a bacterium

closely related to the genus Streptomyces (sediment, San Diego, California, U.S.A.).107

Actinoramide A 75 was coincidentally isolated as pandanamide A from Streptomyces sp.

(sediment, Padana Nahua, Papua New Guinea) along with pandanamide B 78.108

Pandanamide B 78 was cytotoxic to Jurkat T lymphocyte cells, whilst chemical genomics

analysis utilising Saccharomyces cerevisiae mutants implicated actinoramide A (pandanamide

A) 75 as an inhibitor in the biosynthesis of sulfur-containing amino acids, or in some

interaction with them.108 The siderophores streptobactin 79, dibenarthin 80 and tribenarthin

81 were isolated from a Streptomyces sp. (brown alga Analipus japonicus, Charatsunai beach,

Muroran, Japan) along with the known siderophore benarthin.109 Streptobactin 79 and

dibenarthin 80 possessed iron chelating activity comparable to that of deferoxamine

mesylate.110 A Streptomyces strain (sediment, Nasese, Fiji) produced three depsipeptides,

fijimycin A–C 82–84, which occurred as complex conformational mixtures and displayed

significant activity against three methicillin-resistant S. aureus (MRSA) strains.111 The

polyketide ansalactam A 85, which contained a spiro γ-lactam moiety and an isobutyryl

polyketide fragment, was isolated from a Streptomyces species (sediment, Oceanside,

California, U.S.A.). Biosynthetic feeding experiments utilising stable isotopes indicated that

an (E)-4-methyl-2-pentenoic acid-derived branched chain polyketide synthase extender unit

was utilised for polyketide assembly.112 Benzoxacystol 86, a 1,4-benzoxazine-type metabolite

obtained from Streptomyces griseus (deep sea sediment, Canary Basin), was an inhibitor of

glycogen synthase kinase 3β, in addition to displaying weak antiproliferative activity against

mouse fibroblast cells.113 Glucopiericidin C 87 was obtained from a Streptomyces species

(sediment, Laguna de Terminos, Gulf of Mexico) and was active against the fungus Mucor

miehei, in addition to exhibiting cytotoxicity towards a number of HTCLs. Also isolated, for

the first time from a natural source, was the known synthetic compound, 5-oxo-5-o-tolyl-

pentanoic acid.114,115 A Streptomyces sp. (sediment, Nelson, South Australia) yielded a new

member of the reveromycin polyketide spiroketals, reveromycin E 88,116 while

pyridinopyrones A–C 89–91 were isolated from another Streptomyces sp. (sediment, La Jolla,

California, U.S.A.) but with 90 and 91 obtained as an inseparable mixture. Incorporation of

13C-labelled precursors indicated that the starter unit was nicotinic acid and that the polyene

chain and pendant methyl groups are respectively acetate- and methionine-derived.117 A new

species of Streptomyces (unidentified sponge, Ishigaki City, Okinawa, Japan) yielded the

pyrazinones, JBIR-56 92 and JBIR-57 93. JBIR-56 92 was synthesised from 2,6-

dichloropyrazine.118 A Streptomyces sp. from the sponge Craniella australiensis (Sanya Bay,

Hainan Province, China) led to streptomycindole 94, in addition to the known, related

synthetic product, N-phenylacetyl-L-tryptophan119 (isolated for the first time as a natural

product).120 A further Streptomyces sp. (sediment, Bohai Bay, China) produced N1-acetyl-N7-

phenylacetyl cadaverine 95, a diketopiperazine cyclo(2-hydroxy-Pro-R-Leu) 96 and the

known synthetic intermediate, cyclo(4-hydroxy-S-Pro-S-Trp).121 All three were moderately

cytotoxic to the HL-60 cell line.122 The anthramycin-type analogues usabamycin A–C 97–99

obtained from Streptomyces sp. (sediment, Usa Bay, Kochi Prefecture, Japan) were weakly

inhibitory of HeLa cell growth and selective inhibitors of serotonin uptake (5-HT2B).123

Investigation of a Streptomyces sp. (sediment, Kiaochow Bay, Qingdao, China) afforded the

anthracene derivative 100, cytotoxic to the A549 cell line.124 Verrucosispora sp. (sponge

Chondrilla caribensis f. caribensis, Florida Keys, U.S.A.) yielded the known

Micromonospora sp. metabolite thiocoraline,125 in addition to five new analogues, 101–105.

Of these, 101, 104 and 105 were cytotoxic (A549).126 Four new siderophores have been

obtained from various bacteria (Santa Barbara basin, Southern California, U.S.A.).

Amphibactins S 106 and T 107, respectively with a C14:1 ω-7 fatty acid and a saturated C12

fatty acid, were obtained from a Vibrio species, whilst aquachelins I 108 and J 109, which

respectively contain an hydroxylated C12 fatty acid and a saturated C10 fatty acid, were

obtained from Halomonas meridiana.127

Bacteria from Mangroves

Erythrobacter sp. (mangrove sediment, Trinity Bay, Galveston, Texas, U.S.A.) yielded the

benzothiazole diterpenes erythrazole A 110 and B 111, of which erythrazole B 111 was

cytotoxic to three HTCLs.128 The macrocyclic lactones azalomycin F5a 2-ethylpentyl ester

112 and the previously reported azalomycin F4a 2-ethylpentyl ester 113,129 were obtained

from Streptomyces sp. (mangrove rhizosphere soil, Heritiera globosa, Wenchang, China) and

exhibited moderate activity against C. albicans and the HCT-116 cell line.130 An endophytic

Streptomyces sp. (mangrove stem, Kandelia candel, source unspecified) provided the

indolosesquiterpenes xiamycin B 114, indosespene 115 and sespenine 116 and the known

xiamycin A,131 which had moderate to strong activity against several bacteria, including

MRSA and vancomycin-resistant E. faecalis (VREF).132 Divergolides A–D 117–120 were

obtained from an endophytic Streptomyces sp. (mangrove stem, Bruguiera gymnorrhiza,

source unspecified) and exhibited a range of cytotoxic and antibacterial activities. All were

active against B. subtilis and Mycobacterium vaccae, divergolide C 119 was moderately

active against E. faecalis and divergolide D 120 exhibited moderate activity against VREF

and was the most cytotoxic.133 A Streptomyces sp. (mangrove soil, Wenchang, Hainan

Province, China) yielded the benzamide, 3-hydroxy-2-N-isobutyrylanthranilamide 121.134

Marine-sourced Fungi (excluding from mangroves)

The diterpene glycosides virescenoside Z4–Z8 122–126 were isolated from Acremonium

striatisporum (holothurian Eupentacta fraudatrix, Sea of Japan).135 Acremostrictin 127, a

tricyclic lactone representing a new skeletal class from Acremonium strictum (unidentified

Choristida sponge, Gagu-do, Korea), exhibited moderate antioxidant activity in a DPPH

radical-scavenging assay and inhibited hydrogen peroxide-induced death of human

keratinocyte HaCaT cells.136 An Arthrinium sp. (sponge Geodia cydonium, Adriatic Sea,

Italy) produced five new diterpenoids arthrinin A–D 128–131 and myrocin D 132 and the

known compounds myrocin A,137 norlichexanthone138 and anomalin A.139 Myrocins A and D,

anomalin A and norlichexanthone were antiproliferative against four HTCLs and anomalin A

was also antiangiogenic, inhibiting VEGF-A dependent endothelial cell sprouting.140

Coincidentally, the name myrocin D was given to another metabolite with a different structure

133, obtained from A. sacchari (unidentified sponge, Atami-shi, Shizuoka, Japan), together

with two further diterpenes libertellenone E 134 and F 135 and a new isocoumarin,

decarboxyhydroxycitrinone 136.141 The citrinone 136 and co-isolated libertellenone C142

exhibited antiangiogenic activity.141 The sesquiterpenoid asperaculin A 137 with the novel

[5,5,5,6]fenestrane ring system was obtained from Aspergillus aculeatus (sponge Xestspongia

testudinaria, Phi Phi Is., Krabi Province, Thailand).143 Pre-aurantiamine 138, (–)-9-

hydroxyhexylitaconic acid 139 and (–)-9-hydroxyhexylitaconic acid-4-methyl ester 140, were

isolated from A. aculeatus (sponge Stylissa flabelliformis, Phi Phi Is., Krabi Province,

Thailand).144 A. flavus (green alga Codium fragile, GeoMun Is., Yeosu, Korea) provided the

cerebroside derivatives flavuside A 141 and B 142, which, along with the previously

described phomaligol A,145 were weak inhibitors of S. aureus, MRSA, and methicillin-

resistant S. aureus.146 A planar structure of ‘flavuside B’ had been reported previously147 but

the key data required for a structural comparison with flavuside B 142 were not.146 A new

oxylipin 143 and a new steroid 144 were obtained from A. flavus, (red alga Corallina

officinalis, Yantai, China),148 while A. fumigatus (holothurian Stichopus japonicus, Lingshan

Is., Qingdao, China) yielded pseurotins A1 145 and A2 146 containing a 1-oxa-7-

azaspiro[4.4]non-2-ene-4,6-dione core.149 A. insuetus (sponge Psammocinia sp., Sdot-Yam,

Israel) provided three meroterpenoids, insuetolide A–C 147–149, drimane sesquiterpenes,

including 150, the known strobilactone A,150 and (E,E)-6-(6',7'-dihydroxy-2',4'-octadienoyl)-

strobilactone A.151 Of these, insuetolide A 147 and the strobilactones were antifungal

(Neurospora crassa) while 149, 150 and (E,E)-6-(6',7'-dihydroxy-2',4'-octadienoyl)-

strobilactone A were mildly cytotoxic towards MOLT-4 human leukaemia cells.152 A γ-

aminobutyric acid-containing cyclic heptapeptide, unguisin E 151, came from Aspergillus

sp. (soil, Xiamen Beach, Fujian, China)153 and Aspergillus sp. (sponge Tethya aurantium,

Mediterranean Sea, Italy) yielded five meroterpenoid metabolites austalide M–Q 152–156,

together with several known compounds.154 The diketopiperazine disulfide deoxyapoaranotin

157 from A. versicolor (sediment, East Sea, Korea) was cytotoxic and induced apoptotic

activity against HCT-116, as did the co-isolated metabolites acetylaranotin155 and

acetylapoaranotin155 (isolated from a marine source for the first time).156 An Aspergillus sp.

(sediment, Dadaepo Beach, Busan, Korea) gave two oxepin-containing compounds 158 and

159 and two diketopiperazine-type alkaloids 160 and 161.157 The planar structure of 161 had

previously been published in a patent.158 Aspergilone A 162 and the methylene bridged dimer

aspergilone B 163 were obtained from Aspergillus sp. (gorgonian Dichotella gemmacea,

South China Sea). Aspergilone A 162 was cytotoxic to several HTCLs and was a potent

inhibitor of settlement of the barnacle Balanus amphitrite (B. amphitrite).159 A. sydowii (sea

fan Annella sp., Suratthai Province, Thailand) was the source of the sesquiterpenes

aspergillusene A 164 and B 165, (+)-(7S)-7-O-methylsydonic acid 166 and the xanthones

aspergillusone A 167 and B 168.160 (+)-(7S)-7-O-Methylsydonic acid 166 was simultaneously

isolated from a terrestrial fungal endophyte of the Eastern White Pine Pinus strobus.161 The

co-isolated dihydroxanthenone AGI-B4162 exhibited antioxidant activity in a DPPH assay.160

The terremides A 169 and B 170 originated from an A. terreus (sediment, Putian Sea Saltern,

Fujian, China) and were weakly active against P. aeruginosa and Enterobacter aerogenes (E.

aerogenes).163 A co-isolated butenolide was claimed as new and designated terrelactone A but

this compound was identical to aspernolide B,164 previously reported from a soft coral

(Sinularia kavaratiensis)-associated A. terreus. Five ophiobolin-type sesterterpenoids 171–

175 and two new pyrrolidine alkaloids aspergillamide A 176 and B 177 were obtained from

A. ustus (sponge Suberites domuncula, Adriatic Sea).165 Another A. versicolor (sediment,

Yellow Sea) was the producer of an inseparable 2:1 mixture of the cyclic pentapeptides

versicotide A 178 and B 179.166 The cyclopentapeptides versicoloritide A–C 180–182, an

orcinol tetramer tetraorcinol A 183 and the lactones versicolactone A 184 and B 185 were

obtained from A. versicolor (soft coral Cladiella sp., Lingao, Hainan Province, China). The

tetraorcinol A 183 was a weak radical scavenger (DPPH).167 Investigation of A. versicolor

(soft coral Cladiella sp., South China Sea) revealed three alkaloids cottoquinazoline B–D

186–188. Cottoquinazoline C 187 had modest antifungal activity against C. albicans.168 Three

sterigmatocystin derivatives oxisterigmatocystin A–C 189–191 were isolated from A.

versicolor (deep sea sediment, Pacific Ocean)169 and a lipopeptide fellutamide F 192 was also

isolated from A. versicolor (sponge Petrosia sp., Jeju Is., Korea) and was cytotoxic against a

panel of HTCLs.170 Chaetomugilins P–R 193–195 and 11-epi-chaetomugilin I 196 were

obtained from Chaetomium globosum (fish Mugil cephalus, Katsura Bay, Japan) and were

inhibitory against several cancer cell lines.171 The hirsutane sesquiterpenoid hirsutanol E 197

came from Chondrostereum sp. (soft coral Sarcophyton tortuosum, Sanya Bay, South China

Sea)172 and three 14-membered resorcylic acid lactones, cochliomycin A–C 198–200, were

isolated from Cochliobolus lunatus, (gorgonian Dichotella gemmacea, Weizhou Reef, South

China Sea). Cochliomycins A 198 and B 199 possessed a rare natural acetonide group. Four

known analogues, zeaenol,173 LL-Z1640-1,174 LL-Z1640-2174 and paecilomycin F,175 were

obtained for the first time from a marine source. Cochliomycin A 198, zeaenol and

paecilomycin F exhibited potent antifouling activity (B. amphitrite larvae) and cochliomycin

A 198 also exhibited moderate growth inhibition of S. aureus.176 The fungus Coniothyrium

cereale (green alga Enteromorpha sp., Fehmarn, Baltic Sea) produced the new phenalenone

derivatives (Z)-coniosclerodinol 201, (E)-coniosclerodinol 202, sclerodinol 203,

conioscleroderolide 204, coniosclerodione 205 and coniolactone 206, in addition to

coniosclerodin, previously synthesised,177 but now isolated for the first time as a natural

product.178 A number of other known terrestrial fungal metabolites, including a lactone,179 (–

)-sclerodin,179 lamellicolic anhydride,180 (–)-scleroderolide181 and (–)-sclerodione179 were also

isolated for the first time from a marine environment. Of the isolated metabolites,

conioscleroderolide 204 and (–)-scleroderolide inhibited growth of S. aureus, (Z)-

coniosclerodinol 201, sclerodinol 203 and coniolactone 206 inhibited growth of

Mycobacterium phlei (M. phlei), while coniosclerodin, conioscleroderolide 204 and (–)-

sclerodin, were potent inhibitors of human leukocyte elastase (HLE).178 The same isolate

yielded the polyketide-type alkaloids (–)-cereolactam 207, (–)-trypethelone 208 (enantiomer

of the previously reported trypethelone182) and (–)-cereoaldomine 209. While cereolactam

207 and (–)-cereoaldomine 209 selectively inhibited human leukocyte elastase, (–)-

trypethelone 208 was an inhibitor of M. phlei, S. aureus and E. coli and cytotoxic to mouse

fibroblast cells.183 A Curvularia sp. (sea fan Annella species, Similan Islands, Phangnga,

Thailand) yielded the new metabolites curvulapyrone 210, curvulalide 211 and curvulalic acid

212.184 A β-resorcylic macrolide 5'-hydroxyzearalenone 213 was obtained from Fusarium

sp. (seagrass Thalassia hemprichii, location unspecified). The known synthetic compound

relgro185 was isolated as a new natural product and 7′-dehydrozearalenone186 obtained from a

marine source for the first time.187 The endophytic Gibberella zeae (green alga Codium

fragile, Yantai, China) yielded a new pyrrolidine 214, an inhibitor of A549 and BEL-7402

cell lines, and a known steroid, originally incorrectly assigned as (22E)-5,6α-epoxy-

3β,8β,14α-trihydroxy-5α-ergost-22-en-7-one,188 but now corrected to (22E,24R)-7β,8β-

epoxy-3β,5α,9α-trihydroxyergosta-22-en-6-one 215.189 The chlorinated prenyl-indole alkaloid

(–)-spiromalbramide 216 was isolated from Malbranchea graminicola (unidentified

invertebrate, Kona, Hawaii, U.S.A.) along with (+)-isomalbrancheamide B, (first marine

isolation, previously isolated from a terrestrial Malbranchea aurantiaca).190 Production of

two brominated analogues, (+)-malbrancheamide C 217 and (+)-isomalbrancheamide C 218

was induced by enrichment of the growth medium with bromide salts.191

Paecilomyces variotii (jellyfish Nemopilema nomurai, southern coast of Korea) produced four

polyketides 219–222 of which 220 and 221 were moderate inhibitors of MRSA and multi-

drug-resistant Vibrio parahemolyticus.192 Penicillium chrysogenum (P. chrysogenum) (red

alga Laurencia sp., Weizhou Is. South China Sea) was the producer of the polyketide

penicitide A 223, moderately inhibitory/cytotoxic to HepG2, penicitide B 224, the glycerol

derivative 225 and the monoterpene penicimonoterpene 226, a potent inhibitor of Aspergillus

brassicae.193 The tetracyclic cyclopiane diterpenes conidiogenone H 227 and I 228 originated

from the same fungus. Among the known co-isolates, conidiogenone B194 displayed potent

activity against a range of bacteria, and conidiogenol195 was also isolated for the first time

from a marine source and inhibited growth of P. fluorescens and S. epidermidis.196

Penicisteroids A 229 and B 230 are polyoxygenated steroids obtained from P. chrysogenum

(red alga unidentified Laurencia, location unspecified). The known terrestrial fungal

metabolite, anicequol197 was obtained for the first time from a marine source. Penicisteroid A

229 was potently antifungal and selectively cytotoxic to three HTCLs. Anicequol was also

antifungal.198 P. chrysogenum (sponge Tethya aurantium, Limsky Channel, Adriatic Sea,

Croatia) yielded cillifuranone 231 previously postulated as an intermediate in sorbifuranone

biosynthesis199 (weak activity against Xanthomonas campestris and Septoria tritici).200 Of the

citrinin derivatives penicitrinol C–E 232–234 isolated from P. citrinum (sediment, Lanqi Is.,

Fujian, China), penicitrinols C 232 and E 234 were weakly cytotoxic to HL-60 cells.201 The

same strain of P. citrinum yielded penicitrinols F–I 235–238.202 Coincidentally, the names

penicitrinols F–H have also been given to different, but structurally related compounds,

isolated from a terrestrial P. citrinum sample.203 Fermentation of P. commune (sediment,

southern China Sea) gave azaphilone derivatives comazaphilone A–F 239–244.

Comazaphilones C–E 241–243 were potent growth inhibitors of several bacteria and

comazaphilones D–F 242–244 were cytotoxic to the human pancreatic tumour cell line

SW1990.204 The styrylpyrone derivative 4-methoxy-3-methylgoniothalamin 245 came from

parallel fermentations of P. glabrum and P. implicatum (stems and rhizomes, seagrass Zostera

marina, Trinity Bay, Peter the Great Gulf, Sea of Japan),205 while P. paneum (sediment,

South China Sea) was the source of a triazole carboxylic acid penipanoid A 246, two new

quinazolinone alkaloids, penipanoid B 247 and C 248 and a quinazolinone derivative,

recently reported as a metabolite of the Cordyceps-colonising terrestrial fungus Isaria

farinosa206 but here, a first time marine isolate. This quinazolinone derivative was cytotoxic

to the A549 and BEL-7402 cell lines, in contrast to the previous report.206 Penipanoid A 246

was cytotoxic to the SMMC-7721 cell line.207 The chlorinated sorbicillinoids chloctanspirone

A 249 and B 250, together with their likely precursors terrestrol K 251 and L 252 were

obtained from P. terrestre (sediment, Jiaozhou Bay, China). Chloctanspirone A 249 was

cytotoxic to both HL-60 and A549 cells and chloctanspirone B 250 to HL-60 cells only.208

The aromatic butenolides eutypoid B–E 253–256, produced by a Penicillium sp. (water

sample, North Sea), were inhibitors of glycogen synthase kinase-3β209 and the Penicillium sp.

(sponge Stelletta sp., Jeju Is., Korea) was the producer of the hexylitaconic acid derivatives

257–259, along with (3S)-methyl 9-hydroxy-3-methoxycarbonyl-2-methylenenonanoate,210 a

known synthetic compound and here, a first time marine isolate. Hexylitaconic acid derivative

257 and the methylenenonanoate were weak inhibitors of the pro-inflammatory mediator

interleukin-1β in murine macrophage cells.211 Phialocephala sp. (deep sea sediment, East

Pacific Ocean) was the producer of a sorbicillinoid dimer 260, a sorbicillinoid monomer 261

and a benzofuranone derivative phialofurone 262, which were cytotoxic to P388 and K562

cell lines.212 Three new cytochalasins Z21–Z23 263–265 were obtained from an OSMAC

(one strain-many compounds) approach to culture of Spicaria elegans (sediment, Jiaozhou

Bay, China).213 Also produced as a first time marine isolate was the known terrestrial fungal

metabolite 22-oxa-[12]-cytochalasin.214 The O-prenylated natural products stachyline A–D

266–269 came from the fungus Stachylidium sp. (sponge Callyspongia cf. C. flammea, Bear

Is., Sydney, Australia). Stachyline A 266 occured as an interchangeable mixture of E/Z-

isomers.215 The phthalide derivatives marilone A–C 270–272 were also obtained from a

culture of Stachylidium sp. (sponge Callyspongia sp. cf. C. flammea, Bear Is., Sydney,

Australia). It was noteworthy that marilones A 270 and C 272 were isolated as racemic

mixtures. Marilone A 270 was active against Plasmodium berghei liver stages whilst marilone

B 271 was a selective antagonist of the serotonin receptor 5-HT2B. Both marilones A 270 and

C 272 were weakly antiproliferative against three HTCLs.216 Two cytochalasins, 18-

deoxycytochalasin Q 273 and 21-O-deacetylcytochalasin Q 274, were obtained from a

Xylaria sp. (sediment, South China Sea), but only 274 was mildly cytotoxic against three

HTCLs.217 Balticolid 275, a twelve-membered macrolide, was isolated from an

Ascomycetous fungus (driftwood, Greifswalder Bodden, Baltic Sea, Germany) and was anti-

HSV-1 active.218

Fungi from Mangroves

An ever-increasing number of compounds are being reported from fungi associated with

mangrove plants and soils. Three bianthraquinones alterporriol K–M 276–278 were isolated

from an Alternaria sp. (mangrove Aegiceras corniculatum, Guandong, China), of which two,

K 276 and L 277, were cytotoxic against two HTCLs.219 Nigerapyrones A–H 279–286 were

isolated from A. niger (mangrove Avicennia marina, Dongzhai Harbour, Hainan, P.R. China),

together with the known congeners, asnipyrone B and A220 which were isolated from a marine

source for the first time and the structures of which were revised to 287 and 288, respectively.

Nigerapyrones B 280, D 282 and E 283 and asnipyrone A were weakly cytotoxic to several

HTCLs.221 The meroterpenes acetoxydehydroaustin B' 289 and 1,2-dihydro-

acetoxydehydroaustin B' 290 were isolated as a mixed crystal from an Aspergillus

sp. (unspecified mangrove, Shankou Mangrove Nature Reserve, Guangxi Province, China).222

A. taichungensis (mangrove root soil, Acrostichum aureum, unspecified location) was the

source organism for prenylterphenyllins A–C 291–293, prenylcandidusins A–C 294–296 and

4''-dehydro-3-hydroxyterphenyllin 297. Several of these metaboliites showed moderate

activity against cancer cell lines.223 The dimeric naphtho-γ-pyrones rubasperone D–F 298–

300, and the atropisomer rubasperone G 301, were obtained from A. tubingensis (mangrove

radix Pongammia pinnata, Guangxi Province, China).224 Five drimane sesquiterpenes 302–

306 were obtained in an investigation of A. ustus (mangrove soil, Acrostichum aureurm,

Guangxi, China). Two of these structures 304 and 305 were already registered in CAS (CAS

No. 1217857-65-2 and 1217868-38-6 respectively)225 but appear to have no associated

references or data.226 The isoindolones emerimidine A 307 and B 308 and emeriphenolicin A–

D 309–312 were isolated from an Emericella sp. (mangrove Aegiceras corniculatum, Haikou,

China) with the emerimidines A 307 and B 308 having moderate antiviral effects against

H1N1.227 A new alkaloid, 2-methylimidazo[1,5-b]isoquinoline-1,3,5(2H)-trione 313, was

isolated from Hypocrea virens (mangrove Rhizophora apiculata, Shatian country, Guangxi

Province, China).228 Three azaphilones chermesinone A–C 314–316 and three p-terphenyls 6'-

O-desmethylterphenyllin 317, 3-hydroxy-6'-O-desmethylterphenyllin 318 and 3''-deoxy-6'-O-

desmethylcandidusin B 319, were isolated from the endophytic fungus Penicillium

chermesinum (mangrove, Kandelia candel, South China Sea, Guangdong, China).229 There is

some question as to whether chermesinone B 315 is the same as the known terrestrial fungal

metabolite monochaetin.230,231 A discrepancy in the NMR spectroscopic data between the two

suggests that they may be C-12 epimers.229 Terphenyls 317, 318 and the known 3,3''-

dihydroxy-6'-O-desmethylterphenyllin232 were strong inhibitors of α-glucosidase, whilst the

terphenyl 3''-deoxy-6'-O-desmethylcandidusin B 319 and the known 6'-O-

desmethylcandidusin B232 were inhibitors of acetylcholinesterase. The terphenyls, 3,3''-

dihydroxy-6'-O-desmethylterphenyllin and 6'-O-desmethylcandidusin B had previously been

isolated from terrestrial Penicillium raistrickii232 but this was the first marine isolation.229 The

halotolerant fungus P. chrysogenum (mangrove roots, Rhizophora stylosa, Wenchang, Hainan

Province, China) provided the cerebrosides chrysogeside A–E 320–324 and two 2-pyridones,

chrysogedone A 325 and B 326, but only chrysogeside B 321 was active agaist E.

aerogenes.233 15α-Hydroxysoyasapogenol B 327, 7β,15α-dihydroxysoyasapogenol B 328 and

7β,29-dihydroxysoyasapogenol B 329 were isolated from Pestalotiopsis clavispora

(mangrove Bruguiera sexangula, Dongzhai, Hainan Province, China),234 while

pestalotiopyrones A–H 330–336, pestalotiopisorin A 337, pestalotiollides A 338 and B 339,

pestalotiopin A235 and four amides pestalotiopamide A–D 340–343 were sourced from

another Pestalotiopsis sp. (mangrove Rhizophora mucronata, China).236 Pestalotiopyrone A

330 has an identical structure to that of nigrosporapyrone, previously isolated from a marine-

derived Nigrospora,237 but published NMR spectroscopic data did not correspond to the

pestalotiopyrone A 330 data, nor with empirically calculated values. The structure of

nigrosporapyrone requires reinvestigation. Both pestalotiopyrone C238 and pestalotiopin A235

have been synthesised previously but this was the first isolation from a natural source;

pestalotiopyrone G 335 is the (Z)-isomer of pestalopyrone, previously isolated from

pathogenic Pestalotiopsis oenotherae.239 Pestalotiollide A 338 has the same planar structure

as a compound isolated from Penicillium sp., obtained from Taxus cuspidate leaves240 but

different stereochemistry.236 The same culture yielded pestalotiopamide E 344 (leaves,

Rhizophora mucronata, Hainan Is., China).241 The isochroman, (3R,4S)-3,4-dihydro-4,5,8-

trihydroxy-3-methylisocoumarin 345, along with the known fungal metabolites exumolide

A242 and 4-(hydroxymethyl)-7-methoxy-6-methyl-1(3H)-isobenzofuranone243 (first marine

isolation) were obtained from a Phomopsis sp. (mangrove sediment, Zhuhai, Guangdong,

China). All metabolites were active in a zebra fish assay244 with exumolide A and 345 also

moderately cytotoxic to hepG2 cells.245 Talaperoxides A–D 346–349 are norsesquiterpene

peroxides obtained from Talaromyces flavus (mangrove Sonneratia apetala, Hainan Is,

China). The co-isolated steperoxide B246 (or merulin A247) was isolated for the first time as a

marine metabolite and the absolute configuration established (350). Talaperoxides B 347 and

D 349, were moderately cytotoxic to HTCLs.248 Reinvestigation of a fungus of the family

Meruliaceae (mangrove leaves Xylocarpus granatum, Samutsakorn Province, Thailand) from

which nor-chamigrane (merulin A) and chamigrane endoperoxides (merulins B and C) were

obtained,246 led to the isolation of merulin D 351 (an epimer of merulin B), in addition to

merulins B and C and the known analogue steperoxide B.247 Merulin C246 displayed potent

antiangiogenic activity, in addition to promising activities in rat aortic ring sprouting (ex vivo)

and mouse Matrigel (in vivo) assays.249 The xanthone derivative 352 was obtained from the

co-culture broth of two unidentified endophytic fungi (mangrove Kandelia candel and red

alga, Eucheuma muricatum, South China Sea Coast, China) and was antifungal, but not

produced when either fungus was individually cultured.250

Cyanobacteria

Cyanobacteria continue to be a prolific source of new compounds. Grassypeptolides D 353

and E 354 and a lyngbyastatin analogue, Ibu-epidemethoxylyngbyastatin 3 355 were obtained

from both field collections and culture of Leptolyngbya sp. (SS Thistlegorm shipwreck, Red

Sea). Grassypeptolides D 353 and E 354 were cytotoxic to HeLa and mouse neuro-2a

blastoma cells.251 Grassypeptolides F 356 and G 357 were isolated from a collection of

Lyngbya majuscula (Ngerderrak Reef, Palau) and displayed moderate inhibition of the

transcription factor AP-1.252 Malyngamide 2 358, a polyketide-synthase-nonribosomal

peptide synthase (PKS-NRPS)-derived metabolite, was obtained from a collection of L.

sordida (Dutchess Is., Papua New Guinea) and displayed anti-inflammatory activity in

lipopolysaccharide (LPS)-induced RAW macrophage cells with only modest cytotoxicity to

the cell line.253 The new cyclic peptides malyngamide 3 359 and cocosamide A 360 and B

361 were isolated from a collection of L. majuscula (Cocos Lagoon, Guam) and were

modestly cytotoxic to two HTCLs.254 Isomalyngamide A-1 362 was obtained from L.

majuscula (Taiwan) along with isomalyngamide A,255 both of which suppressed cancer cell

migration in vitro.256 The (2Z)-isomer of malyngamide K, isomalyngamide K 363, was

isolated from a collection of L. majuscula (Alotau Bay, Papua New Guinea).257 L. majuscula

(Piti Bomb Holes, Guam) yielded the proline-rich cyclic depsipeptide pitiprolamide 364,

which was moderately cytotoxic against two HTCLs and weakly antibacterial against M.

tuberculosis and B. cereus.258 Pitipeptolides A and B had previously been isolated from the

same source259 and investigation of larger collections yielded pitipeptolides C–F 365–368

(weak cytotoxicity against two HTCLs, but more active against M. tuberculosis).260

Pitipeptolide C 365 had previously been prepared as an hydrogenation product of

pitipeptolides A and B.259 Lagunamide C 369, a cyclodepsipeptide from the same L.

majuscula strain (Pulau Hantu Besar, Singapore) that had produced lagunamides A and B,261

was potently cytotoxic to HTCLs, showed significant antimalarial activity against P.

falciparum and weak antiswarming activity against P. aeruginosa.262 The cyclic depsipeptides

wewakamide A 370 and guineamide G 371 were respectively isolated from L. semiplena

(Wewak Bay, Papua New Guinea) and L. majuscula (Alotau Bay, Papua New Guinea). While

both were potently toxic to brine shrimp, only guineamide G 371 was cytotoxic to a mouse

neuroblastoma cell line.263 Examination of a Lyngbya sp. (Florida Keys, U.S.A.) led to

isolation of the epimeric cyclic depsipeptides porpoisamide A 372 and B 373 (weakly

cytotoxic to HCT-116 and osteosarcoma U2OS cells).264 Reinvestigation of an Okinawan

Lyngbya sp., source of the cytotoxic peptide bisebromoamide,265,266 gave the demethyl

analogue, norbisebromoamide 374 that was also strongly antiproliferative.267 Collections of L.

majuscula (New Ireland, Papua New Guinea) and Oscillatoria sp. (Isla Canales de Afuera,

Coiba National Park, Panama,) yielded the lipids serinolamide A 375 and propenediester 376.

Serinolamide A 375 showed a moderate agonist effect and selectivity for the CB1

cannabinoid receptor.268 The cyclopropyl fatty acid, lyngbyoic acid 377, was isolated as a

major metabolite of L. cf. majuscula (Indian River Lagoon, Florida, U.S.A.) and was a

disruptor of quorum sensing pathways mediated by acylhomoserine lactones (AHLs) in

Gram-negative bacteria. Lyngbyoic acid 377 most strongly affected the AHL receptor LasR

and reduces pyocyanin and elastase (LasB) both on the protein and transcript level in wild-

type P. aeruginosa.269 Interestingly, the enantiomer of lyngbyoic acid 377 was prepared

during a synthesis of the enantiomer of another cyanobacterial metabolite, grenadamide.270 A

phylogeny-guided approach utilised to search for specific classes of new natural products

from Curaçao marine cyanobacteria, led to ethyl tumonoate A 378 from Oscillatoria

margaritifera (Curaçao, Netherlands Antilles) which was anti-inflammatory in the

RAW264.6 murine microphage cell based assay and inhibitory to calcium oscillations in

neocortical neurons.271 Thiopalmyrone 379 and palmyrrolinone 380 were isolated from an

assemblage of the cyanobacteria, cf. Oscillatoria and Hormoscilla spp. (North Beach,

Palmyra Atoll) and were potent molluscicides against the snail Biomphalaria glabrata.272

Seven new cyclic depsipeptides veraguamide A–G 381–387 from Symploca cf. hydnoides

(Cetti Bay, Guam), together with the semi-synthetic 388 were cytotoxic (moderate to weak) to

two HTCLs. Dolastatin 16, originally from the sea hare Dolabella auricularia (Papua New

Guinea)273 was also isolated and the absolute configuration was established as 389.274 The X-

ray crystal structure of dolastatin 16 was published.275 Almost simultaneously with the work

on Symploca cf. hydnoides,274 a number of veraguamides were isolated from O. margaritifera

(Isla Canales de Afuera, Panama) and these included the new analogues, veraguamide H 390

and J–L 391–393, as well as veraguamides A–C and verugamide I 388 which had been

prepared semi-synthetically (see above) but was here isolated as a natural product.

Verugamide A 381 was a potent inhibitor of the H-460 human lung cancer cell line whilst the

others were weak inhibitors.276

Dinoflagellates

The polyoxy linear carbon chain compound, prorocentrol 394, obtained from the cultured

dinoflagellate Prorocentrum hoffmannianum (CCMP683) was moderately cytotoxic to P388

cells and active against the diatom Nitzschia sp. The partially assigned configurations for 394

as shown are not correlated between the four segments.277 12-Methylgymnodimine 395 was

isolated from the dinoflagellate Alexandrium peruvianum (New River, North Carolina,

U.S.A.). The presence of 13-desmethylspirolide C278 was confirmed by NMR

characterisation: this detection of gymnodimines and spirolides in the same organism

provides further evidence for a direct genetic relationship between the biosynthetic pathways

of these two classes of cyclic imine.279 A new pigment, moraxanthin 396 was isolated from

natural samples from a fish mortality site (Torque Canal, Delaware, U.S.A.) and also as the

major carotenoid from cultures of the microalga Chattonella cf. verruculosa.280 Culture of the

diatom Ditylum brightwellii (Boothbay Harbour, Maine, U.S.A.) yielded stigmasta-24,28-

dienol 397 and 23-methylcholesta-7,22-dienol 398, in addition to stigmasta-5,24,28-trienol, a

known synthetic compound281 (first time from a natural source).282

Miscellaneous

Although 4-acetyl-5-hydroxy-3,6,7-trimethylbenzofuran-2(3H)-one from an Alternaria sp.

(sea cucumber, Weihai, Yellow Sea, China) was claimed as new, it is in fact a known

synthetic derivative of a metabolite of the lichen Parmelia livida283 but this is the first

isolation from a natural source.284 The known synthetic intermediate, 2-carboxy-8-methoxy-

naphthalene-1-ol285,286 was obtained as a natural product from Mycelium sterilium (red alga

Kappaphycus alvarezii, coastal Indonesia).287 Myrothecium verrucaria (sponge

Hymeniacidon perleve, Bohai Sea, Lingshui Qiao, Dalian, China) afforded several known

trichothecenes: 8-hydroxyverrucarin J288 was isolated for the first time as a natural product

and isororidin E289 and trichoverrin B290 were isolated from a marine source for the first

time.291 The marine bacterium, Bacillus pumilus (Microbial Type Culture Collection 5560),

produced 4-phenylbutanoic acid.292 4-Phenylbutanoic acid was an inhibitor of biofilm growth

and this was the first isolation from a marine source.293 Investigation of Aspergillus sp.

(sponge Cliona chilensis, Los Molles, Chile) provided the first marine isolation of

butylrolactone VI, which although claimed as new,294 had previously been obtained from a

terrestrial Aspergillus terreus.295 The terpenoid terrestrial fungal metabolite chrodrimanin

B,296 was isolated for the first time from a marine source from an Aspergillus sp. (gorgonian

Dichotella gemmacea, South China Sea).297

Synthetic Aspects

Synthesis of both diastereomers of the proposed structure for the bacterial metabolite

streptophenazine A,298 resulted in revision of the structure to 399, which was subsequently

synthesised. During the course of these studies, streptophenazines B and E298 were also

prepared.299 Enantioselective total syntheses of the diketopiperazine alkaloids (+)-

naseseazines A and B, metabolites of a Fijian Streptomyces sp.,300 were accomplished by a

convergent, late-stage assembly of diketopiperazine structures via a regioselective Friedel-

Crafts based strategy which also revised the absolute configurations to 400 and 401.301 Total

synthesis of glaciapyrrole A from an Alaskan Streptomyces strain302 as well as of seven

stereoisomers via a diastereoselective ruthenium-catalysed approach, from either geraniol or

nerol, clarified the relative configuration of natural glaciapyrrole A and a subsequent

enantioselective synthesis of the unnatural enantiomer determined the configuration of the

natural product as (11R,12S,15S)-(+)-glaciapyrrole A 402.303 Total syntheses of the bicyclic

sesquiterpenoids drechslerine A and B, from culture of the algicolous fungus Drechslera

dematioidea (red alga Liagora viscida),304 were completed from (S)-carvone, utilising three

palladium-catalysed reactions.305,306 Synthesis and NMR spectroscopic analysis were used to

reassign the structure and determine the absolute configuration of pericosine D0, a metabolite

of the sea hare-derived fungus Periconia byssoides,307 as methyl (3R,4S,5S,6S)-6-chloro-

3,4,5-trihydroxy-1-cyclohexene-1-carboxylate 403.308 Synthesis of the proposed structure of

phomopsin B,309 a metabolite of the mangrove endophytic fungus Phomopsis sp., led to

revision of the structure to that of the known dothiorelone A, previously isolated from another

mangrove endophytic fungus Dothiorella sp.310 Total synthesis of dothiorelone

A/phomopsin B through a cross-metathesis with a chiral olefin was then completed. The

authors suggested that the structure of phomopsin A was likely to require revision to that of

dothioreline B310 but as the 13C NMR data of the two compounds were not identical, it might

indicate that the 13C NMR assignments for dothiorelone B also need reinvestigation.311

Seragakinone A was originally isolated from an unidentified red alga-associated fungus.312

The absolute configuration of the subsequently corrected structure313 has been confirmed by

synthesis of the enantiomer, (–)-seragakinone A.314 Syntheses of several malyngamides,

metabolites of the cyanobacterium Lyngbya majuscula, have been completed. Malyngamides

K,315 L315 and 5''-epi-malyngamide C316,317 have been prepared by an enantioselective and

general route, utilising a Suzuki cross-coupling reaction of boronic acids as a key step. The

absolute configuration of malyngamide L,315 was determined as 404.318 Malyngamide W, a

lipopeptide metabolite of Papua New Guinean L. majuscula319 and the 2′ epimer, have been

synthesised enantioselectively which permitted assignment of the absolute configuration of

malyngamide W as 405.320 Synthesis of the four possible N-terminal diastereoisomers of the

linear depsipeptide gallinamide A, first isolated from the cyanobacterium Schizothrix sp.,321

was achieved in a short, high-yielding procedure from a common imide fragment employing a

divergent strategy. Comparative NMR spectroscopic studies of the synthetic diastereoisomers

with isolated gallinamide A showed that gallinamide A is in fact identical to symplostatin 4

(one of the synthetic diastereoisomers but also a metabolite of the cyanobacterium Symploca

sp.)322 As has been shown previously for symplostatin 4,323 all diastereoisomers exhibited

significant antimalarial activity against the 3D7 strain of P. falciparum.324 The tetrapeptide

cyclo-(isoleucyl-prolyl-leucyl-alanyl) originally isolated from a Pseudomonas sp. associated

with the seaweed Diginea sp. and the sponge Halisarca ectofibrosa325 was prepared via a

solution-phase dipeptide coupling technique and displayed potent antifungal and anthelmintic

activity against pathogenic dermatophytes and earthworms, in addition to moderate activity

against P. aeruginosa.326, 327 Alternaramide, a cyclic pentadepsipeptide metabolite of the

fungus Alternaria sp.,328 was prepared by solution-phase coupling via macrolactonisation and

macrolactamisation reactions.329 Synthesis of unguisin A, a γ-aminobutyric acid (GABA)-

containing cyclic heptapeptide originally isolated from the fungus Emericella unguis,330 was

completed in good yield via macrocyclisation of a GABA-containing linear precursor331 and

synthesis of the amide gymnastatin H, from the sponge-associated fungus Gymnascella

dankaliensis,332 was accomplished in fourteen steps with a diastereoselective

photodeconjugation of a diacetone D-glucose ester as a key step.333 (+)-Paecilospirone, a

metabolite of the tropical fungus Paecilomyces sp.,334 was prepared via an enantioselective

method, with an anti-selective lactate-derived aldol reaction and a palladium catalysed double

deallylation/spirocyclisation as key steps.335 It is worth noting that the name paecilospirone

was originally given to an unrelated compound from a soil-derived Paecilomyces sp.336

Concise and flexible syntheses of sorbicillactone A,337 a metabolite of sponge-derived

Penicillium chrysogenum, and the epimer, 9-epi-sorbicillactone A, were completed, enabling

production on a multigram scale.338 The L. majuscula metabolite, (E)-dehydroapratoxin A,339

was prepared from γ-butyrolactone via a procedure utilising Evans alkylation and Corey’s

chiral borane, (CBS)-catalysed reduction.340 Synthesis of the Papua New Guinean

cyanobacterial metabolite hoiamide C,341was completed in a sixteen step procedure, starting

from a homoallylic alcohol342 and a convergent and stereoselective synthesis of amphidinin B,

a polyketide metabolite of the marine dinoflagellate Amphidinium sp.343 was accomplished.344

Brevisin, a polycyclic ether metabolite of the dinoflagellate Karenia brevis345 was synthesised

in 29 steps from commercially available starting materials346 and the dinoflagellate

metabolite, dinophysistoxin-2347 was prepared in 21 steps via a Horner-Wadsworth-Emmons

reaction for coupling of the key fragments.348 Pinnatoxin G,349 reported from a range of

shellfish and environmental samples but almost certainly dinoflagellate-derived, was

synthesised by a scalable synthetic sequence utilising a convergent strategy.350

Assorted bioactivities

Marinoquinoline A, orignally isolated from the marine gliding bacterium Rapidithrix

thailandica351 has been isolated from the terrestrial species Ohtaekwangia kribbensis as a

growth inhibitor of several human tumour cell lines, a modest growth inhibitor of Gram-

negative bacteria, and an inhibitor of P. falciparum.352 Chaetoglobosin Fex, an alkaloid

metabolite of the endophytic fungus Chaetomium globosum,353 was demonstrated to

significantly inhibit induction of inflammatory mediators by toll-like receptor signalling in

peritoneal macrophages, in the murine macrophage cell line RAW264.7 and also down-

regulate the mRNA expressions of these pro-inflammatory cytokines.354

Biosynthesis

Didemnin B355 and nordidemnin B,356 the well known tunicate-derived peptides, have now

been isolated from culture of the α-proteobacterium, Tistrella mobilis (sediment, Tateyama

Cove, Chiba, Japan). This discovery suggests that an α-proteobacterium may be implicated in

didemnin production in tunicates.357 Geographic distribution of biosynthetic genes in strains

of Salinispora arenicola was evaluated by the molecular fingerprinting technique, terminal-

restriction fragment length polymorphism (T-RFLP), in combination with sequence-based

approaches. Results indicated the utility of techniques such as T-RFLP, to rapidly identify

strains that possess distinct sets of biosynthetic genes. Variation in the secondary metabolite

genes in strains that were largely clonal at the 16S rRNA level was observed and in some

cases, collections of secondary metabolic genes in subpopulations of S. arenicola were

endemic to certain locations. Four previously undetected sets of biosynthetic genes were

identified, two of which were only observed in strains derived from Guam or the Sea of

Cortez, suggesting that screening populations from distant locations may aid discovery of new

natural products.358 Metagenomic sequencing of total DNA from the ET-743 (Yondelis®)359

producing tunicate, Ecteinascidia turbinata/microbial consortium was utilised to target and

assemble a sequence containing 25 genes that comprise the core of the NRPS biosynthetic

pathway for ET-743. Rigorous sequence analysis suggested that Candidatus

Endoecteinascidia frumentensis produces ET-743, and subsequent metaproteomic analysis

confirmed expression of three key biosynthetic proteins. The predicted activity of an enzyme

for assembly of the tetrahydroisoquinoline core of ET-743 was also verified in vitro.360

Notoamide E was originally isolated as a short-lived precursor in the biosynthesis of

prenylated indole alkaloids from mussel-derived Aspergillus sp,361 but biosynthetic

experiments involving the feeding of doubly 13C-labelled notoamide E to terrestrial A.

versicolor362 indicated significant incorporation of notoamide E into notoamides C363 and

D.363 Several related prenylated indole alkaloids have been isolated from both marine363,364

and terrestrial-derived Aspergillus species.365 To investigate the proposal that the reverse-

prenylated indole alkaloid, 6-hydroxydeoxybrevianamide E is a biosynthetic precursor to

notoamide J,364 [13C]2-[15N]-6-hydroxydeoxybrevianamide E was synthesised and fed to

terrestrial A. versicolor. Intact incorporation of the triply-labelled intermediate into notoamide

J was observed. This metabolite has only been isolated previously from marine Aspergillus

species, demonstrating that an appropriate indole oxidase must be present in A. versicolor and

that the marine and terrestrial strains must possess very similar, if not parallel, biosynthetic

machinery.366 To investigate the proposal that stephacidin A is a biosynthetic precursor to

notoamide B363 in various Aspergillus species,367,368 doubly 13C-labelled racemic stephacidin

A was synthesised and fed to cultures of terrestrial A. versicolor and a marine-derived

Aspergillus sp. Enantiospecific incorporation resulted, with intact (–)-stephacidin A

incorporated into (+)-notoamide B in terrestrial A. versicolor and (+)-stephacidin A

incorporated into (–)-notoamide B in the marine Aspergillus sp. 13C-Labelled sclerotiamide

was also isolated from both cultures.369 Biosynthetic experiments on the dinoflagellate

Protoceratium reticulatum utilising 13C-labelled precursors, suggested that the carbons in the

ladder-frame polyether yessotoxin (YTX)370,371 were derived from acetates, a methyl of

methionine and glycolate, and that the six-membered ring tetrads (rings A-D and H-K) were

constructed from repeated condensation of C3 units, formed from a methyl group of a deleted

acetate and an intact acetate unit.372

4 Green algae

The rate of discovery of green algal (Chlorophyta) metabolites has slowed further and for

2011 there were only two reports of new metabolites. (E)-6-Heptacosen-5-one 406 and (E)-6-

octadecen-5-ol 407 were characterised from Ulva lactuca (Abu Qir Bay, Egypt) along with

four known compounds: (Z)-10-hexacosene, docosanoic acid, both for the first time from this

species, together with palmitic acid and isofucosterol.373 Studies on a Caulerpa racemosa

(Zhanjiang coastline, China) led to the isolation of the acetylenic fatty acid (8E,12Z,15Z)-10-

hydroxy-8,12,15-trien-4,6-diynoic acid 408, two known acylic diterpenes and three known

sterols.374 The sesquiterpene caulerpenyne, originally isolated from Caulerpa prolifera375 was

identified as a lipoxygenase inhibitor.376 Despite the lack of new metabolites isolated directly

from green algae, it is worth noting that a number of new compounds have been reported

from green algal-associated fungi (see Marine Microorganisms).178,183,189

5 Brown algae

For 2011 the chemistry of the Ochrophyta was again dominated by terpenoids and phenolics

and as for the Chlorophyta, the number of reports is also low for this year. However, a

comprehensive study of Dilophus spiralis, collected by hand on Elafonissos Island (Greece),

led to a large cache of dolabellane diterpenoids.377 Seventeen compounds were isolated of

which seven were new 409–415, eight were subject to structural revision 416–423 and two

were known dolabelladienes [(1R,2E,4R,7E,11S,12R)-18-hydroxy-2,7-dolabelladiene and

(1R,2E,4R,7E,10S,11S,12R)-10-acetoxy-18-hydroxy-2,7-dolabelladiene].378 All compounds

were tested for antibacterial activities. It was noted that the majority of the active dolabellanes

were hydroxy derivatives: the presence of a ketone functionality at C-14 rendered the

dolabellane inactive.377 Another population of Dilophus spiralis, also from Elafonissos Island

(Greece), was the focus of a study which resulted in the discovery of dilospiranes A 424 and

B 425, diterpenoids with unprecedented carbon skeletons.379 A population of Dictoyota

dichotoma (El-shuaiba, Red Sea) was the source of two new 426 and 427, and seven known

diterpenoids,380 one of which 428 was claimed as new but had previously been isolated and

characterised as amijidictyol from the brown alga Dictyota linearis.381 Bioassays established

that 426 and amijidictyol were the most protective against bleomycin-induced DNA damage

and were also mildly cytotoxic against a variety of cell lines. The unusual dissymmetric

diterpenoid dimer, dictyotadimer A 429, was isolated from a Mediterranean Dictyota sp.

(Brusc Lagoon, France).382 Dimeric diterpenoids are rare in the marine environment, but are

known from gorgonians.383–388 This was the first isolation of a bis-diterpenoid from the

Ochrophyta. A plausible biogenetic scheme was presented originating from two common

moieties but the possibility that 429 was an artefact of isolation could not be excluded.382

There have been few studies on species of the genus Sporochnus. In a study of S. comosus

(Shaw Island, Queensland), bioassay-guided fractionation gave four bis-prenylated quinols

comosusol A–D 430–433 and a bis-prenylated cyclohexenone, comosone A 434.389 Also

isolated were the known bis-prenylated phenol390 and a bis-prenylated quinone,391

fucoxanthin and galactitol. Of the isolated compounds 431 was the most active against a

range of HTCLs, but displayed no selectivity.389 Chromanols and plastoquinones were

isolated from two Korean Sargassum species. In a bioassay guided study of S. siliquastrum

(Jeju Island),392 six chromanols were characterised and these included three new compounds

435–437 and the known sargachromanols D, E and K.393 The relative configurations at C-9′

and C-10′ of 435 and 436 were assigned based on comparison of NMR data from similar

compounds. All six chromanols effectively inhibited intracellular radical oxygen species and

increased intracellular GSH levels.392 Studies on the other Korean Sargassum species, S.

yezoense, led to the isolation of four new plastoquinones meroterphenol A–D 438–441, all of

which had potent activation effects on peroxisome proliferator-activated receptor gamma

(PPARγ), a nuclear receptor that plays a key role in energy metabolism.394 In a study of three

brown alga from the Karachi Coast (Pakistan), the unusual indole derivative jolynamine 442

was isolated from Jolyna laminaroides. Jolynamine has structural relationship with caulerpin,

the well known pigment from certain green algae.395 The other two brown algae studied,

Iyengaria stellata and Melanothamnus afaqhusainii, contained the known compounds

saringosterol,396 loliolide,397 methyl and propyl 4-hydroxybenzoates, harmine,398 and 3,4,5-

trimethylaniline (first isolation of from a natural source).399 Diterpenoids and

meroditerpenoids from the Brazilian brown algae Canistrocarpus cervicornis, Dictyota

menstrualis and Stypopodium zonale were evaluated in antileishmanial,400 anti-HIV401 and

anti-HMPV402 assays. The antiproliferative activities of six meroditerpenoids from an Easter

Island S. flabelliforme were evaluated,403 as were the gastro-protective properties of a Chilean

S. flabelliforme extract.404 The antitumour properties of two Mediterranean brown algae,

Dictyoptera polypodioides and Sargassum sp. were examined405 and assays established that

the phlorotannin, diphlorethohydroxycarmalol, from Ishige okamurae was protective against

radiation-induced cell damage.406

6 Red algae

The year-to-year variability in the number of new compounds reported from red algae

continues with a reduction in 2011 to a lower number (42). An extract from Gracilaria

lemaneiformis (Nanao Is., S. China Sea) provided the simple hydroxyoctadienone 443, which,

along with other known compounds from the extract, displayed modest allelopathic effects on

the growth of Skeletonema costatum.407 The antifungal aldehyde 444 was isolated from

Laurencia papillosa (Jeddah, Red Sea).408 There is considerable confusion concerning the

structures of the maneonenes 445–447 reported from L. obtusa (Jeddah, Red Sea).409 What is

claimed as cis-maneonene D 445 has the same structure as either lembyne A,410 or the product

obtained from treatment of cis-maneonene C with p-toluenesulfonic acid.411 These are thought

to be epimeric at C-5, however, the NMR data for 445 do not appear to correspond with those

obtained for either lembyne A or its C-5 epimer. The structure shown for cis-maneonene E

446 is in fact the structure previously reported for cis-maneonene A.411,412 The present report

describes the isolation of the known cis-maneonene A with NMR data identical to the

previous report, but incorrectly shows the structure as the 6-endo isomer (cis-maneonene

C).411,413 If cis-maneonene E 446 were the 6-endo isomer, the NMR data reported for it do not

correspond to those reported for the C-5 epimers (12E)-lembyne A410 or cis-maneonene

C.411,413 Apoptotic activity was shown for compounds 445 and 446. The oxidised levuglandin

D2 448 was obtained from Gracilaria edulis (La Union, Philippines).414 The previously

reported structures for peyssonenynes A and B from Peyssonnelia caulifera415 have been

revised to 449 and 450 respectively following their total synthesis. These positional isomers

at the glycerol moiety are labile in solution due to reversible monoacylglycerol transacylation

making it highly unlikely that either of the enantiopure sn-1 or sn-3 could be isolated.416 Eight

halogenated nonterpenoid acetogenins, 12-epoxyobtusallene IV 451, 452, obtusallene X 453,

marilzallene 454, (+)-4-acetoxymarilzallene 455, (–)-4-acetoxymarilzallene 456, (Z)-

adrienyne 457 and (E)-adrienyne 458 were isolated from L. marilzae (Paraiso Floral, Canary

Is.).417 This same collection of L. marilzae also yielded the marilzabicycloallenes A–D 459–

462.418 The marilzabicycloallenes have an unprecedented [5.5.1]bicyclotridecane ring system,

whose existence in Laurencia spp. had been predicted in earlier biosynthetic studies on the

obtusallenes.419 The halogenated monoterpenes 463 and 464 were obtained from Plocamium

suhrii (Port Elizabeth, S. Africa). Along with other similar known compounds from this

extract, they had significant cytotoxic effects on an esophageal cell line.420 An HPLC-NMR

chemical profiling strategy used on an extract from L. elata (St. Pauls Beach, Vic., Australia)

revealed two chamigrenes, cycloelatanene A 465 and B 466.421 Three cytotoxic

oxasqualenoids, 15-dehydroxythyrsenol A 467, prethyrsenol A 468 and 13-

hydroxyprethyrsenol A 469, were isolated from L. viridis (Paraiso Floral, Canary Is.).422

Molecular docking studies in the αvβ3 integrin binding region were used to explain their

biological properties. From an earlier collection of the same species from the same location,

iubol 470 and the venustatriol and thyrsiferol derivatives 471–473 were isolated as

moderately cytotoxic compounds.423 The pregnane steroids ceratosteroid A–D 474–477 were

obtained from Ceratodictyon spongiosum and the symbiotic sponge Sigmadocia symbiotica

(Ken-Ting, Taiwan).424 Of these steroids, 475 and 477 were moderately cytotoxic. From the

earlier described L. papillosa, source of the aldehyde 444, an antifungal steroid 478 was also

obtained.408 Most of the nineteen bromophenols isolated from Rhodomela confervoides

(Dalian, China), which included six new compounds 479–484, exhibited potent antioxidant

activities.425 Lithothamnin A 485 was isolated from Lithothamnion fragilissimum (Lighthouse

Reef, Palau Is.) as a modestly cytoxic compound. This metabolite is an unusual bastadin-like

molecule with a unique meta-meta linkage between the aromatic rings.426 An extract from

Callophycus oppositifolius (Pugh Shoal, NT, Australia) yielded the cytotoxic tetrahydro-β-

carboline callophycin A 486.427 Callophycin A was subsequently synthesised along with fifty

other variously functionalised tetrahydro-β-carboline derivatives for evaluation as

chemopreventive and anticancer agents.428 Previously reported red algal metabolites continue

to be the targets of synthesis. A highly regioselective intramolecular oxidative coupling,

probably similar to a postulated biosynthetic step, has yielded (±)-polysiphenol.429,430 The

protein phosphatase 2A inhibitor lactodehydrothyrsiferol431 has been synthesised.432

7 Sponges

In 2011 the number of new compounds (296) reported from phylum Porifera has increased

slightly from previous years, mainly due to several studies reporting large numbers of new

metabolites from single collections. The glycolipid sarcotride D 487 was reported from

Sarcotragus sp. (Cheju Is., S. Korea),433 while a polyunsaturated aminoketone reported from a

Haliclona sponge434 was synthesised.435 Twelve brominated acetylenic acids xestospongienol

A–L 488–499 were isolated from Xestospongia testudinaria (Hainan Is., China),436 while

another individual of the same species (Weizhou Is., South China Sea), yielded a further 39

brominated lipids xestospongiene A–Z 500–525 and Z1–Z13 526–538.437 The enantioselective

synthesis of oxylipin topsentolide B3 539 (Topsentia sp.)438 has been achieved.439 Mutafuran

H 540 is a potent AChE inhibitor from Xestospongia testudinaria (Sanya, China).440 Mass

spectrometry-guided isolation from Raspailia agminata (Cavalli Is., New Zealand) yielded

the glycolipids agminoside A–E 541–545.441 Faulknerynes A–C 546–548 are brominated

acetylenes from Diplastrella sp. (Sweetings Cay, Bahamas), named in honour of the original

author of these reviews.442 The absolute configuration of 546 was established by CD methods,

as was the configuration of diplyne C 549 reported earlier from the same species.442,443 A

Leucetta sponge (Kume Is., Okinawa) revealed the first polyacetylene alkaloid 550 from a

sponge.444 A Petrosia sp. collected using a remote operated vehicle at 415 m depth (Miyako

Sea Knoll, Japan) yielded six cytotoxic polyacetylenes (–)-duryne 551 and (–)-duryne B–F

552–556. The compounds were active against HeLa cells comparable to (+)-duryne from

Cribrochalina dura.445,446 From a separate collection of the same species from the same

location, six related compounds miyakosyne A–F 557–562 with similar activity against HeLa

cells were discovered.447 Mollenyne A 563 is a chlorodibromohydrin amide from Spirastrella

mollis (Plana Cays, Bahamas): the configuration was established using NMR, MS, CD

approaches and synthesis.448 The stereochemistry of (+)-bitungolide E (Theonella cf.

swinhoei)449 was confirmed by synthesis.450 The sulfur-containing α-pyrones lehualide E–K

564–570 were obtained from Plakortis sp. (‘Eua Is., Tonga). The lehualides were moderately

toxic to sensitised yeast cells but not to wild type and are therefore susceptible to efflux pump

action.451 Sixteen new cyclic peroxides, plakortolide K–S 571–579, seco-plakortolide K, L, O

and P 580–583 and plakortone L, N and P 584–586, were isolated from Plakinastrella

clathrata (Gneerings Reef, Mooloolaba, Australia).452 Detailed configurational investigation

also revealed that the structure for plakortolide E (Plakortis sp.)453 should be revised to 587

and the commonly assumed biosynthesis of the cyclic peroxide via Diels-Alder addition of

singlet oxygen is incorrect.452 Synthesis of four possible diastereomers of plakortide E 588

(Plakortis halichondrioides)454 established the absolute configuration as shown.455 Plakortide

F (P. halichondrioides)456 interfered with Ca2+ homeostasis to mediate the antifungal

activity.457 Simplextones A 589 and B 590 are unusual polyketide lactones from P. simplex

(Yongxing Is., South China Sea),458 and aurantoside J 591 is a chlorinated tetramic acid

glycoside from Theonella swinhoei (Sulawesi, Indonesia).459 The total synthesis and

confirmation of absolute configuration of (+)-zyggomphic acid (P. zyggompha)460 was

achieved.461 Diketopiperazine 592 came from Stelletta sp. (Jamieson Reef, Bonaparte

Archipelago, Australia).462 Synergistic antilarval settling activity was noted in situ at 120 m

depth for barettin and 8,9-dihydrobarettin (Geodia baretti).463–465 The structures of

dysideaproline E (Dysidea sp)466 and the potent cathepsin B inhibitor tokaramide A

(Theonella aff. mirabilis)467 were confirmed by synthesis.468,469 Two new peptides

solomonamide A 593 and B 594 were reported from T. swinhoei (Vangunu Is., Solomon Is.).

Solomonamide A showed anti-inflammatory activity.470 Four potent microfilament-disrupting

jasplakinolide (jaspamide) congeners V and Z3–Z5 595, 596, 597, 598 were obtained from

Jaspis splendens (Korovou Bay, Fiji) with 595 selected by the NCI for further evaluation. The

study also highlighted structural revisions for jasplakinolides R1 599 and W 600.471–473

Papuamides E 601 and F 602 are new depsipeptides from Melophlus sp. (Karumolum, Russell

Is., Solomon Is.).474 The potent HIV-1 inhibitory mirabamides E–H 603–606 were isolated

from Stelletta clavosa (Torres Strait, Australia).475 Polytheonamide B (T. swinhoei),476–478 was

synthesised.479 The potent cytotoxicity of polytheonamide B (68 pM vs. P388) is due to the

ability to form active H+ channels through cell membranes.480 The absolute configuration of

pinnarine 607 (Halichondria okadai, Mie Prefecture, Japan), was determined by synthesis

from authentic pinnaic acid.481 Insight regarding the pharmacophore of the microtubule

stabilisers peloruside C 608 and D 609 (Mycale hentscheli, Pelorus Sound, New Zealand) has

been aided by semi-synthesis of analogues from peloruside A.482,483 Study of a Madagascar

(Salary Bay, Tulear) Fascaplysinopsis sp. characterised tulearins B 610 and C 611 and

allowed configurational determination (X-ray) of tulearin A 612.484,485 Structural confirmation

of the least abundant congener 611 was achieved by synthesis.486 Precandidaspongiolides A

613 and B 614, and candidaspongiolides A 615 and B 616 are potent (nM) and selective

melanoma inhibitors from a Papua New Guinean Candidaspongia sp.487 The proposed

structure of leiodolide B (Leiodermatium sp.)488,489 was proven incorrect by synthesis but no

alternative was suggested.490 Leiodermatolide 617, a potent antimitotic with a unique mode of

action compared with other G2/M blocking agents, was isolated from Leiodermatium sp.

collected at –401 m using a submersible off Fort Lauderdale, Florida.491 Apo-latrunculin T

618 and 20-methoxyfijianolide A 619 were reported from Cacospongia mycofijiensis (New

Britain, Papua New Guinea),492 while the potent antimalarial kabiramides, J 620 and K 621,

were obtained from Pachastrissa nux (Chumphon Is., Surat-Thani Province, Thailand).493

Swinholide J 622, a potent antiproliferative against KB cells, was reported from T. swinhoei

(Vangunu Is., Solomon Is.).494 A collection of Hyrtios sp. (near Kia Is., Fiji) gave 5,6-

dibromo-L-hypaphorine 623,495 while 5,6-dibromotryptamine (Polyfibrospongia

maynardii)496 and 5,6-dibromo-N,N-dimethyltryptamine (Smenospongia echina)497,498 were

synthesised.499 The Red Sea sponge Suberea mollis yielded subereamines A 624 and B 625

and subereaphenol D 626.500 Stellettazole D 627, a new cytotoxin, was isolated from Jaspis

duoaster (Cape Sada, Ehime Prefecture, Japan).501 The enantioselective total synthesis of

iminosugar batzellaside B 628 (Batzella sp)502 established the absolute configuration,503 while

a racemic synthesis of chelonin C (Chelonaplysilla sp.)504 was also achieved.505 Both cis- 629

and trans-4-hydroxysalsolinol 630 were reported from a natural source (Xestospongia cf.

vansoesti, North Sulawesi, Indonesia) for the first time.506 The absolute configurations of the

bispiperidines xestoproxamine A–C 631–633 (Neopetrosia proxima, Stirrup Cay, Bahamas)

were established using a combination of degradation and CD measurements.507 From a study

of Neopetrosia exigua (Lingshui Bay, Hainan, China), a new xestospongin 634 was

characterised.508 The zwitterionic solution structures of saraine A–C509,510 (Reniera

(Haliclona) sarai, North Adriatic Sea) were established using extensive combinations of

NMR, HRMS and DFT calculations.511 Spironaamadine 635, a unique spiroquinone, was

reported from Leucetta microraphis (Sulawesi, Indonesia)512 and haliclocyclin C 636, a

monomeric alkylpyridinium antibiotic was obtained from Haliclona viscosa (Kongsfjord,

Spitsbergen).513 An Amphimedon sp. (Zamami, Okinawa), contained pyrinodemins E 637 and

F 638; pyrinodemin E was isolated as a racemate.514 A racemic synthesis of hyrtiazepine

(Hyrtios erectus)515 was achieved.516 Manzamine A (Haliclona sp)517 was shown to inhibit

cancer cell invasion and may therefore be a suitable therapeutic adjuvant.518 The structure of

citharoxazole 639 from Latrunculin cithariste (La Citotat, Banc de Banquiere, France), was

unequivocally determined using extensive heteronuclear NMR coupling data.519 A dredged

Biemna sp. (Oshima-Shinsone, S. Japan) yielded N-methylisocystodamine 640 and N-

methyoxymethylisocystodamine 641. Both were potent inducers of erythroid differentiation

in human leukaemia cells.520 The heteroaromatic nakijinamines C–E 642–644 are racemic

antibiotics from a Suberites sp. (Unten Port, Okinawa).521 The brominated pyrrole 645 was

reported from Agelas cerebrum (Boca de Calderas, Cuba).522 A highly sensitive in vivo

protocol using β-imaging with radio-labelled amino acids has shown that proline and lysine

were the precursors to the central metabolite oroidin (originally Agelas oroides,523,524 current

study Axinella damicornis), and not proline and histidine as previously thought.525 Oroidin

was shown to inhibit the drug exporter Pdr5p, an MDR component in yeast.526 A New

Caledonian Cymbastela cantharella yielded two pairs of diastereomeric hymenialdisine

congeners 646–649,527 while a Hyrtios sp. (Seragaki, Okinawa) gave the antimicrobial

hyrtioseragamines A 650 and B 651.528 Investigation of Monanchora pulchra collected by

dredging (Urup Is., Sea of Okhost) revealed monanchocidin B–E 652–655 which were potent

antileukaemia agents.529 Four new cyclic guanidine alkaloids, araisoamine A–D 656–659,

were isolated from Clathria (Thalysias) araiosa (Aore Is., Vanuatu).530 The Ca2+ channel

modulating and antiproliferative activities of the bastarane and isobastarane skeletons,

exemplified by bastadins 5 and 6 (Ianthella basta)531 and (E,E)-bastadin-19 (I. basta),532

respectively, were linked to stable solution conformers.533 Sixteen bromotyrosine compounds

660–675 were reported from Aplysina sp. (Ladd Reef, South China Sea).534 The syntheses of

subereamollines A and B (Suberea mollis)535 confirmed their absolute configurations.536

Pseudoceramines A–D 676–679 are bromotyrosine-derived alkaloids from Pseudoceratina sp.

(Erskine Is., Great Barrier Reef), with 677 inhibiting secretion of the virulence factor Yersinia

Outer Protein E.537 MS-directed isolation from Pseudoceratina sp. (Holmes Reef, Coral Sea,

Australia) led to the antimalarial psammaplysin H 680 (chloroquine resistant P.

falciparum).538 Study of an unidentified Dictyoceratid sponge (Gneerings Reef, Mooloolaba,

Australia) revealed the purine N-6-methyl mucronatine 681.539 The merosesquiterpenoids

metachromin U–W 682–684 were obtained from Thorecta reticulata (Hunter Is., Tasmania)

with 682 and 683 active against a variety of human tumour and mammalian cell lines.540 An

MS-proteomics approach showed that bolinaquinone (Dysidea sp.)541 inhibited clathrin-

mediated endocytosis.542 Nakijinol B 685 and smenospongines B 686 and C 687 are

antitumour merosesquiterpenoids from Dactylospongia elegans (Pugh Shoal, Northern

Territory, Australia).543 A deep water collection (-104 m, St Ann’s Bay, Jamaica) of

Neopetrosia proxima afforded benzoquinones neopetrosiquinone A 688 and B 689 with

micromolar activity versus five HTCLs.544 Diplopuupehenone 690 is an unsymmetric

puupehenone-dimer from Dysidea sp. (American Samoa).545 Two merosesterterpenoids 691

and 692 were reported from Coscinoderma sp. (Weno Is., Chuuk State),546 while halioxepine

693 was an antioxidant meroterpenoid hydroquinone isolated from Haliclona sp. (Baubau,

Buton Is., Indonesia).547 A Fasciospongia sp. obtained by dredging off southern Australia

yielded six meroditerpenoids fasciquinol A–F 694–699, with 694 and 695 having activity

against Gram-positive bacteria.548 The relative configuration of akaterpin 700 (Callyspongia

sp.)549 was established by synthesis.550 Aignopsanoic acid B 701 and aignopsane ketal 702 are

bicyclic sesquiterpenoids from Cacospongia mycofijiensis (New Britain, Papua New

Guinea).492 The new compound (–)-halichamine 703 has been reported along with (–)-

axisonitrile and (+)-axamide 3 (Halichondria sp., PP Is., Thailand), although the enantiomers

of the latter two had been isolated from sponges previously.551,552 The stereoselective

synthesis of both antipodes of spiniferin-1 (Pleraplysilla spinifera)553 with planar chirality has

shown that the natural product was isolated as a nearly racemic mixture (~ 1% e.e.).554

Halichonines A–C 704–706 (Halichondria okadai, Mie Prefecture, Japan) are rare examples

of a terpenoid alkaloid further elaborated with prenyl substituents.555 A Chinese (Lingshui

Bay, Hainan Province) Axinyssa variabilis yielded the sesquiterpenoid dimer trans-dimer D

707.556 The sesquiterpene dimers halichonadin G–I 708–710 are reported from Halichondria

sp. (Unten Port, Okinawa) along with the monomeric halichonadin J 711.557 Officinoic acids

A 712 and B 713 are linear diterpenes from Spongia officinalis (off Mazara del Vallo,

Sicily).558 A series of diterpenes and diterpene isonitriles (and one sesquiterpene), isolated

from Australian Cymbastela hooperi and Acanthella kletra, were evaluated for a broad range

of activities with all active in at least two assays.559 The racemic synthesis of 7-isocyano-

11(20),15-epiamphilectadiene (Adocia sp)560,561 was achieved,562 while diterpene isonitrile

714 was obtained from Pseudoaxinella flava (Sweeting Cay, Bahamas).563 A degraded nor-

spongian diterpene 715 was isolated from Spongia sp. (Suwarrow Atoll., Cook Is.).564 The

syntheses of the phospholipase A2 inhibitory spongidines A and D (Spongia sp.)565 were

achieved,566 as was the synthesis of the heavily rearranged spongian diterpene aplyviolene

(Chelonaplysilla violacea).567,568 The absolute configurations of cyanthiwigins B (Epipolasis

reiswigi)569 and G (Myrmekioderma styx)570 were confirmed by total synthesis.571 7,8-

Epoxyfurospongin-1 716 and isofurospongin-4 717 are linear furanoterpenoids from Spongia

officinalis (off Mazara del Vallo, Sicily).558 The absolute configuration of (–)-untenospongin

C (Hippospongia sp)572 was confirmed by total synthesis.573 A sample of Ircinia sp. (Orchid

Is., Taiwan) yielded three cytotoxic γ-lactone nor-terpenes, ircinolin A 718, 15-

acetylirciformonin B 719 and 10-acetylirciformonin B 720, while also establishing the

absolute configuration of irciformonin B 721 (I. formosana).574,575 A structure-activity

relationship was established for the hypoxia-selective growth inhibitor furospinosulin-1 (I.

spinosula)576 following total synthesis along with several analogues.577 An unusual S-oxide

722 was reported from Xestospongia sp. (Sikao Bay, Andaman Sea, Thailand).578 Hippolides

A–H 723–730 are manoalide derivatives from Hippospongia lachne (Yongxing Is., China).

Hippolide A was an inhibitor of protein tyrosine phosphatase 1B activity, a negative regulator

of insulin signal transduction.579 Phorbasones A 731 and B 732 were isolated from Phorbas

sp. (Gageo Is., S. Korea). Phorbasone A enhanced Ca2+ deposition in osteoblasts.580 Six

antibacterial sesterterpenes 733–738 were obtained from Coscinoderma sp. (Weno Is., Chuuk

State),546 while five new scalarane-type sesterterpenoids 739–743 were sourced from Hyatella

sp. (Soheuksan-Do, S. Korea).581 16-Deacetoxy-12-epi-scalarafuran acetate (Spongia

officinalis)582 was independently synthesised by two different groups.583,584 Also reported was

the synthesis of 16-deacetoxy-scalarafuran (Spongia sp.).585,586 The symbiotic pairing of the

sponge Sigmadocia symbiotica with the red alga Ceratodictyon spongiosum that produced the

pregnanes ceratosteroid A–D 474–477 has been described in the previous section.424 The

configuration at C-24 of 744, originally reported by Djerassi (Pseudoaxinyssa sp.),587 was

confirmed by synthesis.588 Solomonsterols A 745 and B 746 (T. swinhoei, Solomon Is.) are

potent pregnane-X-receptor (PXR) agonists.589 Solomonsterol A 745 was also synthesised.590

Desulfohaplosamate 747 is a selective cannabinoid CB2-receptor ligand from Dasychalina sp.

(Bunaken Marine Park, Manado, Indonesia).591 The theonellasterols B–H 748–754 and

conicasterols B–D 755–757 reported from T. swinhoei (Malaita and Vangunu Is., Solomon

Is.) had PXR-agonist/farnesoid-X-receptor antagonist activity.592 A unique PXR-agonist bis-

secosterol, malaitasterol A 758 was isolated from T. swinhoei (Malaita, Solomon Is.).593

Several of the saponins pandaroside K–M 759–761 and derivative methyl esters 762–764

from Pandaros acanthifolium (Martinique Is., Caribbean) had antiprotozoal activity,594 while

acanthifoliosides A–F 765–770 and F-methyl ester 771 were obtained from the same sponge

but were less active in the same assay.595 Both steroid dimers shishicrellastatin A 772 and B

773 from Crella (Yvesia) spinulata (Shishi Is., Kagoshima, Japan), inhibited cathepsin B.596

Pouosides F–I 774–777 and pouogenins A–E 778–782 are triterpene galactosides from

Lipastrotethya sp. (Weno Is., Chuuk State),597 while erylosides R1 783 and T1–T6 784–789 are

triterpene oligosaccharides from Erylus formosus (Puerto Morelos, Mexico).598 Stelliferins J–

N 790–794 are isomalabaricane-type triterpenes from Rhabdastrella cf. globostellata

(Ishigaki, Okinawa).599 The nona-prenylhydroquinone 795 was reported from Sarcotragus

spinosulus (Callejones, Ceuta, Mediterranean Sea).600

8 Cnidarians

There was a pronounced increase in the number of new metabolites reported from cnidarians

(290) compared with recent previous years. A series of simple alkaloids and purines,

including 796–798, was isolated as modest bacterial anti-adhesion constituents of

Paramuricea clavata (Marseilles, France and Ceuta, Spain).601 Bromotyramine 797 was a

monomethyl analogue of an ascidian metabolite,602 while 798 was previously known as a

synthetic product.603 Co-metabolite 1,3,7-trimethylisoguanine604 exhibited potent anti-

adhesion properties towards one particular strain of bacteria. New zoanthoxanthin alkaloids

799 and 800 and sesquiterpenes 801 and 802 were isolated from Echinogorgia pseudossapo

(South China Sea), with the latter exhibiting mild antilarval activity towards B. amphitrite.605

Isovalerianic acid esterified eicosanoids 803 and 804 (Dichotella gemmacea, Sanya, Hainan

province, South China Sea) exhibited very mild toxicity towards Artemia salina.606

Calamenene sesquiterpenes 805 and 806607 (Subergorgia reticulata, Kavaratti, Lakshadweep

Is., India) both inhibited settlement of B. amphitrite cyprids, but the potent activity of 806 was

attributable to toxicity.608 Clovanes 807 (rumphellclovane B) and 808, the latter previously

known as a synthetic product,609 were isolated (Rumphella antipathies, South Coast, Taiwan)

as weak suppressors of superoxide anion generation by human neutrophils.610 In two separate

accounts, flavalins A–J 809–818 were reported from the same collection of the soft coral

Lemnalia flava (Green Is., Taiwan).611,612 It was speculated that 811 and 812 could be

artefacts of methanol used in the purification process however incubation studies with 810 did

not yield either compound. Flavin A inhibited LPS-induced iNOS and COX-2 protein

expression, while both 809 and 810 protected cells from 6-hydroxydopamine-induced

neurotoxicity. The latter paper also reported determination of absolute configuration of known

co-metabolite 819.613 Structurally-related nardosinane-type sesquiterpenes paralemnolin Q–U

820–824 were reported from Paralemnalia thyrsoides (Green Is., Taiwan).614 Neuroprotective

effects were demonstrated for 820 and 822 and two known related metabolites.613,615 Three

separate papers reported sesquiterpenes menelloide A 825 and B 826, (+)-chloranthalactone B

827, menelloide C 828 and D 829 and (–)-hydroxylindestrenolide 830 from the same trawled

(Southern Taiwan) specimens of Menella sp.616–618 Both 827 and 830 are enantiomers of

known terrestrial plant metabolites.619,620 Moderately cytotoxic α-tocopherols,

crassumtocopherol A 831 and B 832 (Lobophytum crassum, Dongsha Atoll, Taiwan) were

assigned absolute configurations.621 The unusual tetracyclic farnesylquinol capilloquinol 833

(Sinularia capillosa, Dongsha Atoll, Taiwan) exhibited mild cytotoxicity towards the P388

cell line.622 A diverse array of cembranoid diterpenes were reported from cnidarins in 2011.

Tello et al. rigorously refined or defined the absolute configuration of C-8 epimeric

plexaurolone cembranoids 834–841 isolated from Pseudoplexaura flagellosa (Santa Marta

Bay, Colombia).623 While (8R)-cembranes 835–837 and 839 are new, the remaining examples

have been reported previously but with either incomplete or contradictory characterisation.624–

626 Several of the natural products inhibited biofilm formation by P. aeruginosa, Vibrio

harveyi and S. aureus and interfered with quorum sensing in Chromobacterium violaceum

without affecting organism growth. Specimens of Eunicea sp. collected at the same

Colombian site as the preceding organism yielded the new cembradiene 842.627 The absolute

configuration of the co-occuring but previously reported antimalarial analogue 843628 was

determined. The absolute configuration at the furanaone C-2 position of the mildly cytotoxic

ent-sarcophine analogue 844 (Sarcophyton glaucum, Hurghada, Red Sea) was established by

ECD analysis.629 Ether and carbamate semi-synthetic derivatives of sarcophine (S.

glaucum)630 were identified as non-toxic inhibitors of tumour cell migration in a model of

metastasis.631 Of the seven new α-methylene-γ-lactone-bearing cembranoids

sarcocrassocolide F–L 845–851 (S. crassocaule, Dongsha Atoll, Taiwan), only 849 and 851

failed to exhibit cytotoxicity towards a panel of tumour cell lines, highlighting the SAR

significance of 13-acetoxy substitution and C-8 configuration.632 All seven metabolites

inhibited LPS-induced up-regulation of the pro-inflammatory protein iNOS. 13-

Acetoxysarcocrassolide (S. crassocaule)633 exhibited antiproliferative activity towards bladder

female transitional cancer cells via induction of apoptosis and exerted an anti-migration effect

on the cells.634 Proteomic analysis identified a number of pro-apoptotic elements that were up-

regulated in the presence of the diterpene. cis-Fused α-methylene-γ-lactones crassocolide N–

P 852–854 (S. crassocaule, Kenting, Taiwan) exhibited cytotoxicity, though in a somewhat

cell-line specific manner.635 Crassocolide P shares identity with an un-named cembrane

reported in 2010 by the Miyamoto group (Lobophytum crassum).636 Triangulenes A 855 and

B 856 (Sinularia triangula, Taitung County, Taiwan) are C-8 epimers of previously

reported628,637 soft coral metabolites.638 It should be noted that the spelling of the species

name was corrected in a subsequent paper by the group.639 Discrepanolide A 857 is a new ε-

lactone-containing cembranoid isolated from Sinularia discrepans (Taitung County,

Taiwan).640 The same study also reported that the structurally related co-metabolites

sinulariolide, 11-dehydrosinulariolide and 11-epi-sinulariolide acetate641,642 inhibited the

accumulation of pro-inflammatory inducible NO synthase protein in LPS-stimulated

macrophages. The apoptotic effects of 11-dehydrosinulariolide towards oral squamous cell

carcinoma was investigated by proteomic analysis identifying numerous up-and down-

regulated proteins.643 Nineteen examples of C-19 (olefin methyl) oxidised cembranoids

sinulariol A–S 858–876 were characterised from an extract of S. rigida (Sanya Bay, Hainan

Is., China).644 Mild antifouling activity towards B. amphitrite and Bugula neritina was shown

by 867 and 873 respectively. Of the eight cembrane diterpenes crassarine A–H 877–882, 860

and 883 reported from S. crassa (Sansiantai, Taitung County, Taiwan),645 crassarine G 860

appears to share identity with sinulariol C 860 (published four months earlier, NMR data in

different solvents).644 Rare chlorinated norcembranes chloroscabrolide A 884 and B 885 and

prescabrolide 886 were isolated from Sinularia sp. (Siladen Is., Manado, Indonesia).646

Relative configuration was assigned to 884 by comparison of experimental 13C NMR data

with DFT-calculated chemical shifts. Hydroxycembranes 887 and 888 were isolated from

Sinularia facile (Pingtung County, Taiwan).647 As part of a study to discover inhibitors of

HIF-2α induced gene expression, lactone 889 (Sarcophyton sp., Darwin Harbour, Northern

Territory, Australia) and artefactual methylether 890 (Lobophytum sarcophytoides, Luconia

Bombie, Sarawak, Malaysia) were identified as inactive soft coral secondary metabolites.648

The study identified known xenicin-type diterpenes649,650 as relatively potent gene expression

and tumour cell growth inhibitors. Extracts of Lobophytum crassum (Gueishan Is., Taiwan)

yielded epoxyhydroxycembranes locrassolide A 891 and B 892 and the known cembranolide

B (S. mayi),651 with the latter being found to inhibit the accumulation of pro-inflammatory

proteins iNOS and COX-2 in stimulated macrophages.652 Two independent collections of L.

crassum from Dongsha Atoll (South China Sea) yielded crassumolides G–I 893–895653 and

crassumols A–C 896–898 and 13-acetoxysarcophytoxide 899.654 Crassumolides G and H are

trivial acetylated analogues of the co-metabolite 'sinularolide B'655,656: all three crassumolides

inhibited the accumulation of iNOS in simulated macrophages. Modest cytotoxicity was

reported for 899. Mild to moderate cytotoxicity was observed for lobocrassins A–E 900–904

(L. crassum, northeast Taiwan).657 While lobocrassin A can be considered a chlorohydrin

derivative of sarcocrassolide (S. crassocaule),633 lobocrassin B is the C-14 epimer of 14-

deoxycrassin and lobocrassin C is the enantiomer of pseudoplexaurol (both from

Pseudoplexaura porosa).658 A Dongsha Atoll, Taiwan collection of Lobophytum sp. yielded

tetrahydrofuran-containing cembranes lobophylin A–D 905–908 and secocembrane

lobophylin E 909.659 Cultured specimens of L. crassum (originally collected at Pingtung,

Southern Taiwan) yielded culobophylins A–C 910–912660 each of which are either more

highly oxidised analogues or isomers of co-metabolites lobophylin A and B.659 Durumolides

M–Q 913–917 (L. durum, Dongsha Atoll, Taiwain) could be artefacts derived from methanol

addition to 'sinulariolide B', however the authors could not replicate the transformation.661

Durumolide Q showed mild antiviral activity. Furan analogues laevigatol A–D 918–921, in

addition to known cembranes (+)-sarcophine,630 emblide662 and biscembranes ximaolide F,663

methyl tortuoate B664 and nyalolide,665 were isolated from L. laevigatum (Khanh Hoa

province, Vietnam).666 Modest cytotoxicity towards HL-60 cells was observed for (+)-

sarcophine and emblide, while the biscembranes were more generally cytotoxic towards a

panel of tumour cell lines. An ethanolic extract of Lobophytum pauciflorum (Hainan Is.,

South China Sea) yielded biscembranoids lobophytone U–Z1 922–928 as well as the

structurally-related known congeners methyl sartortuoate and nyalolide.667 All nine natural

products proved to be essentially equipotent moderate inhibitors of NO production by LPS-

stimulated mouse macrophages. Diterpenes lobocompactol A 929 and B 930 were identified

as mildly cytotoxic and moderate peroxy radical scavenging metabolites of L. compactum

(Bay Canh Is., Khanh Hoa, Vietnam).668 The structurally-related prenylgermacrane-type

diterpenes lobophytumin A 931 and B 932, dimeric analogues lobophytumin C 933 and D

934 and tricyclic lobophytumins E 935 and F 936 were isolated from L. cristatum (Lingshui

Bay, Hainan Province, China).669 Absolute configuration was assigned to 933 by comparison

with (–)-β-selinene, a volatile constituent of celery.670 Lobophytumins C and D exhibited

modest levels of cytotoxicity towards two HTCLs. Fuscoside E 937 was isolated as a strongly

anti-inflammatory (TPA-induced mouse ear edema) constituent of Eunicea fusca (Santa

Marta Bay, Colombian Caribbean).671 Fuscoside E 937, co-metabolite (+)-germacrene D and

a sterol mixture also showed antibacterial activity towards a range of biofouling marine

bacteria. Semi-synthesis of unnatural glycosylated and PEG derivatives of fuscol and eunicol

(E. fusca) has identified the importance of the carbohydrate group and α-anomeric

configuration to the observed anti-inflammatory activity of this compound class.672 Further

investigation of extracts of Sinularia triangula (Taitung County, Taiwan) that afforded

cembranes 855 and 856 (see earlier) also yielded a new carbon skeleton. This was the weakly

cytotoxic diterpene sinutriangulin A 938.639 In two separate accounts, a southeastern Taiwan

collection of Asterospiuclaraia laurae was found to contain xenicane diterpenes asterolaurin

G–M 939–945.673,674 Of the seven, only asterolaurin L 944 exhibited (mild) cytotoxicity

towards a panel of HTCLs. Eunicellin-skeletoned diterpenes klysimplexin I–X 946–961 were

isolated from cultured specimens of Klyxum simplex.675,676 While 954 and 957 were the only

examples to exhibit (mild) cytotoxicity, 947–951, 955 and 956 inhibited the LPS-induced up-

regulation of the pro-inflammatory protein iNOS. (–)-6α-Hydroxypolyanthellin A 962 was

isolated as a moderate barnacle antifouling constituent of Cladiella krempfi (Kavaratti Is.,

Lakshadweep, India).677 Diterpenes isolated from a single collection of Cladiella sp. from an

unspecified Indonesian location were the subject of three publications in 2011. Of the six

cladieunicellins A–F 963–968 reported, 963–965 and 967 exhibited mild cytotoxicity, while

965 and 968 were found to be relatively potent inhibitors of superoxide anion generation by

stimulated neutrophils.678,679 The second study also reported the structure of (–)-solenopodin

C 969,679 the enantiomer of a known Solenopodium stechei metabolite,680 and also corrected

the structures of cladielloides A and B (previously reported from the same extract)681 to 970

and 971 as shown. The third paper in the series detailed the isolation of cladielloides C 972

and D 973: while the former exhibited more pronounced cytotoxicity than the latter, both

were found to inhibit superoxide generation and elastase release from stimulated

neutrophils.682 Of the butanoyl esters krempfielin A–D 974–977 and known analogues683,684

of 975 and 976 (Cladiella krempfi, Penghu Is., Taiwan), all but 974 inhibited the

accumulation of iNOS in stimulated macrophages.685 The same biological effect was observed

for eunicellins klymollin A–H 978–985 (Klyxum molle, Penghu Is., Taiwan).686 Klymollins F

and G also inhibited accumulation of COX-2 protein in stimulated macrophages. Un-named

metabolites 986–990 (Litophyton viscudium, Otsuki Town, Kochi Prefecture, Japan), simple

congeners of previously reported litophynin687 and litophynol683 diterpenes, were found to

exhibit modest to moderate levels of cytotoxicity towards the HL-60 cell line.688 Of the six

highly substituted eunicellins simplexin J–O 991–996 isolated from K. simplex (Dongsha

Atoll, Taiwan), the latter three were shown to inhibit the accumulation of iNOS in stimulated

macrophages.689 Previously reported cembranes sarcophytol A, sarcophytol A acetate,690

sarcophytol H691 and sarcophytonolide J692 exhibited modest antifouling activity against B.

amphitrite.693 A library of known pseudopterosin and seco-pseudopterosin diterpenes

(Pseudopterogorgia elisabethae) demonstrated moderately potent non-selective cytotoxicity

towards a panel of malignant and non-malignant cell lines and activity towards Gram-positive

bacteria but were inactive against Gram-negative bacteria and yeast.694 Facile methodology

has been reported that can convert the pseudopterosin G–J aglycone to a range of novel

pseudopteroxazole and isopseudopteroxazole analogues, some of which show more potent

and wider spectrum of antibacterial activity than the original natural products.695 Waixenicin

A (previously reported from Anthelia edmondsoni)696 inhibited cell proliferation due to potent

inhibition of TRPM7 channels, which represent the major magnesium-uptake mechanism in

mammalian cells.697 Brialalepolides A–C 997–999 (Briareum sp., Vanuatu) exhibited

moderate levels of cytotoxicity towards Caco-2 cells while 998 and 999 decreased the

expression of COX-2 in RAW 264.7 murine macrophages.698 Absolute configuration was

established for 997 (X-ray, Hooft method) and on biogenetic grounds applied to the other two

metabolites. Five briaranes dichotellide A–E 1000–1004, unusually containing an iodo

substituent, were isolated from Dichotella gemmacea (Meishan Is., South China Sea).699 The

same species of gorgonian, collected at an unspecified site in the South China Sea, yielded

gemmacolides G–S 1005–1017.700,701 The structure of gemmacolide H was unfortunately

identical702 to that of 12-epi-fragilide G, previously reported from Ellisella robusta.703 Mild to

moderate cytotoxicity was observed for gemmacolides G–K and Q–S. Absolute configuration

was assigned to gemmacolide N 1012 via TDDFT calculation of ECD spectra, with similar

configurations assigned to gemmacolide O–S by comparison of ECD spectra.701 Of the four

briaranes frajunolide L–O 1018–1021 reported from Junceella fragilis (Tai-Tong County,

Taiwan),704 frajunolide O appears to be identical to nui-inoalide C reported by the Scheuer

group in 1996.705 Un-named briarane 1022 (J. juncea, Tuticorin coast, Indian Ocean)

inhibited the growth of fungi but was inactive towards bacteria.706 In addition to several

known congeners, briareolate esters L–N 1023–1025 were isolated from Briareum asbestinum

(Boca Raton, Florida).707 Briareolate ester L was observed to react reversibly with thiol

nucleophiles, while Hg lamp irradiation yielded the corresponding (Z,Z)-dienone isomer. This

photoisomerisation product, which lacked thiol reactivity, was identical to co-metabolite

briareolate ester G, the present study helping define (Z,Z)-geometry of the previously reported

diterpene (B. asbestinum, Tobago).708 Briareolate ester L was the most active of the series of

metabolites in inhibiting cell growth, suggestive of the importance of the Michael acceptor

functionality for bioactivity. A diverse array of 9,10-seco-sterols and a putative biogenetic

sterol precursor astrogorgol A–N 1026–1039 were isolated from Astrogorgia sp. (Beibuwan

Bay, Guangxi, China).709 A selection of the metabolites were found to exhibit potent

inhibition of four kinases (ALK, SRC, VEGF-R2, IGF-1R) from a larger set of sixteen. The

9,11-seco leptosterols A–C 1040–1042 were isolated from Sinularia leptoclados (Dongsha

Atoll, Taiwan): leptosterol B possessed moderate cytotoxicity towards the P388 cell line.710

Further examples of modestly cytotoxic 9,11-secosterols and the putative biogenetic precursor

sterols hirsutosterol A–G 1043–1049 were isolated from Cladiella hirsute (Taiwan).711 The

antibacterial spiropregnane carijodienone 1050 and pregnane 1051 were sourced from Carijoa

multiflora (Archipelago Las Perlas, Panama).712 Photolysis of a second known pregnane713

co-metabolite yielded 1050. Two ∆22 sterols 1052 and 1053 were isolated from Sinularia

brassica (Naozhou Is., Zhanjiang, China).714 None of the A-ring phenolic or dienone sterols

1054–1062 (Dendronephthya studeri, Xiaodong Sea, Hainan, China) exhibited cytotoxicity,

but 1062 was described as a natural product for the first time.715,716 Mild cytotoxicity was

observed for the cross conjugated dienones 1063 and 1064 (Sinularia sp., Naozhou Is.,

Zhanjiang, China)717 and 1065 (Paraminabea sp., Okinawa).718 In addition to known

congeners the minabeolides (Minabea sp.),719 steroidal lactones paraminabeolide A–F 1066–

1071 were isolated from Paraminabea acronocephala (Pingtung county, Taiwan).720 The

17,20-epoxysterols hipposterone M–O 1072–1074, hipposterol G 1075 and hippuristeroketal

A 1076 were isolated from Isis hippuris (Orchid Is., Taiwan)721 and the related analogue

lobophytosterol 1077 was reported from Lobophytum laevigatum (Khanh Hoa province,

Vietnam).722 Hipposterone N exhibited mild antiviral activity (human cytomegalovirus) while

lobophytosterol exhibited cytotoxicity by induction of apoptosis. I. hippuris was also the

source of polyhydroxylated sterols 1078–1081 (Izena Is., Okinawa)723 and 1082–1087

(Orchid Is., Taiwan).724 Sterols 1078–1081 were mildly cytotoxic while 1084 exhibited

antiviral activity (human cytomegalovirus). In contrast to the more regular β-D-

arabinopyranoside muricellasteroids A–D 1088–1091 (Muricella flexuosa, Sanya, Hainan

province, China), muricellasteroid E 1092 contains an unusual 4-hydroxyphenylmethylene

moiety.725 While 1088–1091 were claimed to have the β-D-arabinopyranoside units (as shown

here), the diagrams provided showed L-ribopyranoside units. The C-3 β-D-arabinopyranosides

fragilioside A 1093 and B 1094 (Dichotella fragilis, Meishan, Sanya, China) were essentially

biologically inactive in toxicity and antifouling assays, though co-metabolites juncin P726 and

junceellolide D727 demonstrated potent antifouling activity.728 As for the previously described

compounds 1088–1091, no evidence was provided to support the claimed configuration of the

D-arabinopyranoside units. The sesquiterpene lemnalol (Lemnalia tenuis)729 exhibits activity

in a rat model of neuropathic pain, where it appears to inhibit pro-inflammatory responses in

microglial cells and astrocytes.730 Syntheses of the structures proposed for one of the un-

named conjugated triyne butenolides isolated from Sarcophyton trocheliophorum731 and the

macrolactone lytophilippine A (Lytocarpus philippinus)732 have shown both structures to be

incorrect.733,734 Two syntheses of norcembrenolides have been reported, providing

clarification of the structures of the natural products and congeners but also inadvertently

leading to the introduction of trivial name synonymy. In the first account, Lee's group

reported735 the stereospecific synthesis of one of the natural products originally described as

an un-named metabolite of Sinularia sp. by the Fenical group in 1985.736 The synthetic

material possessed opposite sign of optical rotation to that of the natural product, defining the

absolute configuration of the natural product as shown 1095. Lee's group attributed a trivial

name of 10-epigyrosanolide E to the natural product. Shortly thereafter, Theodorakis' group

disclosed their stereoselective (rac) synthesis of the same natural product, which they named

norcembrenolide B, and the synthesis of a second un-named cembranoid 1096 also contained

in the original Fenical paper.737 Theodorakis' group assigned the trivial name

norcembranolide C to this natural product. Close inspection of NMR data of their synthetic

material, which has a relative configuration in which the epoxide oxygen is on the opposite

face to the lactone carbonyl oxygen, revealed it to share identity with scabrolide D (S.

scabra).738 Thus the structure of scabrolide D, originally proposed to have syn-facial epoxide

and lactone oxygen stereochemistry should be revised to the previously reported

norcembrenolide 1096. In an extension to studies previously undertaken by Rodríguez,739 the

cembranoid rubifolide upon exposure to UV irradiation740 undergoes Z/E isomerisation

followed by either photooxidation to yield epilophodione (Gersemia rubiformis)741 or by

[1,3]-sigmatropic ring-contraction to yield kallolide B (Pseudopterogorgia kallos).742 The

bromoindoleacetamide bunodosine 391 1097, isolated from venom of the sea anemone

Bundosoma cangicum (São Sebastião, São Paulo state, Brazil) exhibits a potent analgesic

effect, likely mediated via serotonin receptors.743 The structure and configuration were

confirmed by synthesis. Hct-S4 is a new 19.4 kDa actinoporin, isolated from haemolytically

active extract fractions of the anemone Heteractis crispa (South China Sea).744

9. Bryozoans

As in past reviews, there have been few investigations of bryozoan chemistry reported, but

numbers have increased slightly this year. Amathia tortusa (Bass Strait, Tasmania, Australia)

yielded the brominated alkaloids convolutamine I 1098 and J 1099 which both displayed

activity against the parasite T. brucei brucei, but only convolutamine I 1098 was cytotoxic

against HEK293 cells.745 A population of A. wilsoni (Point Peur, Tasman Penninsula,

Tasmania, Australia) provided the alkaloids wilsoniamine A 1100 and B 1101 and

amathamide H 1102 and C 1103. Wilsoniamines A and B represent a new class of alkaloid

with a bicyclic ring system not previously found in nature. Amathamide C 1103 was

previously isolated from A. wilsoni746 but spectroscopic data analysis of amathamides H 1102

and C 1103 indicated that each contained a 2,4,6-tribromo-3-methoxyphenyl moiety rather

than the 2,3,4-tribromo-5-methoxyphenyl moiety previously assigned to other amathamides.

Structures of amathamide C–F therefore, should be revised to 1103–1106. Amathamides C

and H were moderate growth inhibitors of chloroquine sensitive and resistant strains of P.

falciparum.747 The Arctic bryozoan Tegella cf. spitzbergensis (Bear Is., North Atlantic)

afforded the brominated tryptophan-derived metabolites ent-eusynstyelamide B 1107 and

eusynstyelamide D–F 1108–1110. Eusynstyelamide B has previously been isolated from the

Australian ascidian Eusynstyela latericius,748 and although absolute configuration

determination of ent-eusynstyelamide B 1107 was unsuccessful, it could be assigned as the

enantiomer from a CD spectrum with opposite maxima to those reported for eusynstyelamide

B. Ent-eusynstyelamide B 1107 and eusynstyelamide D–F 1108–1110 were growth inhibitiors

of S. aureus with ent-eusynstyelamide B 1107 and eusynstyelamide F 1110 possessing the

best activity. Ent-eusynstyelamide B 1107 and eusynstyelamide E 1109 were modest

inhibitors of C. albicans growth whilst eusynstyelamide D 1108 and eusynstyelamide E 1109

were weakly active against the melanoma cell line A-2058.749 The oxygenated sterols 1111

and 1112 from Bugula neritina (Daya Bay, Shenzhen, Guangdong Province, China) were

cytotoxic (weak) to two HTCLs,750 while the bryozoan Cryptosula pallasiana (Huang Is.,

Shandong, China) gave a new sterol 1113 and four known sterols, 7β-methoxy-cholesta-5-en-

3β-ol,751 (23E)-3β-hydroxy-27-norcholesta-5,23-dien-25-one,752 (24R)-cholesta-5,25-diene-

3β,24-diol753 and (24S)-cholesta-5,25-diene-3β,24-diol,753 that have been synthesised

previously but have now been isolated as natural products.754 After many years of synthetic

interest, the antineoplastic and anti-Alzheimers lead compound bryostatin 1 (Bugula

neritina)755 has been synthesised by a highly convergent route in 30 steps, from commercially

available (R)-isobutyl lactate.756 The total synthesis of bryostatin 9757 was accomplished via a

step-economical and convergent Prins-driven macrocyclisation strategy (42 total steps).758 A

bromotryptamine metabolite of Amathia alternata, alternatamide D,759 has also been

synthesised.499

10 Molluscs

The last three years have seen a decline in the number of new metabolites reported from

molluscs. Minor carotenoids 1114–1116 were isolated from Mytilus galloprovincialis (Black

Sea, Ukraine), with absolute configurations attributed to 1114 and 1115 via comparison of

ECD spectra with previously reported data.760 Bathymodiolamides A 1117 and B 1118 were

isolated from the mussel Bathymodiolus thermophilus collected at 1700 m depth by DSV

Alvin near hydrothermal vents on the Mid-Atlantic Ridge,761 and both ceramides inhibited

tumour cell growth. The dinoflagellate-derived diarrhetic poison okadaic acid was acylated by

the mollusc Mytilus galloprovincialis, a process attributable to the action of digestive gland

cells that express acyltransferase activity.762 Treatment with antibiotics did not abrogate

activity, suggesting bacteria play no role in this excretion pathway. Investigation of the

herbivorous cephalaspidean mollusc Bulla occidentalis (Yucatan coast, Gulf of Mexico)

yielded the known polypropionates niuhinone A and B and a new congener niuhinone C

1119.763 The original published source of niuhinones A and B was the carnivorous mollusc

Philinopsis speciosa,764 with the current results suggesting the true origin of the metabolites

in P. speciosa is dietary, acquired from an undetermined species of Bulla. Three new

mycosporine-like amino acids aplysiapalythine A–C 1120–1122 were isolated from the

defensive ink secretion of the sea hare Aplysia californica (Southern California).765 Alarm cue

properties were attributed to 1120 and 1121, but not 1122, although no data were reported.

Synthetic haminol A (Haminoea navicula)766 induces an avoidance response in the well-

characterised biological model organism Caenorhabditis elegans.767 The first synthesis of the

cytotoxic macrolide dolabelide C (Dolabella auricularia)768 has been reported, with the

phosphate tether-mediated route also affording a non-natural E/Z isomer.769 Replacement of

the dolaphenine subunit of dolastatin 10 (D. auricularia)770 with aminoquinoline or tyramine

phosphate groups led to the identification of analogues that exhibited potent cytotoxicity, and

in the case of the phosphate derivatives, also with enhanced water solubility.771 Preclinical

anticancer development of dolastatin 16 (D. auricularia)273 will be accelerated with the report

of an X-ray structure of the depsipeptide (as noted earlier in the Microorganisms section),

establishing absolute configuration, and scalable syntheses of two unusual amino acid

subunits, dolamethylleuine and dolaphenvaline.275 Semi-synthetic reductive alkylation of

kahalalide F/isokahalalide F (Elysia rufescens) yielded two analogues that exhibited growth

inhibition properties towards fungi, potent in vitro antitumour activity and modest in vivo

activity in a hollow fibre assay.772 An aurilide (D. auricularia)773-functionalised affinity

matrix has identified prohibitin 1 (PHB1) to be a target of the apoptosis-inducing

depsipeptide.774 As a consequence of binding to PHB1, aurilide activates proteolysis of optic

atrophy 1, a dynamin-like GTPase, leading to permeabilisation of the outer membrane and

cell death. The first examples of marine natural products bearing a 1,2,4-oxadiazole ring,

phidianidine A 1123 and B 1124, were isolated as sub-micromolar cytotoxins from the aeolid

nudibranch Phidiana militaris (Hainan Is., South China Sea).775 Investigation of the chemistry

of a single specimen of the nudibranch Actinocyclus papillatus (Wei Zhou Is., South China

Sea) yielded the modestly cytotoxic isonitrile-containing lipid actisonitrile 1125.776 Absolute

configuration was assigned by total synthesis and comparison of chiroptical properties.

Dotofide 1126, a guanidine-interrupted terpenoid, was isolated from the nudibranch Doto

pinnatida (Ferrol, Spain), but not from its hydrozoan prey Nemertesia antennina.777 The

absolute configuration of dotofide was assigned by chemical degradation to a known

diketone. The aeolid nudibranch Phyllodesmium magnum (Xiaodong Hai, Hainan province,

China) afforded 1127, a member of the relatively rare asteriscane sesquiterpene family.778

Unusual pyran-ring containing cladiellane diterpenes tritoniopsin A–D 1128–1131 were

isolated from both the nudibranch Tritoniopsis elegans and its soft coral prey Cladiella

krempfi (Wei Zhou Is., South China Sea).779 Two specimens of Chromodoris reticulata

(Gneerings Reef, SE Queensland) yielded new diterpenes 1132 and 1133, chromoculatimine

A 1134 and B 1135, and 1136 and 1137 in addition to seventeen previously reported

dendroceratid sponge and nudibranch metabolites.780 Tissue localisation studies located

fifteen of the diterpenes solely in mantle tissue, one (ambliofuran, Dysidea amblia)781 only in

internal organs, with the remaining seven metabolites spread across both tissue types.

11 Tunicates (ascidians)

The thirty-seven new tunicate-derived natural products presented in this review is

approximately the number reported per annum over the last decade. 4-Bromo-3-pentylphenol

1138, cyclopropyl fatty acid 1139 and cyclopentenones 1140 and 1141 were isolated from

two collections of Diplosoma sp. (Hateruma Is., Okinawa).782 The structure of phenol 1138

was confirmed by synthesis, while biological testing identified 1138 as a potent inhibitor of

cell division in a fertilised sea urchin egg assay and 1140 as mildly cytotoxic. 1H NMR

analysis identified 1140 and 1141 in the Prochloron sp. associated with the ascidian. New

examples of palmerolide macrolides D–G 1142–1145 were reported from the Antarctic

ascidian Synoicum adareanum.783 The relative configurations of 1142–1145 were related to

the corrected stereostructure of palmerolide A.784–786 Comparative evaluation of vacuolar

ATPase activity and cytotoxicity towards a melanoma cell line identified palmerolide D to be

a less potent inhibitor of V-ATPase while being a more potent cytotoxin compared to

palmerolide A, suggestive of multiple modes of cytotoxicity. Palmerolide E 1143 was a poor

inhibitor of V-ATPase and only mildly cytotoxic, a finding confirmed by the Chen group in

their synthesis and biological evaluation of 1143 and a number of analogues.787 This latter

study identified benzamide analogues that exhibited similar or superior cytotoxicity profiles

relative to palmerolide A. In addition to three known structurally-related Sargassum brown

algal metabolites,788,789 tuberatolides A 1146 and B 1147 and 2'-epi-tuberatolide B 1148

(Botryllus tuberatus, Tong-Yong City, South Sea of Korea) were identified as potent

antagonists of farnesoid X receptor, a bile acid sensor which plays a role in cholesterol

homeostasis.790 Absolute configuration of the new metabolites was assigned by ECD analysis.

Quinol sulphate 1149 and dimeric meroterpenoids scabellone A–D 1150–1153 were isolated

from Aplidium scabellum (Hauraki Gulf, New Zealand).791 Scabellone B exhibited moderate

activity towards a drug resistant strain of P. falciparum. In addition to three simple phenyl-

and indole-glyoxylic acid derivatives, zorrimidazolone 1154 was isolated as a weakly

cytotoxic racemate (Polyandrocarpa zorritensis, Bay of Taranto, Mediterranean Sea).792

Herdmanines A–D 1155–1158 were simple amino acid derivatives (Herdmania momus, Jeju

Is., Korea) that contain D-arginine or L-tyrosine moieties.793 Both 1157 and 1158 exhibited

mild anti-inflammatory properties including the ability to inhibit the production of pro-

inflammatory cytokines. The relatively rare 6-bromo-5-hydroxyindole moiety present in

herdmanine D was also contained within another ascidian metabolite, kingamide A 1159

(Leptoclinides kingi, Hook and Hardy Reefs, Queensland).794 Indole-glyoxamidospermidine

analogues didemnidine A 1160 and B 1161 were isolated from Didemnum sp. (Tiwai Pt.,

Southland, New Zealand); didemnidine B exhibited mild antimalarial activity.795 A bicyclic

oxazolidinone analogue synoxazolidinone C 1162 was isolated from sub-Arctic Synoicum

pulmonaria (Troms, Norway).796 Absolute configuration was assigned by analogy with

previous congeners reported from the same organism;797 1162 exhibited modest antibacterial

and antitumour activities. Of the four new metabolites 7-bromohomotrypargine 1163 and

guanidinylated β-carbolines opacaline A–C 1164–1166, isolated from Pseudodistoma opacum

(Auckland, New Zealand), the latter three exhibited mild antimalarial activity.798 Tetrahydro-

β-carboline 1163 was the dominant metabolite present in extracts of separated zooids, while

1164–1166 were concentrated in the test. Re-examination of an Okinawan collection of

Eudistoma glaucus (Ie Is., Okinawa) afforded the fused tetracycles eudistomidin H 1167 and I

1168, eudistomidin J 1169 (the sulfoxide of eudistomidin C799) and acyl-β-carboline

eudistomidin K 1170.800 Of the four metabolites, eudistomidin J exhibited cytotoxicity

towards tumour cell lines, being nearly an order of magnitude more active than eudistomidin

C. The absolute configuration of eudistomin X 1171 (Eudistoma sp.)801 was established as

(10R) by stereospecific synthesis.802 Variation in magnitude and sign of specific rotation was

observed for free base, mono- or disalt forms of the alkaloid, raising a cautionary note for

assignment of absolute configuration by simple comparison of optical rotation values. 3-

Bromohomofascaplysin A 1172, homofascaplysin A803,804 and fascaplysin805 (Didemnum sp.,

Pratt Reef, Fiji) are potent growth inhibitors of all life stages of a multiple drug resistant strain

of P. falciparum, with homofascaplysin A being particularly potent towards ring stage

parasites.806 The absolute configurations of 1172 and homofascaplysin A were determined by

comparison of calculated vs experimental ECD data. A purple chromotype of Cystodytes

dellechiajei (Catalonia, Western Mediterranean) contained, in addition to a number of known

pyridoacridine alkaloids, 13-didemethylaminoshermilamine D 1173 and

demethyldeoxyamphimedine 1174.807 The putative biosynthetic relationship between co-

metabolite styelsamine D808 and 1174 was supported by conversion of the former to the latter

when formalin was added to the organic extract of the ascidian. N,N'-Methyleno-didemnin A

1175, previously known as a semi-synthetic analogue of didemnin A, was isolated as a

potently cytotoxic constituent of Trididemnum solidum (Little San Salvador, Bahamas).809

The structures and stereo-configuration of clavaminols A and C, cytotoxic alkylamino

alcohols isolated from Clavelina phlegraea,810 have been confirmed by total synthesis.811 Two

independent syntheses812,813 of the protein kinase inhibitor meridianin F (Aplidium

meridianum)814 made use of a seldom-utilised 1930s reaction815 for the preparation of the 5,6-

dibromoindole core moiety. An extensive investigation of bromo, nitro or amino-substituted

meridianin816-like alkaloids identified 6- and 7-bromo analogues as potent and relatively

selective kinase inhibitors, although there was poor correlation with whole cell

antiproliferative data.817 A one-pot multicomponent reaction of

alkylsulfonamidoacetophenones, aldehydes and activated methylene compounds provided a

rapid entry into tetrasubstituted pyrroles,818 exemplified by the first syntheses of rigidins B–D

(Cystodytes sp.).819 The first synthesis of the pentasubstituted, pyrrole-containing ascidian

metabolite lamellarin S (Didemnum sp.)820 utilising combinations of Suzuki-Miyaura cross-

coupling and Heck cyclisation steps was reported.821 Structure-activity relationship

investigation of lamellarin 20-sulfate (unidentified ascidian)822 has established that anti-HIV-

1 activity requires sulfation but appears to be independent of position of the sulfate group and

that in addition to the previously reported effect on integrase activity, the alkaloids may also

function by inhibiting viral entry.823 Improved second generation syntheses824,825 and

preliminary SAR studies826 of the cytotoxic macrolide iejimalide B (Eudistoma cf. rigida)827

have been reported. While modifications to the macrocycle and sidechain led to reduced

activity, peptide terminus analogues showed good potency and selectivity. No in vivo activity

against human tumour xenografts was observed. Investigation of SAR of N-acyl derivatives

of the tetrahydroisoquinoline ring of ecteinascidin 770359,828 has identified a quinoline

derivative with enhanced cytotoxicity compared to the original natural product.829 O-Allyl-

protected derivatives were found to be devoid of activity. N,N'-Diphenethylurea (Didemnum

molle, D. ternatanum,830 and Streptomyces sp.831) promoted adipocyte differentiation and

activated PPARγ suggesting a potential use in improving insulin sensitivity in type 2

diabetes.832

12 Echinoderms

The twenty-nine new metabolites reported from echinoderms in 2011 is a significant decrease

from the number usually reported. A mixture of cerebrosides, AMC-2 1176, isolated from the

sea cucumber Acaudina molpadioides (purchased dried powder) was found to reduce hepatic

triglyceride and total cholesterol levels in fatty liver mice by down regulation of stearoyl-CoA

desaturase.833 The commercially available starfish Archaster typicus (China) yielded five new

sulfated cholestanes 1177–1181.834 In addition to six known glycosides, cariniferosides A–F

1182–1187 were isolated from the starfish Asteropsis carinifera (Van Phong Bay, South

China Sea). Sulfated sterols including 1187 inhibited colony formation of human breast and

melanoma cells in a soft agar clonogenic assay.835 Nine new asterosaponins (steroidal

oligoglycosides) were reported from starfish collected from well-dispersed sites. Extracts of

the Antarctic starfish Diplasterias brucei (Ross Sea, Terra Nova Bay) afforded the

diplasteriosides A 1188 and B 1189. Both were mildly cytotoxic to a human melanoma cell

line.836 A Korean collection of Asterias amurensis (Pohang) gave the pentaosides 1190–1192,

which in anti-inflammatory testing were cytotoxic to the RAW 264.7 assay cells,837 while Far

Eastern (Kuril Is., Sea of Okhotsk) specimens of Hippasteria kurilensis afforded the

hexaosides hippasterioside A–D 1193–1196.838 In the case of the latter compounds, 1196 was

found to be the more active in inhibiting colony formation of human HT-29 colon cancer

cells. Disulfated holostane triterpenoids liouvilloside A4 1197 and A5 1198 (trawl, Bouvet Is.,

South Atlantic Ocean) contain the rare 3-O-methylquinovose terminal saccharide.839 Two

sulfated holostanol triterpenes patagonicoside B 1199 and C 1200 (Psolus patagonicus, The

Bridges Is., Tierra del Fuego, Argentina) exhibited moderate antifungal activity towards

Cladosporium cucumerinum.840 The related co-metabolite patagonicoside A841 was more

active in the same assay, while the respective semi-synthetic desulfated analogues were

consistently less active. Cytotoxic and haemolytic mono-sulfated branched pentaosides

cucumarioside H5 1201, H6 1202, H7 1203 and H8 1204 were isolated from the sea cucumber

Eupentacta fraudatrix (Troitsa Bay, Sea of Japan).842 Cucumarioside H8 contained an unusual

16,22-ether linkage. Two unsaturated fatty acids, (7Z)-octadecenoic acid and (7Z,10Z)-

octadecadienoic acid isolated from the body wall of commercially available (Gangneung,

Korea) sea cucumber Stichopus japonicas, were moderate α-glucosidase inhibitors.843 High-

energy collision-induced dissociation tandem mass analysis using a four-sector tandem mass

spectrometer has been demonstrated to be a valuable tool in structure elucidation of

cerebrosides isolated from starfish eggs.844 A combination of TLC and HPLC-DAD-MS845 or

UPLC-MS846 analytical techniques allowed for the separation and identification of

polyhydroxylated naphthoquinone (spinochrome) metabolites of sea urchins of the genus

Strongylocentrotus. Mixtures of spinochromes and echinochromes exhibited moderate

antioxidant, Fe2+ chelating, lipid peroxidation inhibition and oxidative stress protection

properties.846 Further investigation of the inhibition of NF-κB activation847 by the angular

naphthopyrone comaparvin (Comanthus sp.)848 revealed that the natural product inhibited NF-

κB activation by TNF-α, IL-1β and PMA and also suppressed expression of NF-κB-regulated

genes leading to an increased apoptotic response.849 Pure compound library screening

identified a known disulfated sterol (Ophiolepis superba)850 as an antagonist of farnesoid-X-

receptor.851 Prophylactic doses of cumaside, a complex of monosulfated triterpene glycosides

(Cucumaria japonica), possessed moderate radioprotective properties in mice.852 The

immunomodulatory activity of cucumarioside A2-2,853 a purified component of cumaside,

appeared to be due to its ability to stimulate immune cell adhesion, spreading and motility,854

while desulfated echinoside A (Pearsonothuria graeffei) exhibited antimetastatic activity via

inhibition of NF-κB-dependent matrix metalloproteinase-9 and vascular endothelial growth

factor.855

13 Mangroves and the intertidal zone

Sulfated methyl epimers of pterosin C 1205 and 1206 were isolated from aerial parts of the

mangrove fern Acrostichum aureum (coastal Sundarban, Bangladesh).856 The absolute

configurations of both sesquiterpenes were determined by ECD analysis. Biological

evaluation of 1205 and 1206 and a desulfated co-metabolite indicated that only 1206

exhibited (modest) cytotoxicity and induced early apoptosis against a gastric adenocarcinoma

cell line. The isopimarane diterpene 1207, in addition to a large number of known

metabolites, was isolated from Rhizophora apiculata (Hainan Province, China).857 The seeds

of Xylocarpus moluccensis (Phuket province, Southern Thailand) afforded thaimoluccensins

A–C 1208–1210.858 In an assay measuring the ability to inhibit the production of NO by

stimulated macrophages, 1208 and 1210 exhibited only modest activity, while co-metabolite

7-deacetylgedunin859 was considered active. Godavarin K 1211, formally a 8,9-dehydrated

analogue of xylogranatin E,860 was reported from the seeds of the same species of mangrove,

this time collected from the Godavari estuary, Andhra Pradesh, India.861 Triterpenoid

saponins catunaroside A–D 1212–1215 (bark of mangrove associate Catunaregam spinosa,

Sanya, Hainan province, China) exhibited antifeedant activity towards second-instar larvae of

the diamondback moth Plutella xylostella, with C-3/C-28 disubstituted saponins being less

deterrent than analogues bearing glycosylation at only the 3-position.862

14 Miscellaneous

Bis-steroidal pyrazine model compounds of the cytostatic tube worm metabolite cephalostatin

1,863 exhibited moderate GI50 values in screening at the NCI.864 Activity towards E. faecalis

was also observed for one pyrazine. The simple hexapeptides 1216 and 1217 were isolated

from the polychaete nematode Eunicidae sp. (Seychelles Is., Indian Ocean).865,866 It is

interesting to note that the sequence of 1216, which co-incidentally is present in larger

proteins of several vectors of hazardous diseases including plague and leprosy, is an L-alanine

analogue of dalargin, a commercially available opiate. Peptide 1217, the first example of a

natural product containing the homoserine residue, was found to be a modest inhibitor of

HIV-1 integrase.

15 Conclusion

In the review of the marine natural products literature for 2008867 it was the preference in

journals selected for publishing that was examined, while in the 2007 review it was the recent

trends in the geographic zones sampled that was the focus.868 In the 2011 review the number

of publications containing new compounds and the chosen journal for the period 2006 to 2011

is examined by country of origin along with the number of compounds/publication and

citations/publication. Figure 1 depicts the variation in publications from contributing

countries by year since 2006. Since 2006 there has been a steady increase in the number of

these publications/year rising from 283 in 2006 to 352 in 2011. This corresponded to 779 new

compounds in 2006 rising to 1152 new compounds in 2011. While most of the output in

marine natural products research can be associated with just five or six countries, Figure 1

includes data from those countries contributing more than 10 publications over that period.

Most notable has been the steady rise in output across this period from the Chinese and

Taiwanese chemists. In this era, with its fascination with quantitation, citation rates are

apparently also important for comparative purposes. The numbers of citations/country/year

for the publications dealing with new compounds for the period 2006–2010 have been

extracted from SCOPUS.869 No attempt has been made to compare the citation rate on an

annual basis as older publications accumulate more citations. Rather, the citations were

summed and reported in Figure 2 as the number of citations/paper/country. Also included is

the average number of compounds/paper/country over the period 2006–2011. For

comparative purposes the average citations/paper across all countries is 8.1 and that for

compounds/paper is 2.8. When the choice of journal for the publication of new compounds

was examined (see Figure 3) interesting trends appeared. Over 110 journals have been used

over the past six years to report results. The 22 journals used most frequently are listed by

name in Figure 3. The other journals were split into two groups, 12 in Level II (between 10

and 19 papers each) and 80 in Level III (between 1 and 9 papers each).870 For the 41 countries

surveyed J. Nat. Prod. was first choice, in most cases by a considerable margin. Beyond that

initial choice national or regional journals such as Chem. Pharm. Bull., Eur. J. Org. Chem.,

Chin. Chem. Lett., and Russ. Chem. Bull. were then selected appropriately. In past years

Tetrahedron Lett. was the preferred journal for reporting results. It now lies in fourth place

behind J. Nat. Prod., Tetrahedron and Org. Lett., but remains a very popular journal for

publications from Japanese marine natural product chemists. To complete the analytical

picture, Figure 4 shows the numbers of papers published by journal (2006–2011) and the

number of citations/paper that these publications attracted (2006–2010). The five journals

with the most citations/paper over that period were J. Am. Chem. Soc., J. Org. Chem., Org.

Lett., J. Nat. Prod. and Tetrahedron followed closely by Bioorg. Med. Chem., Phytochemistry

and Tetrahedron Lett.

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869 http://www.scopus.com/. Accessed September, 2012.

870 An Excel spreadsheet containing all the data is available on application to

murray.munro@canterbury.ac.nz.