Professional Documents
Culture Documents
NPR
REVIEW
www.rsc.org/npr
Covering: 2009. Previous review: Nat. Prod. Rep., 2010, 27, 165
This review covers the literature published in 2009 for marine natural products, with 857 citations (588
for the period January to December 2009) 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 (1011 for 2009), 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
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Introduction
Reviews
Marine microorganisms and phytoplankton
Green algae
Brown algae
Red algae
Sponges
Cnidarians
Bryozoans
Molluscs
Tunicates (ascidians)
Echinoderms
Mangroves and the intertidal zone
Miscellaneous
Conclusion
References
1 Introduction
This review is of the literature for 2009 and describes 1011 new
compounds from 352 articles, a small decrease from the number
(1065) of compounds reported for 2008.1 As in previous reviews,
the structures are shown only for new compounds, or for
a
Department of Chemistry, University of Canterbury, Christchurch, New
Zealand. E-mail: john.blunt@canterbury.ac.nz
b
Department of Chemistry, University of Auckland, Auckland, New
Zealand
c
School of Chemical and Physical Sciences, Victoria University of
Wellington, Wellington, New Zealand
d
Department of Chemistry, University of Waikato, Hamilton, New
Zealand
This paper is part of an NPR themed issue on Marine Natural
Products.
John Blunt
Reviews
Mich
ele Prinsep received her
BSc (Hons) and PhD degrees
from the University of Canterbury, where she studied the
isolation and structural elucidation of biologically active
secondary metabolites from
sponges and bryozoans under the
supervision of Professors Blunt
and Munro. She undertook
postdoctoral research on cyanobacteria with Richard Moore at
the University of Hawaii before
Michele Prinsep
returning to New Zealand to
take up a lectureship at the University of Waikato, where she is
currently a Senior Lecturer.
Nat. Prod. Rep., 2011, 28, 196268 | 197
antibiotic-resistant S. pneumoniae.76 Bacillistatin 2 13 was synthesised via a 24-step convergent route utilising the Mitsunobu
reaction.77
Ammosamides A 37 and B 38 are chlorinated tricyclic pyrroloquinoline alkaloids from Streptomyces sp. [sediment, (Bahamas)]. Ammosamide A 37 contains an unusual thio-g-lactam
ring and gradually converted to ammosamide B 38 on exposure
and 77115 and a glycoside very similar to 76, but with a rearranged isoprene unit,116 have been previously isolated as plant
metabolites.
The known terrestrial fungal metabolite 4-O-demethylhypothemycin118 was isolated from the marine environment for the
Nat. Prod. Rep., 2011, 28, 196268 | 201
first time.119 Two new perylene derivatives, 7-epi-8-hydroxyaltertoxin I 86 and 6-epi-stemphytriol 87, were isolated from
culture of Alternaria alternata, [Laurencia sp., (Weizhou Is.,
South China Sea)].120
Alternaria raphani [sediment, sea salt field, (Qingdao, China)]
yielded three cerebrosides, alternaroside AC 8890 and a diketopiperazine alkaloid, alternarosin A 91,121 while alternaramide
92, a cyclic pentadepsipeptide, was isolated from culture of
Alternaria sp. [sediment, (Masan Bay, S. Korea)].122
Five cytochalasins, Z16Z20 9397, were isolated from Aspergillus flavipes [inner bark of the mangrove Acanthus ilicifolius,
(Dongzhai Gang, China)]. The known fungal metabolite rosellichalasin123 was also isolated.124
Fermentation of Aspergillus aculeatus [Xestospongia testudinaria, (Ton Sai Bay, Phi Phi Islands, Thailand)] resulted in the
isolation of the tyrosine-derived aspergillusol A 98, which
selectively inhibited a-glucosidase from Saccharomyces cerevisiae. A methyl ester of 4-hydroxyphenylpyruvic acid oxime,
a known synthetic compound,125 was also isolated, but may be
an artefact derived via methanolysis of 98 during isolation.126
202 | Nat. Prod. Rep., 2011, 28, 196268
A heptacyclic alkaloid, 21-hydroxystephacidin 104, was isolated from Aspergillus ostianus [unidentified sponge, (Pohnpei)],133 while investigation of Aspergillus sclerotiorum [Mycale
sp., (Ishigaki Is., Okinawa)] gave N-demethyl aspochracin 105.134
The cyclic hexapeptides sclerotide A 106 and B 107 were isolated from A. sclerotiorum [Putian Sea Salt Field, (Fujian,
China)] in a nutrient-limited hypersaline medium. Sclerotides A
106 and B 107 were photo-interconvertible. Both 106 and 107
displayed moderate activity against C. albicans, and 107 was
weakly cytotoxic to HL-60 cells and inhibited P. aeruginosa
growth.135
The alkaloid cottoquinazoline A 133 and the cyclopentapeptides, cotteslosin A 134 and B 135 were isolated from
Aspergillus versicolor [sand, (Cottesloe, Western Australia)].144
paecilopyrones A 170 and B 171 and the cyclohexenones phomaligol B 172 and C 173.173
Three new breviane spiroditerpenoids, brevione FH 174176,
were obtained from the extreme-tolerant Penicillium sp.
206 | Nat. Prod. Rep., 2011, 28, 196268
A Penicillium sp. [brown alga Xiphophora gladiata, (Macrocarpa Point, New Zealand)] gave the 2-pyridone alkaloids 177
and 178, of which 177 had been previously prepared as a derivative of the co-isolated N-hydroxypyridone antibiotic PF1140.176
This represents the first isolation as a natural product.177 Penicipyrone 179 and penicilactone 180 were isolated from Penicillium sp. [sea fan, Annella sp., (Similan Islands, Thailand)],178
while the sesquiterpenoids JBIR-27 181 and JBIR-28 182 are
eremophilane analogues isolated from Penicillium sp. [ascidian,
Didemnum molle, (Ishigaki Is., Okinawa)]; 182 was moderately
cytotoxic to HeLa cells.179
Kong)] was the source of 7-hydroxyjanthinone 194. This was the
first marine occurence of the co-isolated janthinone,182 a known
metabolite from Penicillium janthinellum found as an endophyte
of Melia azedarach (chinaberry).183 Chromanone A 195 from
a Penicillium sp. [green alga, Ulva sp., (Suez Canal, Egypt)]
possessed a range of biological activities including cytochrome
P450 1A (CYP1A) inhibition, glutathione S-transferases (GST)
and epoxide hydrolase (mEH) induction and potent radicalscavenging activity against hydroxyl radicals.184
4-Hydroxyphenethyl methyl succinate 196 and 4-hydroxyphenethyl 2-(4-hydroxyphenyl)acetate 197 were obtained from
Penicillium griseofulvum [mangrove, Lumnitzera racemosa,
Nat. Prod. Rep., 2011, 28, 196268 | 207
The polyketides spartinol AD 198201 came from the endophyte Phaeosphaeria spartinae [Ceramium sp., (North Sea,
B
usum, Germany)].188 Culture of Phoma sp. [sponge Ectyplasia
perox, (Caribbean Sea, Dominica)] led to isolation of the prenylated polyketides epoxyphomalin A 202 and B 203. Both
compounds were active against a panel of 36 human tumour cell
lines but epoxyphomalin A 202, which was extremely potent,
displayed significant selectivity toward 12 of the cell lines and
possessed a unique cytotoxic selectivity pattern as determined by
COMPARE analyses.189
Chemical investigation of a collection of Lyngbya sp. (Okinawa) resulted in isolation of biselyngbyaside 267, an 18membered macrolide glycoside with broad-spectrum cytotoxicity
in a human tumour cell line panel, likely by a novel mechanism as
indicated by COMPARE analyses.223
Bisebromoamide 268 was isolated from Lyngbya sp. (Okinawa), and was cytotoxic to HeLa S3 cells and a panel of human
cancer cell lines, in addition to exhibiting potent protein kinase
inhibition.224
of aspergillide C, also from Aspergillus ostianus,239 was accomplished from a commercially available chiral glycidol derivative.242 The structure of neomarinone, a furanonaphthoquinone,
isolated from a marine filamentous bacterium243 was revised after
a biosynthetic study and NMR analysis.244 The total synthesis of
neomarinone (utilising a regioselective DielsAlder reaction) has
now been achieved, and established the absolute configuration as
285.245
Total synthesis of both isomers of the bisanthraquinone antibiotic BE-43472B, originally isolated from Streptomyces sp.
found in a cyanobacterium associated with the ascidian Ecteinascidia turbinata,246 was achieved via a cascade sequence initiated by an intermolecular DielsAlder reaction, and defined the
absolute configuration of the natural product as 286.247,248
Aquastatin A, previously isolated from Fusarium aquaeductuum,249 has now been isolated from the marine environment
(Cosmospora sp. [sediment, (Gejae Is., S. Korea)] and the absolute configuration determined (287).250 Malyngamides O and P
were originally isolated from the sea hare Stylocheilus longicauda,251 whilst malyngamides Q and R were isolated from the
cyanobacterium Lyngbya majuscula.252 All four metabolites have
now been synthesised via a flexible and convergent route, which
established the configurations of malyngamides Q and R as 288
and 289 respectively.253,254
Ypaomide was isolated as a herbivore-feeding deterrent from
the cyanobacterium Lyngbya majuscula.255 An enantioselective
synthesis of the (R)-enantiomer established that the natural
product was the (S)-enantiomer 290.256
from a natural source for the first time. It too may also be an
artefact. Finally, 12a-hydroxy-3-ketocholanic acid270 and 12ahydroxy-3,7-diketocholanic acid,271 while known, were isolated
from a marine source for the first time.272 Culture of Halobacillus
salinus [sea grass, (South Kingstown, Rhode Is., USA)] produced
N-(20 -phenylethyl)isobutyramide,273 a known inhibitor of
quorum sensing-regulated behaviour in Gram-negative bacteria,
but isolated from a marine source for the first time.274 Known
fungal metabolites pyripyropene A, B and D275 were isolated from
Aspergillus sp. [sediment, (Gokasyo Gulf, Japan] as selective
antiproliferative substances against human umbilical vein endothelial cells (HUVECs). Pyripyropenes B and D were isolated
from the marine environment for the first time.276 Marinoquinoline A, a pyrroloquinoline from the marine gliding bacterium
Rapidithrix thailandica,277 exhibited strong inhibition of acetylcholinesterase. Two related pyrrole derivatives, 3-(20 -aminophenyl)pyrrole278 and 2,2-dimethylpyrrolo-1,2-dihydroquinoline,
were isolated from two other strains of R. thailandica, but the
quinoline was proposed as an artefact of the pyrrole, which was
isolated from a natural source for the first time.279 Culture of an
unidentified fungal strain isolated from a sea salt pan in Australia
resulted in the first marine-based isolation of 3-O-methylfunicone,280 a selective inhibitor of mammalian Y-family DNA
polymerases (pols) and growth suppressor of HCT-116 and HeLa
cells.281 N-Methyl-2-indolecarboxamide, a known synthetic
compound,282 was isolated from a natural source for the first time
as a metabolite of Cladosporium cladosporiodes [Cliona sp., (Los
Molles, Chile)]283 while 2,20 -dithiobis-benzothiazole, a known
plant metabolite,284 was isolated from the marine environment for
the first time from an unidentified endophytic fungus [mangrove,
(South China Sea)].285 The known terrestrial fungal siderophore
fusigen286 was isolated from the marine environment for the first
time from the fungus Aureobasidium pullulans [sea saltern,
(Yellow Sea, China)] as a growth inhibitor of Vibrio anguillarum
and V. parahaemolyticus.287 Sporolide B, a halogenated macrolide
from the actinomycete Salinispora tropica,288 was synthesised by
a convergent strategy featuring a ruthenium-catalysed [2 + 2 + 2]
cycloaddition reaction,289 while synthesis of bacillamide 3, originally isolated from Bacillus endophyticus [hypersaline microbial
mat, (Bahamas)],290 was accomplished from D-alanine.291 The
total synthesis of emericellamide B, a metabolite of the fungus
Emericella sp. produced during co-culture with the actinomycete
Salinispora arenicola,292 was achieved by a flexible, convergent
strategy.293 Gymnastatins F294 and Q,295 metabolites of the fungus
Gymnascella dankaliensis (Halichondria japonica), were synthesised via a biomimetic route from the corresponding spirodienone derivatives.296 The first297 of several298300 total
syntheses of brevisamide, a cyclic ether alkaloid from the dinoflagellate Karenia brevis,301 was achieved in 21 linear steps from
cis-but-2-ene-1,4-diol.297 A series of synthetic studies established
the configurations of various fragments of symbiodinolide,
a polyol macrolide from the symbiotic marine dinoflagellate
Symbiodinium sp.302 For example, a stereoselective synthesis of the
C-23C-34 bis-epoxide fragment of symbiodinolide and related
diastereomers
led
to
configurational
revision
to
(26S,27R,28R,29S,30R,32S),303 while synthesis of the C-14C-23
fragment established the configurations (17S,18R,21R).304
Synthesis of the C-33C-42 fragment established the configurations (36S,40S),305,306 and also the absolute configuration of the
This journal is The Royal Society of Chemistry 2011
Green algae
A significant find was the discovery of two new cyclic depsipeptides from Bryopsis pennata (Kahala Bay, Ohau, Hawaii).
These were 5-OHKF 297 and norKA 298, and join the other
seventeen congeners of the kahalide family that have to date been
isolated from B. pennata or molluscs of the genus Elysia. Interestingly, 5-OHKF 297 showed no antitumour properties, in
keeping with the importance of the aliphatic group in the known
compounds KF 299 and isoKF 300.335 Six known sterols were
identified from Chaetomorpha basiretorsa.336 In each case this
was the first discovery of these compounds from that genus.
The biological roles of two well-known Caulerpa metabolites
have been examined. Both natural (+)-caulerpenyne and the
synthetic enantiomer inhibited microtubule formation, with the
() enantiomer having a lower IC50 for inhibition of tubulin
polymerisation.337 In this recent study, ()-caulerpenyne was
demonstrated to bind slowly to tubulin in a non-covalent and
poorly reversed fashion, but not at the colchicine, Taxol or
Brown algae
The majority of the new metabolites from brown algae each year
were terpenoid, or part terpenoid in origin. In 2009 well over half
of the 60 papers published were descriptive in nature, or dealt
with sulfated polysaccharide (fucoidan) chemistry. Eicosapentaenoic acid, isolated for the first time from Zonaria tournefortii (Tipaza, Algeria), was proposed as the biosynthetic
precursor for the co-occuring acylphloroglucinols and chromone
derivatives.344 The diacylglycerol 301 was reported from Zonaria
diesingiana (unspecified location, South China Sea),345 while
ishigoside 302 was isolated from Ishige okamurae (Busan, S.
Korea). The free-radical-scavenging activity of ishigoside 302
was evaluated using an ESR technique.346
Red algae
Africa) was the source of five antiplasmodial (to a chloroquinesensitive strain of Plasmodium falciparum) halogenated monoterpenes, of which the two new ones 349 and 350 were the least
active.380
The biologically active halophenol 2,20 ,3,30 -tetrabromo4,40 ,5,50 -tetrahydroxydiphenylmethane, originally from Rhodomela larix,396 was synthesised along with a series of related
halogenated bis(hydroxyphenyl)methanes in a study of antimicrobial activities.397 The syntheses of four analogues of the
oxylipin agardhilactone (Agardhiella subulata)398 has resulted in
a revision of the absolute configuration of this compound.399
Radioactive 82Br was used in a study of the biosynthesis of laurencin, laureatin and other brominated metabolites in some
220 | Nat. Prod. Rep., 2011, 28, 196268
7 Sponges
The number of new compounds reported from sponges in 2009
(287) is similar to that in each of the previous few years. The alkyl
amino alcohol halaminol A (Haliclona sp.)402 induced rapid
larval settling in ascidians but prevented their subsequent
metamorphosis. For the larvae of other phyla, halaminol A
inhibited settlement, and was toxic.403 Iotrochotamides I 383 and
II 384 were isolated from Iotrochota purpurea (Pulau, Indonesia).404 A Haliclona species (Jeddah, Saudi Arabia) yielded
a series of cytotoxic sphingolipids, 385390.405
A Haliclona (Reniera) species (Ulleung Is., S. Korea) contained a series of glucocerebrosides, renierosides C1C3, C5C14
392404.408
Amphiceramides A 405 and B 406 and the related N-acetylglucoside 407 were obtained from Amphimedon compressa (Key
This journal is The Royal Society of Chemistry 2011
The carteriosulfonic acids AC 418420, isolated from Carteriospongia sp. (San Miguel Is., Philippines), were inhibitors of
the kinase GSK-3b.414
A series of long-chain-substituted pyrroles, mycalenitriles 414
421431 and mycalazals 1420 432438, inhibited HIF-1 activation in human breast tumour cells.415
Jaspine B (Jaspis sp.)416 inhibited sphingomyelin synthase in
human melanoma cells, thereby increasing ceramide levels and
thus triggering apoptosis which accounts for the compounds
reported cytotoxicity.417 The cytotoxic acetylenes 439 and 440
and the unusual dihydrothiopyranone 441 were obtained from
Reniochalina sp. (Chuuk, Micronesia).418 A weakly cytotoxic and
weakly antimicrobial thiophene 442 was obtained from the
calcareous sponge Paragrantia cf. waguensis (Okinawa).419
A Petrosia species, collected by dredging (150 m, Kurose Hole,
Hachijo Is., S. Korea), contained the cytotoxic neopetroformynes AD 443446.420
Diacarnus bismarckensis (Sanaroa, Papua New Guinea) yielded ent-()-muqubilone 447 and (+)-muqubilone B 448, active
against Trypanosoma brucei (African sleeping sickness).421
The absolute configuration of muqubilone (Diacarnus erythraeanus)422 was assigned by the establishment of absolute
configuration of 447. The aromatic peroxides 449452 and
compounds 453 and 454 were isolated from Plakortis sp. (Orote
Peninsula, Guam); 449452 were weakly active against S.
aureus.423
Total syntheses of the tryptophan-containing peptides kapakahine B and F (Cribrochalina olemda)450,451 have been
This journal is The Royal Society of Chemistry 2011
derived alkaloid, JBIR-44 570, was obtained from Psammaplysilla purpurea (Kinwan Bay, Okinawa).523 The non-selective
pyruvate
phosphate
dikinase
(PPDK)
inhibitor
Nat. Prod. Rep., 2011, 28, 196268 | 229
A Psammoclema species (Nelson Bay, NSW, Australia) contained the antiproliferative steroids 656659.584 Petrosterol-3,6dione 660 and 5,6a-epoxy-petrosterol 661, isolated from
Ianthella sp. (Namyet Is., Vietnam), were cytotoxic and caused
apoptosis.585
The norselic acids AE 662666, isolated from Crella sp.
(Norsel Point, Palmer Station, Antarctica), were weakly antimicrobial and antifeedants to mesograzers.586
siphonellinol hydroperoxide 694 were obtained from Callyspongia (Siphonochalina) siphonella (Hurghada, Red Sea,
Egypt). In the same report the structure of sipholenol I 695 (S.
siphonella)595 was revised.596
8 Cnidarians
There was a pronounced decline in the number of new metabolites reported from cnidarians compared with previous years. The
total content of mycosporine-like amino acids in six species of
This journal is The Royal Society of Chemistry 2011
The meroterpenoid sarcophytonone 702, isolated from Sarcophyton crassocaule (Lingshui Bay, Hainan Province, South
China Sea), also exhibited mild toxicity to Artemia salina.601
Asymmetric synthesis of the originally proposed structure of
the cytotoxic hydroid (Gymnangium regae) pentapeptide gymnangiamide602 requires that the configuration of the terminal aguanidino-serine residue be reassigned from L- to D- as shown
(703).603
A highly strained cyclo-1,3-carbazole structure 704 (antipathine A) was deduced for a metabolite isolated from the black
coral Antipathes dichotoma (Sanya, Hainan Province, South
China Sea).604 Cycloaplysinopsin C 705, a dimeric alkaloid isolated from the hard coral Tubastraea sp. (Hanish Is., Yemen),
had micromolar antimalarial activity towards both chloroquinesensitive and chloroquine-resistant strains of Plasmodium falciparum.605
Methyl 5-[(10 E,50 E)-20 ,60 -dimethylocta-10 ,50 ,70 -trienyl]furan-3carboxylate (Sinularia capillosa)622 induces apoptosis via a caspase-dependent pathway in the THP-1 leukaemia cell line.623
Extensive in vitro and in vivo evaluations of the soft coral
sesquiterpene metabolite D9(12)-capnellene-8b,10a-diol624 and
a monoacetate derivative established inhibition of interferon-gstimulated expression of inducible nitric oxide synthase and
cyclooxygenase-2, and so represent lead compounds in the
development of new treatments of neuroinflammatory effects.625
An examination of the sesquiterpene chemistry of over 100
individuals of five of the six known species of soft corals of the
genus Plexaurella has determined that there was no correlation
between species and chemistry, nor was there any correlation
and the precursor cembrane pseudopterolide.653 Both bisditerpenoids were prepared by bubbling NH3 through a solution
of pseudopterolide. Mild cytotoxicity was exhibited by 793.
The structures and relative configurations of the sevenmembered lactone-containing diterpenes sinulaparvalide A 794
and B 795 (Sinularia parva, Lingshui Bay, Hainan Province,
South China Sea) were established.654 The structurally-related
lactones flexibilisolide A 796 and ring-opened analogue flexibilisin A 797 were isolated from cultivated specimens of Sinularia flexibilis, while flexibilisolide B 798 and flexibilisin B 799
were isolated from wild specimens of the same species (Southern
Pintung, Taiwan).655 Base-catalysed hydrolysis of the cometabolites 11-epi-sinulariolide acetate656 and sinulariolide657
yielded 797 and 799 respectively.
Lobocrasol 790 (Lobophytum crassum, Dongsha Is., Taiwan)649 and corallolides A 791 and B 792 (Pseudopterogorgia
bipinnata, Providencia Is., Colombia)650 embody unusual carbon
skeletons and exhibit mild biological activities.
Norverticillanes cespihypotin W 822 and X 823, and verticillane diterpenes cespihypotin Y 824 and Z 825 and cespihypotone 826 were sourced from Cespitularia hypotentaculata
(Green Is., Taiwan).663
While excavatoids A 855 and B 856 were isolated from cultivated specimens of B. excavatum, wild-type specimens of the
same organism (Southern Taiwan) yielded the 5,6-epoxy-briaranes excavatoids C 857 and D 858.683
The structures and relative configurations of excavatoid A 855,
and cultivated gorgonian known co-metabolite briaexcavatin
I,684 were established. Excavatoid C 857 is unusual in that it bears
a 3-lactone ring. A second publication reported the characterisation of excavatoids E 859 and F 860 from the same samples of
cultivated B. excavatum.685 Both metabolites were modest
inhibitors of elastase release from human neutrophils.
The xenicane diterpenes asterolaurin AF 861866 (Asterospicularia laurae, southern coast, Taiwan) generally inhibited
elastase release and superoxide production by human neutrophils.686
In addition to the norhumulene metabolite presented earlier,
xeniaphyllanes gibberosin OS 867871 and sinugibberoside
242 | Nat. Prod. Rep., 2011, 28, 196268
887.689 Two of these sterols, 886 and 887, were also isolated from
an ascidian Trididemnum inarmatum (Achladi Bay, Maliakos
Gulf, Greece).
Artificial predation of Sinularia polydactyla led to a statistically significant increase in production of 11b-acetoxypukalide699
which correlated with upregulation of gene expression.700 A
study of light dependency on the growth, budding frequency and
production of flexibilide701 by cultivated Sinularia flexibilis found
a curvilinear response, indicating that both low and high light
intensity were detrimental to growth and metabolite production.702 A comparative study of fatty acid content of soft corals
that either harbour symbionts or are symbiont-free suggests that
18:3n6, 18:4n3 and 16:2n7 acids are markers of the presence
of zooxanthellae.703 Concentrations of several fatty acids in
zooxanthellae associated with jellyfish of the genus Cassiopea
decrease with a decrease in light intensity, but the same acids
increase in concentration in host tissue.704 A Plane Is.
(Marseilles) collection of the colonial sea anemone Parazoanthus
axinellae, an epibiont on the sponge Axinella damicornis, afforded the 3,5-disubstituted hydantoins parazoanthine AE 899
903.705 Absolute configuration at C-5 of 899, and by analogy 902,
9 Bryozoans
Although there are still very few reports on bryozoan chemistry,
there are several more this year than has been usual in past
reviews. Chemical investigations of Flustra foliacea (Minas
Basin, Bay of Fundy, Canada) resulted in 11 new flustramines F
P 904914. The dimers flustramine O 913 and flustramine P 914
may be artefacts of isolation. The metabolites possessed
a different bromination pattern from that of previously reported
flustramines712717 and some also possessed a new hydroxylation
pattern on the aromatic ring. Flustramines F 904, I 907 and L
910 had broad-spectrum antimicrobial activity.718 Investigation
of flustramines L 910 and N 912 after several years of storage
indicated a slow interconversion. Examination of flustramine H
906 indicated that it also behaves in an analogous manner, but on
a longer timescale.718
10 Molluscs
The last two years have seen a considerable decline in the number
of new metabolites reported from molluscs. Mytilin-A, an antimicrobial peptide isolated from the mussel Mytilus edulis,725
exhibited moderate levels of activity towards marine Vibrio
species, yeasts and filamentous fungi that was not modulated by
saline concentrations, suggesting a potential role in the control of
marine pathogens in aquaculture settings.726 Capillary electrophoresisESI-MS has been demonstrated as an analytical tool to
detect the lipophilic marine toxins yessotoxin and pectenotoxins
with limits of detection of 10 mg kg1 and 130 mg kg1 respectively.727 The use of solid-phase extraction as an enrichment and
clean-up procedure before LCMS/MS analysis lowers the limit
of quantification for okadaic acid, pectenotoxin 2, azaspiracid 1
and yessotoxin to 1 mg kg1.728 Two new peptides of the Dsuperfamily (aD-Ms and aD-Cp) were reported from crude
venom extract of Conus mustelinus and C. capitaneus (Olango Is.,
Sebu, Philippines).729 The 11 kDa dimeric aD-conopeptides are
potent nanomolar blockers of a7, a3b2 and a4b2 subtype
neuronal nicotinic acetylcholine receptors.729,730 Lt3a is a new Mfamily toxin purified from the venom of the worm-hunting cone
snail C. litteratus (Yalong Bay, Hainan Province, South China
Sea).731 Automated sequence analysis indicated three residues
were non-standard, with subsequent comparison with a cDNA
sequence identifying carboxyglutamate and hydroxyproline
post-translational modifications (PTMs). The peptide was found
to enhance tetrodotoxin-sensitive sodium channel currents. An
86 amino acid-containing mature peptide, named con-ikot-ikot,
purified from C. striatus (unknown location), inhibits the depolarisation of glutamate-gated ion channels, leading to neuronal
death.732 Two I-superfamily peptides, ca11a (38 residues) and
ca11b (34 residues) of unknown function, were purified from the
venom of South China Sea collections of C. caracteristicus.733 A
full-length cDNA of ca11a was generated, revealing the
precursor peptide was comprised of a 20-residue signal peptide,
a 22-residue pro-peptide and a 38-residue mature peptide. Using
a cDNA probe of the signal peptide sequence, a number of new
conotoxin peptide sequences were identified, including two Osuperfamily toxins, suggesting a close evolutionary link between
I- and O-superfamily toxins. Turritoxin pal9a, isolated from the
turrid snail Polystira albida, contains 34 residues, including 6
cysteines, the pattern of which makes it a framework IX P-conotoxin peptide.734 A Mexican Caribbean Sea collection of Conus
delessertii yielded a 28 amino acid mature peptide, de7b, that
included 6 cysteines, and exists as a mixture of different
g-carboxyglutamate
and/or
4-hydroxyproline
PTM
isomorphs.735 Mass spectrometry was used to investigate the
distribution of PTM peptides related to Vc1.1 in the venom ducts
of Conus victoriae (Broom, Western Australia): the finding of
unmodified mature peptide in venom duct tissue indicated that
some of the pre- and pro- region of the immature peptide was
cleaved prior to PTM.736 The study also noted that of 3 different
disulfide isomers prepared, only the naturally occurring isomer
exhibited nAChR activity and that some PTMs were detrimental
to mammalian receptor activity. A homo-dimeric toxin,
TxXIIIA, containing an odd number of cysteine residues in the
monomer, has been identified in venom extracts of C. textile.737
The use of synthetic oligomers to probe cDNA libraries
246 | Nat. Prod. Rep., 2011, 28, 196268
generated from venom duct tissue continues to lead to identification of previously unreported conotoxins.738740 Given the
potency of binding of conotoxins to their respective biological
targets, it is of no surprise that they continue to act as highly
specific molecular probes of receptors and ion channels. A
number of studies have reported on structureactivity effects of
modified a-conotoxins with nicotinic acetylcholine receptors
(nAChRs),741743 including a-ImII binding to nAChRs on
Torpedo membranes,744 the use of fluorescent analogues,745 and
the preparation and biological evaluation of a hydrolytically
stable dicarba-bridged (as opposed to disulfide-bridged) a-ImI
analogue.746 Structurally minimised analogues of the voltagegated sodium channel-targeting m-conotoxin KIIIA have been
reported to retain biological activity,747,748 and non-peptide
mimics of analgesic u-conotoxin GVIA have been reported.749,750
A chimera of u-conotoxins CVID and MVIIC, prepared using
native chemical ligation methodology, was used to investigate the
contributions of N- and C-terminal peptide segments to observed
biological activity.751 A study of the mucus and external body parts
of a Hainan (South China Sea) collection of the pulmonate mollusc
Onchidium sp. led to the characterisation of an intriguing bis-gpyrone polypropropionate, onchidione 919.752 Onchidione acted as
a strong feeding deterrent, making treated food unpalatable to
marine shrimps.
11 Tunicates (ascidians)
With 35 new metabolites being the average reported from
ascidians since 2007, the 52 natural products presented in this
review indicates elevated productivity on the part of isolation
chemists. The simple long-chain amino alcohols clavaminols G
N 937942 were isolated as bioactive constituents of the ascidian
Clavelina phlegraea (Bay of Naples, Italy).776 Limited SAR
analysis indicated that free amino and alcohol groups were
required for cytotoxicity, while the presence of an additional
hydroxyl group or lipid unsaturation were detrimental to
activity.
Bicyclic acids and amides 954959, isolated from a Jeju Is. (S.
Korea) collection of an unidentified didemnid ascidian, exhibited
mild cytotoxicity towards a panel of human tumour cell lines.779
Notionally, the natural products could be derived from Diels
Alder cyclisation of long chain fatty diacids.
The potently cytotoxic (A2780, IC50 0.34 mM) lipopeptide 39oxobistramide K 988 was isolated from Trididemnum cyclops
(Madagascar).792 The similarity of CD spectra with co-occurring
bistramide A suggested the skeletal configuration shown.
This journal is The Royal Society of Chemistry 2011
12 Echinoderms
The number of new metabolites reported annually from echinoderms has remained relatively constant over the 20022008
period. Bioassay-directed (P388) fractionation of extracts of the
inter-tidal ophiuroid Ophiocoma scolopendrina gave the mildly
cytotoxic tetrameric phenylpropanoids ophiodilactones A 989
Protoxylocarpins FH 10351037 were isolated as non-cytotoxic constituents of the seed kernels of Xylocarpus granatum
(Samutsongkram Province, Thailand).842 The absolute configuration at C-24 of 1035 was determined, while all other stereogenic centres were assigned as relative only.
A collection of seeds of X. granatum (Krishna Estuary,
Andhra Pradesh, India) yielded granatumins AG 10381044,843
while seeds of X. moluccensis, collected in the same locale, contained the C-30 keto-bearing moluccensins AG 10451051.844
14 Miscellaneous
The absolute configuration of ()-complanine, isolated from the
fireworm Eurythoe complanata,845 was determined by stereoselective synthesis from (R)-malic acid.846 Starting from D-
15 Conclusion
The value of natural products as a source of drug leads has been
well documented, with the majority of small-molecule pharmaceuticals across the disease spectrum being of natural product
origin, or natural product derived/inspired.852 Of the estimated
153,000 known natural products,853 22,000 are of marine
origin.66 Currently very few marine natural products have been or
are being developed into marketable drugs,5 and this may be
attributed in part to the fact that marine natural products have
a much shorter history of discovery than their terrestrial and
microbial counterparts. Furthermore, the major drug companies
have invested little effort into the development of natural product
leads over the past decade. However, it could be helpful to
compare the potential drug-likeness of marine natural products
with all other natural products, as measured by an examination of
their Lipinski characteristics, to determine whether there are any
features of marine compounds that might lead to them being
inherently more or less suitable as drug candidates. In 2008 Quinn
et al. analysed the drug-likeness of all the natural products,
including those of marine origin, as listed in the Dictionary of
Natural Products853 (DNP) (April, 2005; 126,140 unique
compounds)854 using the rule of five criterion described by
Lipinski.855 Briefly, this suggests that to be drug-like and orallybioavailable a molecule must have a partition coefficient (logP) <
5, a molecular weight <500 Da, <5 hydrogen bond donors (HBD)
and <10 hydrogen bond acceptors (HBA). By analyzing the
derived Lipinski data from this set, it was found that the molecular weight plot peaked in the 300400 Da range, clogP (calculated octanolwater logP) had a Gaussian distribution with
a maximum at 22.5, HBA peaked at 35 and then fell off rapidly,
while the HBD count rapidly fell from a maximum at 0. The
Lipinski data for a marine natural product selection (20,174
compounds), calculated using ACD algorithms,856 has now been
compared to those reported for the DNP selection. This analysis
shows great similarity between the two data sets. The most
significant difference however was in the distribution of the clogP
values for the marine compounds that had a maximum between 4
and 5, suggesting a greater average lipophilicity of the marine
compounds. This skewing of the clogP distribution to higher
values is not favourable in terms of bioavailability, but clogP
values are not considered entirely reliable, especially with Br
substituents.854 When the Lipinski violations were compared for
the marine vs. the DNP compound sets there was a marked
change in distribution (see Fig. 1), with only 42% of all marine
metabolites having zero Lipinski violations. However, the relative
proportion of compounds having zero or one violations of
This journal is The Royal Society of Chemistry 2011
Fig. 1 Lipinski violations for marine natural products (blue) and all
natural products (red).
Lipinskis rule of five was closer (74% vs. 80%). The broad
conclusion that can be drawn from this very simple analysis of the
general physico-chemical properties of marine natural products is
that they too are Lipinski-worthy, and in the future they should
be a source of many more small-molecule pharmaceuticals.
An aim of the rule of five was to highlight bioavailability
problems based on calculable physico-chemical parameters. In
Fig. 2 the major marine phyla explored to date (each having >2%
of all compounds isolated) are compared on the basis of zero or
one Lipinski violation.
The analysis given in Fig. 2 highlights the lipophilicity of many
of the compounds in the phyla examined, particularly for the
Ochrophyta, Porifera, Mollusca and Cnidaria. Given the overall
importance of logP to permeability and bioavailability, any
conclusions that could be drawn from Fig. 2 about any particular
phylum being a source of compounds with fewer Lipinski violations should be made with caution. More recently, simple rules
that have been derived from an extensive analysis of ADMET
(adsorption, distribution, metabolism, excretion and toxicity)
parameters highlight the role of MW and clogP.857 Increasing
values in either MW or clogP are generally detrimental to more
than one ADMET parameter. As a consequence it was suggested
that a molecule has more desirable oral-bioavailability physicochemical properties if MW < 400 and clogP < 4. An analysis of
the marine natural products data based on these parameters is
shown in Fig. 3, and suggests that the Actinobacteria and Ascomycota have a greater proportion of compounds that meet these
criteria. These two phyla were also distinctive in the analysis
shown in Fig. 2. Physico-chemical parameters can suggest the
optimum combinations for potential pharmaceuticals, but the
real test is placing purified compounds into biological testing, or
implementing a bioassay-guided approach to selection. Ultimately, however, the potential of a marine natural product as
a drug candidate will be determined by the biological evaluation
results, not the calculated physico-chemical parameters.
Nat. Prod. Rep., 2011, 28, 196268 | 255
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