ArticlePDF AvailableLiterature Review

Abstract and Figures

Covering: 2009 to 2013.This review covers the 188 novel marine natural products described since 2008, from deep-water (50->5000 m) marine fauna including bryozoa, chordata, cnidaria, echinodermata, microorganisms, mollusca and porifera. The structures of the new compounds and details of the source organism, depth of collection and country of origin are presented, along with any relevant biological activities of the metabolites. Where reported, synthetic studies on the deep-sea natural products have also been included. Most strikingly, 75% of the compounds were reported to possess bioactivity, with almost half exhibiting low micromolar cytotoxicity towards a range of human cancer cell lines, along with a significant increase in the number of microbial deep-sea natural products reported.
Content may be subject to copyright.
Recent advances in deep-sea natural products
Danielle Skropeta*
a
and Liangqian Wei
b
Covering: 2009 to 2013.
This review covers the 188 novel marine natural products described since 2008, from deep-water (50
>5000 m) marine fauna including bryozoa, chordata, cnidaria, echinodermata, microorganisms, mollusca
and porifera. The structures of the new compounds and details of the source organism, depth of
collection and country of origin are presented, along with any relevant biological activities of the
metabolites. Where reported, synthetic studies on the deep-sea natural products have also been
included. Most strikingly, 75% of the compounds were reported to possess bioactivity, with almost half
exhibiting low micromolar cytotoxicity towards a range of human cancer cell lines, along with a
signicant increase in the number of microbial deep-sea natural products reported.
1 Introduction
2 Reviews
3 Deep-sea life
4 Bryozoa
5 Chordata
6 Cnidaria
7 Echinodermata
8 Microorganisms
8.1 Bacteria
8.2 Fungi
9 Mollusca
10 Porifera
10.1 Order Astrophorida
10.2 Order Dictyoceratida
10.3 Order Halichondrida
10.4 Order Haplosclerida
10.5 Order Homoscleropherida
10.6 Order Lithistida
10.7 Order Poecilosclerida
11 Recent advances in the development of deep-sea-derived
drugs
12 Conclusions
13 Acknowledgements
14 Notes and references
1 Introduction
The deep sea is home to unprecedented biological diversity
17
and a myriad of marine species that are not encountered in
shallow waters, including carnivorous ascidians,
8,9
mussels,
10
and sponges.
11,12
Deep-sea organisms survive under extreme
conditions in the absence of light, under low levels of oxygen
and intensely high pressures, necessitating a diverse array of
biochemical and physiological adaptations that are essential for
survival. These adaptations are oen accompanied by modi-
cations to both gene regulation and to primary and secondary
metabolic pathways,
13,14
increasing the likelihood of nding
structurally unique natural products that dier from those
produced by shallow-water organisms.
In recent years, several groups have reported astonishingly
high hit-rates from screening deep-sea organisms, up to 74% by
Schupp and co-workers for deep-sea sponges and gorgonians
evaluated for anticancer activity.
15,16
Furthermore, Blunt et al.
recorded an approximate doubling in the frequency of cytotox-
icity towards the P388 murine tumour cell line from a single
deep-water collection at a depth of 100 m othe Chasam Rise,
New Zealand, compared with the average activity of >5000
shallow-water collections over the preceding 13-year period.
17
In
our previous review of deep-sea natural products, 76%
possessed biological activity, with over half exhibiting signi-
cant cytotoxicity towards a range of human cancer cell lines.
18
With multidrug resistance reaching a critical point,
19
in partic-
ular in the case of antibiotic resistance,
20
it is imperative that the
search for new chemical entities moves into uncharted waters.
The vast oceans cover 70% of the world's surface, with 95% of
them being greater than 1000 m deep.
21
The decade-long Census
of Marine Life, which assessed the diversity, distribution, and
abundance of marine life, expanded the number of known
marine species from 230 000 to 250 000 and conjectured that
the total number of marine species worldwide is at least one
million, along with hundreds of millions of microbial species.
22
Further analyses have shown that the deep sea is one of the most
a
School of Chemistry, University of Wollongong, Wollongong, NSW 2500, Australia
b
Centre of Medicinal Chemistry, University of Wollongong, Wollongong, NSW 2500,
Australia
Cite this: DOI: 10.1039/c3np70118b
Received 13th November 2013
DOI: 10.1039/c3np70118b
www.rsc.org/npr
This journal is © The Royal Society of Chemistry 2014 Nat. Prod. Rep.
NPR
REVIEW
Published on 29 May 2014. Downloaded by University of Wollongong on 03/07/2014 03:18:20.
View Article Online
View Journal
biodiverse and species-rich habitats on the planet, rivalling
those of coral reefs and rainforests.
17
Yet, of the 24 000 marine
natural products described to date,
23
less than 2% derive from
deep-water fauna, with a third of those compounds being
described in the last ve years. Although diculty in accessing
the deep sea has previously hindered research, improved
acoustic technology and collaboration with marine-based
industries is providing greater access to submersible tech-
nology, giving momentum to the growing frontier of deep-sea
research and uncovering a wealth of new species on continental
shelves and seamounts worldwide (Fig. 1).
24
In 2008, we published the rst comprehensive review to
focus solely on marine natural products isolated from deep-sea
fauna totalling almost 400 compounds.
18
Herein, this review
describes a further 188 new deep-sea natural products reported
in the last ve years. The deep sea is variably dened as
commencing at depths of anywhere between 100 and 1000 m;
however, for the purposes of this review deep-sea fauna are
dened as those inhabiting depths of greater than 50 m
(164 ), in order to include fauna beyond the depths of scuba.
The majority of deep-sea natural products in this review have
been isolated from deep-sea sponges, echinoderms, and
microorganisms obtained using manned submersibles, or from
commercial and scientic dredging and trawling operations
from all regions around the world. Herein, where no biological
activity or stereochemistry is ascribed to a particular metabolite
(or stereochemical centre) it is because, to the best of our
knowledge, no such data have yet been reported.
2 Reviews
In 2009, Wilson and Brimble reviewed molecules derived from
the extremes of life, including some deep-sea examples.
25
In
2010, Thomas and Kavlekar et al. reviewed marine drugs from
spongemicrobe associations, including some deep-sea exam-
ples.
26
A detailed review on the potential of deep-sea hydro-
thermal vents as hot spots for natural product discovery by
Thornburg and co-workers appeared in 2010,
27
including
biogeography and the diversity of vent communities, and
collection and cultivation of vent organisms. The culturability
and diversity of extreme microbes was also covered in 2011 by
Pettit.
28
In 2011, Winder and Pomponi et al. reviewed Lithistida
sponge metabolites from both shallow- and deep-water habitats
reported since 2000,
29
while in 2012, Silva and Alves et al. pub-
lished a review on polymeric and ceramic materials isolated
from marine sources, which included deep-sea sponges.
30
3 Deep-sea life
There are vastly dierent environmental conditions and
oceanographic parameters operating in the deep-sea (Fig. 2).
31,32
Pressure increases by 1 atm for every 10 m below sea level,
thereby varying from 10 atm at the shelf-slope interface to >1000
atm in the deepest part of the trenches. Consequently, species
inhabiting these depths must adapt their biochemical
machinery to cope with such pressures. Temperatures taper o
rapidly with increasing depth down to 2C at bathyal depths
Fig. 1 Deep-sea fauna. From left to right: the carnivorous giant club
sponge Chondrocladia gigantea and cerianthid anemone in the
background; the basket star Gorgonocephalus caputmedusae; and
the hydroid Tubularia sp. All images from 920930 m depth, Norway,
courtesy of SERPENT Project, Southampton, UK.
Danielle Skropeta obtained her
BSc(Hons) degree from Monash
University and her PhD degree
from the Australian National
University. She has held post-
doctoral appointments in
marine natural products with F.
Pietra at Trento University,
Italy, and in carbohydrate
chemistry with R. R. Schmidt at
Konstanz University, Germany,
as well as at the University of
Sydney and the Heart Research
Institute. In 2006 she took up a lectureship at Wollongong
University, where she is now a Senior Lecturer, working in the area
of bioorganic and medicinal chemistry, with particular interests in
deep-sea natural products.
Liangqian Wei received his
BMed from the First Military
Medical University in P. R.
China in 2002. He received his
PhD in Pharmaceutical Science
under the guidance of Dr David
Watson at the University of
Strathclyde in the United
Kingdom in 2008. His PhD
research focused on the analysis
of sugars in dierent Echinacea
tinctures. Aerwards he worked
as a teaching assistant in the
Strathclyde Institute of Pharmacy and Biomedical Sciences in
Scotland for two years. He then joined the research group of Dr
Danielle Skropeta at the University of Wollongong in Australia in
2011 working on the isolation and structural elucidation of
bioactive metabolites from deep-sea sponges.
Nat. Prod. Rep. This journal is © The Royal Society of Chemistry 2014
NPR Review
Published on 29 May 2014. Downloaded by University of Wollongong on 03/07/2014 03:18:20.
View Article Online
of >2000 m. As lower temperatures reduce the rates of chemical
reactions, deep-sea species must adjust their biochemical
processes to function at depressed temperatures. Light pene-
tration decreases exponentially with depth, such that below
250 m essentially no light penetrates. In the dark, cold depths of
the ocean, vision becomes less important, and it is presumed
that chemoreception and mechanoreception play greater roles.
The near-bottom current is much slower in the deep sea
compared to shallow-water with speeds of around 10 cm s
1
at
bathyal depths and 4 cm s
1
at abyssal depths. The average
metabolic rates and growth rates are lower than shallow-water
species; however, the latter is closely aligned to food availability.
In the deep-sea the pH is typically around 8
33,34
and the salinity
about 3.5% (35 g kg
1
) and therefore entirely marine, with a
relatively low level of variability. Oxygen concentration drops
from 7 mL L
1
at the surface to 3 mL L
1
at around 500 m, and
to less than 0.1 mg L
1
in oxygen minimum zones. The sediment
comprises weathered rock washed into the sea by wind and
rivers, as well as planktonic material obtained from the water
above, with intensied rates of microbial carbon turnover
observed in the deepest oceanic trenches.
31,32
The extraordinarily high level of diversity of deep-sea benthic
fauna has been well known, and the mechanism to explain it
hotly debated, since the 1960s.
3539
So-bottom deep-sea fauna
are found to be similar at the higher taxonomic level to shallow-
water fauna and consist primarily of megafauna such as echi-
noderms (sea cucumbers, star sh, brittle stars) and anemones;
macrofauna such as polychaetes, bivalve molluscs, isopods,
amphipods and other crustacea; and meiofauna which
primarily comprise foraminifers, nematodes and copepods,
whereas hard-bottom deep-sea fauna are dominated by sponges
and cnidarians (socorals, gorgonians).
At the species level, however, there are a high number of
single rare species, with more than half being new to science,
with some taxa possessing >95% of undescribed species. In
addition, many of the species are found to exclusively inhabit
the deep sea, with high levels of biodiversity extending to
abyssal depths of 5000 m.
31,32
Although abundance decreases
with increasing depth, species richness appears to increase with
the highest number of species found at depths of 3000 m and
beyond.
A number of deep-sea psychrophilic (cold-loving) and ther-
mophilic (heat-loving) microorganisms have been isolated, and
their mechanisms of adapting to high pressure,
4045
and either
cold temperatures (in the majority of the deep-sea)
4648
or high
temperatures (around hydrothermal vents),
4952
have been well
documented. There is a multitude of recent papers detailing the
characterisation, cloning, expression and function analysis of
various genes from deep-sea organisms along with investiga-
tions into the microbial diversity of deep-sea sponge-associated
bacteria and other deep-sea sediment-derived microbes.
5357
However, it is beyond the scope of this review to cover the
diverse range of developments in the elds of marine biotech-
nology, ecology and biology. For an introductory overview of the
biology of deep-sea life, see the earlier review in this series.
18
4 Bryozoa
Bryozoans such as moss animals and lace corals are abundant
in the marine environment with over 5000 species described to
date, ranging from shallow-water species to those living at
depths of over 8500 m.
5961
The secondary metabolites of bryo-
zoans have been reviewed elsewhere.
6264
Although shallow-
water bryozoan species have produced such medicinally
important compounds as the anti-cancer lead bryostatin 1 iso-
lated from Bugula neritina,
6567
there is only a single report on
secondary metabolites from a deep-sea bryozoan. In 2011, Davis
et al. described the rst deep-water bryozoan metabolites, the
brominated alkaloids convolutamine I (1) and J (2), isolated
from Amathia tortusa collected by trawling at a depth of 63 m
(Bass Strait, Tasmania, Australia). Compound 1displayed
Fig. 2 World ocean bathymetric map.
58
The vast oceans cover 70% of the world's surface, with 95% greater than 1000 m deep.
This journal is © The Royal Society of Chemistry 2014 Nat. Prod. Rep.
Review NPR
Published on 29 May 2014. Downloaded by University of Wollongong on 03/07/2014 03:18:20.
View Article Online
cytotoxicity (IC
50
of 22.0 mM) against the human embryonic
kidney (HEK293) cell line, whereas both 1and 2were active
against the parasite Trypanosoma brucei with IC
50
values of 1.1
and 13.7 mM, respectively.
68
5 Chordata
Ascidians comprise >2800 species and have yielded a diverse
array of bioactive metabolites,
69,70
including anticancer agents
such as didemnin B from Trididemnum solidum, diazonamide
from Diazona angulata, and the approved anticancer drug
Ecteinascidin 743 (Yondelis) from Ecteinascidia turbinata.
71,72
Deep-water ascidians from both the Atlantic and Pacic oceans
are found at up to depths of over 8000 m,
7375
and present a
potentially rich source of interesting new metabolites. In 2008,
Moser reviewed the cytotoxic cephalostatins and ritterazines
isolated from the colonial marine worm Cephalodiscus gilchristi
and the colonial marine tunicate Ritterella tokioka;
76
however, to
date, only a small number of reports on the secondary metab-
olites of deep-water ascidians have been reported.
Rossinones A (3) and B (4) were isolated from an Aplidium
ascidian species collected from Ross Sea, Antarctica by dredging
at a depth of 200 m. While rossinone A (3) showed only modest
biological activities, rossinone B (4) exhibited antileukemic,
anti-inammatory and antiviral properties.
77
Use of the Mosher
ester method established the absolute conguration of
rossinone A as 90R, while a biomimetic synthesis of the racemic
rossinone B has also been reported.
78
A series of colonial ascidians belonging to the genera Aplidium
and Synoicum collected in Antarctic waters at depths of 280
340 m, were recently evaluated for their chemical defensive
properties towards the starsh Odontaster validus and the
amphipod Cheirimedon femoratus. Four known meroterpenoids,
rossinone B, 2,3-epoxy-rossinone B, 3-epi-rossinone B, and 5,6-
epoxy-rossinone B, along with the indole alkaloids meridianins A
G, were isolated from several of the deep-water ascidian species.
79
6 Cnidaria
The phylum Cnidaria, comprising over 10 000 species, is divided
into four classes: sessile Anthozoa (anemones, corals, sea pens),
swimming Scyphoza (jellysh), Hydrozoa (hydroids), and
Cubozoa (box jellysh). Cnidarians are the second largest source
(aer sponges) of new marine natural products reported each
year, with a predominance of terpenoid metabolites
8082
and are
also well represented in the deep sea. In 2010, the stinging
venoms of the Mediterranean scyphozoan jellysh were
reviewed by Mariottini et al.
83
In 2012, the chemical constituents
and biological properties of the marine socoral Nephthea were
reviewed by Amir et al. including deep-sea species.
83,84
Anthozoans are the most abundant class of cnidarians with
over 6500 species known. Since 2008, of the four cnidarian
classes, only a small handful of reports on novel secondary
metabolites have appeared, all from deep-sea anthozoans, from
the order Alcyonacea (socorals). The deep-sea cnidarian
Acanthoprimnoa cristata collected by dredging at a 138 m depth
in the Yakushima-Shinsone, Kagoshima Prefecture, Japan,
yielded a new xenicane diterpenoid, cristaxenicin A (5) that
exhibited potent antiprotozoal activities against Leishmania
amazonensis and Trypanosoma congolense with IC
50
values of 88
and 250 nM, respectively.
85
Two new dolabellane diterpenoids (6and 7) were also reported
from the cnidarian Convexella magelhaenica collected from the
SouthAtlanticbydredgingatadepthof93m.Both5and 6
exhibited signicant cytotoxic activities against a human pancre-
atic adenocarcinoma cell line at micromolar concentrations.
86
The cnidarian Echinogorgia pseudossapo (from Sanya, Hainan
Province, P.R. China) was the source of two new alkaloids,
pseudozoanthoxanthins III and IV (8and 9) and two new
Nat. Prod. Rep. This journal is © The Royal Society of Chemistry 2014
NPR Review
Published on 29 May 2014. Downloaded by University of Wollongong on 03/07/2014 03:18:20.
View Article Online
sesquiterpenes (10 and 11). Compound 8showed moderate anti-
HSV-1 (Herpes Simplex Virus type-1) and anti-RSV (Anti-Respira-
tory Syncytial Virus) activity, whereas the guaiane 11 displayed
signicant antilarval activity towards Balanus amphitrite larvae.
87
7 Echinodermata
There are over 7000 living species of echinoderms worldwide,
divided into ve classes: Asteroidea (sea stars, starsh); Crin-
oidea (sea lilies, feather stars); Echinoidea (sea urchins); Hol-
othuroidea (sea cucumbers); and Ophiuroidea (brittle stars).
Echinoderms are well known producers of bioactive glycosy-
lated metabolites, dominated by steroidal metabolites, sapo-
nins and glycolipids.
8082
They are the most abundant species of
invertebrate fauna found in the deep sea, and while many new
natural products have been described from deep-sea examples
from the rst four classes, new secondary metabolites from
deep-water ophiuroids are yet to be described.
Recently, gymnochromes E (12) and F (13) and 7-bromoe-
modic acid (14), together with anthraquinone metabolites and
emodic acid, were reported from the crinoid Holopus rangii
collected from the south coast of Curaçao at a depth of 358 m.
Gymnochrome E inhibited not only the proliferation of the NCI/
ADRRes (multi-drug-resistant ovarian cancer cell line) with an
IC
50
value of 3.5 mM, but also histone deacetylase-1 (HDAC-1)
with an IC
50
value of 10.9 mM. Gymnochrome F was a moderate
inhibitor of myeloid cell leukemia sequence 1 (MCL-1) binding
to Bak with an IC
50
value of 3.3 mM. Gymnochrome E exhibited
minimum inhibitor concentrations (MICs) of 25 mgmL
1
against both Staphylococcus aureus and methicillin-resistant
S. aureus (MRSA), while gymnochrome F exhibited MICs of
12.5 mgmL
1
against S. aureus and MRSA.
88
Isolation work on the scarlet-coloured crinoid Proisocrinus
ruberrimus obtained from Aguni Knoll, central Okinawa Trough,
at a depth of approximately 1800 m, gave six new brominated
anthraquinone pigments named proisocrinins AF(1520), all
of which were present as optically active enantiomers, although
their absolute conguration could not be assigned from the
available data. This is the rst report of tribromo- and tetra-
bromo-anthraquinones isolated from a natural source.
89
The Antarctic deep-sea cucumber Achlionice violaecuspidata,
collected by trawling at a 1525 m depth, was the source of three
new triterpene glycosides, achlioniceosides A
1
(21), A
2
(22), and
A
3
(23). These disulfated pentaosides are branched at the rst
xylose residue with a sulfate attached to C-6 of the glucose
residues, and constitute the rst report of sea cucumber tri-
terpene glycosides from the order Elasipodida.
90
This journal is © The Royal Society of Chemistry 2014 Nat. Prod. Rep.
Review NPR
Published on 29 May 2014. Downloaded by University of Wollongong on 03/07/2014 03:18:20.
View Article Online
8 Microorganisms
Marine microorganisms are a rich source of diverse and struc-
turally unique metabolites.
9193
Recently, the bioactive metabo-
lites isolated from marine cyanobacteria with cytotoxicity, anti-
inammatory and antibacterial activities were reviewed,
15
along
with peptides isolated from the Moorea (formerly Lyngbya)
genus of cyanobacteria.
28
Marine drugs isolated from microbes
associated with marine sponges of the class Demospongiae and
the orders Halichondrida, Poecilosclerida and Dictyoceratida
were also recently reviewed.
26
8.1 Bacteria
The culture broth of the marine bacterium Bacillus subtilis,
isolated from deep-sea sediment collected at a depth of 1000 m
in the Red Sea, was found to yield four novel amicoumacins,
lipoamicoumacins AD(2427), and one new bacilosarcin
analogue (28) along with six known amicoumacins.
94
Two of the
known amide-containing amicoumacin and bacilosarcin
analogues were found to display both signicant cytotoxicity
against HeLa cells and antibacterial activity against B. subtilis,S.
aureus and Laribacter hongkongensis, with the amide group
essential for activity.
Seven dermacozines AG(2935) were reported from the
actinobacteria Dermacoccus abyssi sp. nov., strains MT1.1 and
MT1.2, isolated from Mariana Trench sediment collected at a
depth of 10 898 m by the remotely operated submarine Kaik¯
o.
Dermacozines F (34) and G (35) displayed moderate cytotoxic
activity against the leukaemia cell line K562 with IC
50
values of 9
and 7 mM, respectively, whereas dermacozine C (31) also
exhibited high radical scavenger activity with an IC
50
value of
8.4 mM.
95
DNA extraction of sediment samples obtained at depths of
3006 m in the south western Indian Ocean, followed by met-
agenomic cloning and transformation into Escherichia coli,
has yielded eight known compounds along with the novel,
optically-active indole alkaloid (36) from the fermentation
broth. The alkaloid, for which the stereochemistry at the
chiral centre was not dened, exhibited some analgesic
activity.
96
The culture broth of a Verrucosispora sp. actinomycete
obtained from marine sediment collected at a depth of 3865 m
in the northern South China Sea was found to contain the
unique b-carboline alkaloids, the marinacarbolines AD
(3740), two new indolactam alkaloids, 13-N-demethyl-methyl-
pendolmycin (41) and methylpendolmycin-14-O-a-glucoside
(42), and the three known compounds 1-acetyl-b-carboline,
methylpendolmycin and pendolmycin. The six new compounds
exhibited strong antiplasmodial activities against Plasmodium
falciparum lines 3D7 and Dd2, with IC
50
values ranging from 1.9
to 36.0mM, but were inactive against a range of tumour cell
lines.
97
The rst total synthesis of marinacarbolines AD was
described in 2013,
98
along with discovery of an enzyme cata-
lyzing the b-carboline skeleton construction in the mari-
nacarboline biosynthetic pathway.
99
Nat. Prod. Rep. This journal is © The Royal Society of Chemistry 2014
NPR Review
Published on 29 May 2014. Downloaded by University of Wollongong on 03/07/2014 03:18:20.
View Article Online
Two novel 20-membered macrolides, levantilide A (43) and B
(44), have been obtained from the actinobacterium Micro-
monospora strain M71-A77, recovered from a 4400 m deep-sea
sediment sample from the Eastern Mediterranean Sea.
Levantilide A exhibited moderate antiproliferative activity
against several tumour cell lines.
100
Nocardiopsins A (45) and B (46) have been isolated from a
marine-derived actinomycete Nocardiopsis sp. (CMB-M0232)
cultured from deep-sea sediment collected at a depth of 55 m o
the coast of Brisbane, Australia, in 2010, while a further two new
prenylated diketopiperazines, nocardioazine A (47) and B (48),
were isolated from the same sediment sample and reported in
2011. Compounds 45 and 46 were examined for their bioactivity
and found to be neither antibacterial, antifungal nor cytotoxic,
although they did exhibit binding to the immunophilin
FKBP12.
101
Attempts at assigning absolute conguration at the
C-5 centre via a Mosher ester were not successful, and only the
partial absolute (15Z,21E,24S) and relative (9,12-cis) congura-
tions were determined. Nocardioazine A (47) was found to be a
non-cytotoxic inhibitor of the membrane protein eux pump P-
glycoprotein, reversing doxorubicin resistance in a multidrug-
resistant colon cancer cell line.
102
The total synthesis of
nocardioazine B in an overall yield of 11.8% has been described,
along with determination of the absolute conguration.
103
The actinobacterium Pseudonocardia sp. strain
(SCSIO 01299), recovered from deep-sea sediment obtained at
3258 m depth in the South China Sea, yielded three new dia-
zaanthraquinone derivatives, pseudonocardians AC(4951),
along with a previously synthesized compound deoxy-
nyboquinone. The pseudonocardians AC exhibited cytotoxic
activity against three tumour cell lines SF-268 (central nervous
system cancer), MCF-7 (breast cancer) and NCI-H460 (lung
cancer) with IC
50
values ranging between 0.01 and 0.21 mM. The
compounds also showed antibacterial activities against S. aureus
ATCC 29213, Enterococcus faecalis ATCC 29212 and Bacillus
thuringensis SCSIO BT01, with MIC values of 14mgmL
1
,
104
and
are the subject of a recent Chinese patent.
105
The deep-sea actinomycete Serinicoccus profundi sp. isolated
from deep-sea sediment from the Indian Ocean yielded the new
indole alkaloid (52), together with ve known compounds. The
new indole alkaloid displayed weak antimicrobial activity
against S. aureus ATCC 25923 with an MIC value of 96 mgmL
1
,
This journal is © The Royal Society of Chemistry 2014 Nat. Prod. Rep.
Review NPR
Published on 29 May 2014. Downloaded by University of Wollongong on 03/07/2014 03:18:20.
View Article Online
and was not cytotoxic when tested against a normal human liver
cell line (BEL7402) and a human liver tumour cell line (HL-
7702).
106
Fermentation of the actinobacteria Streptomyces lusitanus,
obtained from 3370 m deep sediment collected in the South
China Sea, provided ve new C-glycoside angucycline metabo-
lites, grincamycins BF(5357), and a known angucycline
antibiotic, grincamycin. With the exception of grincamycin F,
all other compounds displayed in vitro cytotoxicities against the
human cancer cell lines HepG2 (hepatocellular liver), SW-1990
(pancreatic), HeLa (epithelial carcinoma), NCI-H460 (lung), and
MCF-7 (breast adenocarcinoma); and the mouse melanoma cell
line (B16), with IC
50
values ranging from 1.1 to 31 mM.
107
The
gene cluster responsible for the biosynthesis of grincamycin
derviatives in S. lusitanus SCSIO LR32 has been identied and
patented.
108,109
A deep-sea-derived actinobacterium Streptomyces sp.
SCSIO 03032, recovered from a sediment sample at 3412 m
depth in the Indian Ocean, yielded four novel bisindole alka-
loids spiroindimicins AD(5861), together with two known
compounds, lynamicins A and D. Spiroindimicins BD with a
[5,5] spiro-ring displayed moderate cytotoxicities against several
cancer cell lines
110
and are the subject of a recent patent on the
application of using Streptomyces for the preparation of anti-
tumour compounds.
111
Another Streptomyces sp. (KORDI-3973), obtained from a
deep-sea sediment sample collected at the Ayu Trough region in
the Philippine Sea, was found to contain the unique benzyl
pyrrolidine derivative streptopyrrolidine (62), with signicant
anti-angiogenesis activity.
112
Stereoselective synthesis of the
four possible isomers of streptopyrrolidine established the
absolute conguration as (4S,5S),
113
and there have been several
other synthetic investigations into this novel but structurally
unassuming anti-angiogenic compound.
114117
A further Streptomyces sp. (NTK 937), recovered from an
Atlantic Ocean deep-sea sediment core collected at a depth of
3814 m, yielded a new benzoxazole antibiotic, caboxamycin (63),
which exhibited inhibitory activity against Gram-positive
bacteria and the enzyme phosphodiesterase, as well as cytotoxic
activity towards gastric adenocarcinoma (AGS), hepatocellular
carcinoma (HepG2), and a breast carcinoma cell line (MCF7).
118
Caboxamycin has been synthesised using environmentally-
friendly reagents,
119
and is also the subject of a recent patent on
inhibitors of hepatitis C virus.
120
Nat. Prod. Rep. This journal is © The Royal Society of Chemistry 2014
NPR Review
Published on 29 May 2014. Downloaded by University of Wollongong on 03/07/2014 03:18:20.
View Article Online
The highly coloured ammosamides A (64)andB(65)were
isolated from a Streptomyces strain (CNR-698a) recovered from
deep-sea sediment collected at a depth of 1618 m othe Baha-
mas Islands.
121
The compounds exhibited potent cytotoxicity
against the HCT-116 colon carcinoma cell line with IC
50
values of
320 nM each, along with marked selectivity in a diverse cancer
cell line panel. Fluorescent labelling of ammosamide B and
subsequent cellular studies identied a member of the myosin
family, which is important for cell cycle regulation and migra-
tion, as the ammosamide target.
122
The ammosamides, and in
particular ammosamide B, have been the subject of several
synthetic investigations including by Hughes and Fenical in 17
19 steps from 4-chloroisatin in 2010,
123
later reviewed by Zur-
werra;
124
in 9 steps and 7% overall yield by Reddy et al. and in 5
steps by Wu et al., both in 2010;
125
and by a FriedelCras
strategy by Takayama et al. reported earlier this year.
126
A series of
ammosamide B analogues have been prepared and evaluated as
inhibitors of quinone reductase 2 (QR2) by Reddy and co-workers
in 2012. The natural product ammosamide B was the among the
most potent QR2 inhibitor of the series, with potencies
decreasing as structures diverged from ammosamide B, apart for
methylation of the 8-amino group of ammosamide B, which led
to an increase in activity from an IC
50
value of 61 nM to 4.1 nM.
127
AStreptomyces sp. strain NTK 935, recovered from a deep-sea
sediment sample collected at a depth of 3814 m in the Canary
Basin, yielded a new 1,4-benzoxazine-type metabolite, benzox-
acystol (66), which displayed inhibitory activity against the
enzyme glycogen synthase kinase-3band weak antiproliferative
activity against a mouse broblast cell line.
128
Bioassay-directed fractionation of a large-scale culture of the
deep-sea sediment-derived actinomycete, Verrucosispora sp.
(MS100128), from the South China Sea (2733 m depth) yielded
three new examples of a rare class of polyketides, abyssomicins
JL(6769),
129
along with the four known abyssomicins BD
130
and H.
131
The compounds were discovered by screening for
growth inhibitory activity against Bacille Calmette Gu´
erin (BCG),
a non-pathogenic strain of the bovine tuberculosis bacillus
Mycobacterium bovis, with anti-BCG activities for abyssomicin J
comparable to those of the known abyssomicin C, with MIC
values of 3.13 and 6.25 mgmL
1
, respectively.
129
The authors
proposed that abyssomicin J acts a natural prodrug undergoing
in situ reverse Michael addition to give the more active Michael
acceptor-containing derivative atrop-abyssomicin C.
129
Abysso-
micins BD were originally described from the deep-sea
Verrucosispora sp. (AB-18-032),
130,132
now identied as the new
taxon Verrucosispora maris sp. nov.;
133
however, it should be
noted that the abyssomicin scaold is not exclusive to the deep-
sea and has also been found from terrestrial sources including
abyssomicin E and I from the soil Streptomyces sp. HK10381
134
and CHI39
135
respectively, and ent-homoabyssomicins A and B
from another soil Streptomyces sp. (Ank 210).
136
8.2 Fungi
In the last ve years, fungi derived from deep-water sediments
have yielded an array of interesting new metabolites. Two new
indole diketopiperazines, luteoalbusins A and B (70 and 71),
along with eight known ones, T988A, gliocladines CD, cheto-
seminudins BC, cyclo(L-Trp-L-Ser-), cyclo(L-Trp-L-Ala-) and
cyclo(L-Trp-N-methyl-L-Ala-), were isolated from the fungus
Acrostalagmus luteoalbus SCSIO F457 originating from a deep-
sea sediment sample collected at a depth of 2801 m in the South
China Sea
137
The novel compounds displayed strong cytotoxic
activities against four cancer cell lines (SF-268, MCF-7, NCI-
H460 and HepG2) with IC
50
values in the range of 0.231.31 mM,
and were signicantly more potent that the control cisplatin.
This journal is © The Royal Society of Chemistry 2014 Nat. Prod. Rep.
Review NPR
Published on 29 May 2014. Downloaded by University of Wollongong on 03/07/2014 03:18:20.
View Article Online
The deep-sea fungus Aspergillus sp., obtained from a soil
sample collected at a depth of 50 m near Waikiki Beach (Hon-
olulu, Hawaii), was found to produce two novel metabolites: a
new complex prenylated indole alkaloid named waikialoid A
(72), and a polyketide metabolite, waikialide A (73).
Waikialoid A, inhibited Candida albicans biolm formation
with an IC
50
value of 1.4 mM, whereas waikialide A was less
potent with an IC
50
value of 32.4 mM.
138
The deep-sea-derived fungus Aspergillus versicolor obtained
from 800 m depth in the Pacic Ocean has furnished three new
sterigmatocystin derivatives, oxisterigmatocystin AC(7476),
along with the known compound, 5-methoxyster-
igmatocystin.
139
The compounds were evaluated for cytotoxicity
towards the A-549 and HL-60 cell lines, with only the known
compound being shown to exhibit moderate low micromolar
cytotoxicity.
A rich collection of both novel and known alkaloids were also
obtained from Aspergillus westerdijkiae DFFSCS013, obtained
from South China Sea at a depth of 2918 m. The metabolites
included two new benzodiazepine alkaloids, circumdatins K and
L(77 and 78); two new prenylated indole alkaloids, 5-chloro-
sclerotiamide (79) and 10-epi-sclerotiamide (80); a novel amide,
aspergilliamide B (81); and six known alkaloids. The compounds
were evaluated against a range of human cancer cell lines (A549,
HL-60, K562, and MCF-7) but did not exhibit any cytotoxicity.
22
In 2013, two highly oxygenated polyketides, penilactones A
and B (82 and 83) of related structure but opposite absolute
stereochemistry, were isolated from the Antarctic deep-sea-
derived fungus Penicillium crustosum PRB-2, along with ve
known compounds.
140
The penilactones contain a new carbon
skeleton formed from two 3,5-dimethyl-2,4-diol-acetophenone
units and a g-butyrolactone moiety, and have been prepared by
a biomimetic synthesis reported the following year.
141
The novel
triazole carboxylic acid, penipanoid A (84), two new quinazoli-
none alkaloids, penipanoids B (85) and C (86), and a known
quinazolinone derivative were isolated from the marine sedi-
ment-derived fungus Penicillium paneum SD-44 obtained at a
depth of 201 m in the South China Sea.
142
The cytotoxic and
antimicrobial activities of the compounds were evaluated, and
found to possess mid-to-low micromolar activity towards
SMMC-7721 (liver), BEL-7402 (liver), and A-549 (lung) cancer
cell lines, but no activity when screened against two bacteria
and ve plant-pathogenic fungi. Penipanoid A is reportedly the
rst example of a triazole derivative from marine sediment-
derived fungi, while penipanoid B is a rare quinazolinone
derivative containing a dihydroimidazole ring system.
Nat. Prod. Rep. This journal is © The Royal Society of Chemistry 2014
NPR Review
Published on 29 May 2014. Downloaded by University of Wollongong on 03/07/2014 03:18:20.
View Article Online
In 2011, berkeleyones AC(8789) along with the known
preaustinoids A and A1 were obtained from the deep-water
fungus Penicillium rubrum from sediment obtained at a 270 m
depth from the acid mine waste Berkeley Pit Lake, in Montana,
USA.
143
The compounds were evaluated for inhibition of the
signaling enzyme caspase-1 and for mitigation of interleukin-1b
production in induced THP-1 cells, with activity comparable to
that of the commercially supplied inhibitor Ac-YVAD-CHO in
the latter assay.
In 2009, Lis group reported the isolation and characteriza-
tion of three new bioactive breviane spiroditerpenoids, bre-
viones FH(9092), from the deep-sea sediment-derived fungus
Penicillium sp. (MCCC 3A00005) collected at a depth of 5115 m
in the East Pacic.
144
In 2012, the same group reported the
isolation of breviones IK(9496), a novel polyoxygenated
sterol, sterolic acid (93), along with four known breviones, from
the same fungal strain. Brevione I exhibited signicant cyto-
toxicity against MCF-7 cells.
145
Earlier members of the brevione
family (AC) have been the subject of several recent synthetic
studies,
146,147
along with the synthesis of the western half of
brevione C, D, F and G by Macias et al. in 2010.
148
Synthetic
studies on breviones and structurally-related natural products
have been reviewed by Takikawa.
149
The fungus Penicillium sp. (F00120), recovered from deep-sea
sediment obtained at a depth of 1300 m from northern South
China Sea, yielded the new sesquiterpene quinone,
penicilliumin A (97), along with known ergosterol and ergos-
terol peroxide. Penicilliumin A moderately inhibited the in vitro
proliferation of mouse melanoma (B16), human melanoma
(A375), and human cervical carcinoma (HeLa) cell lines.
150
This journal is © The Royal Society of Chemistry 2014 Nat. Prod. Rep.
Review NPR
Published on 29 May 2014. Downloaded by University of Wollongong on 03/07/2014 03:18:20.
View Article Online
The fungus Phialocephala sp., isolated from deep-sea sedi-
ment obtained from the East Pacic at a depth of 5059 m, was
the source of two new sorbicillinoids (98 and 99), together with
a novel benzofuranone derivative named phialofurone (100). All
compounds displayed cytotoxicity towards P388 murine
leukemia (IC
50
values of 11.5, 0.1, and 0.2 mM, resp.) and K562
human erythromyeloblastoid leukemia (IC
50
values of 22.9, 4.8
and 22.4 mM, resp.) cell lines.
151
A novel cytotoxic cyclopentenone, trichoderone (101), was
isolated from a marine-derived fungus Trichoderma sp.
obtained from deep-sea sediment collected in the South China
Sea. Trichoderone displayed potent activity against six cancer
cell lines, with a selectivity index of over 100 compared to
normal cells. The compound also exhibited activities against
HIV protease and Taq DNA polymerase.
152
9 Mollusca
The deep-sea mollusc Bathymodiolus thermophilus, collected
using a deep submergence vehicle at a depth of 1733 m from an
active hydrothermal vent in the north of Lucky Strike in the Mid-
Atlantic Ridge, has furnished the rst reported molluscan deep-
sea small-molecular metabolites, two novel ceramide derivatives,
bathymodiolamides A (102)andB(103), both of which exhibited
apoptosis induction and potential anticancer activity.
153
10 Porifera
Sponges are extremely well represented in the marine environ-
ment, with over 8000 species ranging from shallow-water to
those inhabiting depths of over 8800 m, with some deep-water
species adopting carnivorous behaviour.
11,154
Marine sponges
are the largest source of new marine natural products reported
annually
8082
and have provided a rich array of biologically
important compounds,
155
including the natural product
analogue cytosine arabinoside from the Caribbean sponge
Tethya crypta, halichondrin B from the Japanese sponge Hal-
ichondria okadai, discodermolide from the Caribbean sponge
Discodermia dissoluta and agelasphin from Agelas maur-
itianus.
71,156
Sponge metabolites, predominantly from shallow-
water species, have been reviewed previously,
154,157
while in
2011, Winder et al. reviewed the natural products isolated from
lithistid sponges collected since 2000 including deep-sea
species.
29
Deep-water species of marine sponges have already
provided important anticancer leads such as halichondrin and
discodermolide
71
and are certain to be a rich new source of
biologically and structurally interesting molecules.
10.1 Order Astrophorida
Four novel alkaloids, the bistellettazines AC(104106) and the
bistellettazole A (107), were described from a deep-water Pacic
Nat. Prod. Rep. This journal is © The Royal Society of Chemistry 2014
NPR Review
Published on 29 May 2014. Downloaded by University of Wollongong on 03/07/2014 03:18:20.
View Article Online
sponge belonging to the genus Stelletta, retrieved from a 90 m
depth from the Great Australian Bight.
158
From the same Order, three cytotoxic polyketides, frank-
linolides AC(108111), were isolated from the deep-sea sponge
Geodia sp. thinly encrusted with a Halichondria sp., collected at
a depth of 105 m, also from trawling operations in the Great
Australian Bight.
159
10.2 Order Dictyoceratida
ThemarinespongeAplysinopsis digitata,obtainedduring
deep-sea dredging at a depth of 150 m at Oshima-shinsone,
Kagoshima Prefecture, Japan, was found to produce the
three novel sesterterpenoids, aplysinoplides AC(112114),
with cytotoxic activity against the P388 murine leukemia
cell line.
160
Bioassay-directed fractionation of a deep-sea collection of
the sponge Spongia (Heterobria) sp. at a 125 m depth in the
Great Australian Bight by Capon's group, led to the isolation
of six new compounds, the fatty acid heterobrins A1 (115)
and B1 (118), along with related monolactyl and dilactyl
esters, heterobrins A2 (116), B2 (119), A3 (117)andB3
(120).
161
Subsequent studies by the same group demonstrated
that heterobrin A1 inhibited lipid droplet biogenesis in
A431 cells and AML12 hepatocytes and also signicantly
reduced intracellular accumulation of fatty acids in both
cultured cells and zebrash (Danio rerio)embryos.
162
Ziva-
novic et al. described the fatty acid prole of a mixed spec-
imen of Ircinia/Sarcotragus sp.froman84mdepthfromthe
North West Shelf of Australia, reporting a greater proportion
of saturated fatty acids than their shallow-water counterparts
and an absence of the C
24
C
25
D
5,9
demospongic acids typical
of marine sponges.
163
A deep-water sponge of the genus Fasciospongia, collected
during scientictrawlingoperationsatadepthof100m,west
of Cape Leeuwin, Western Australia, has yielded the new
meroterpene sulfate fascioquinol A (121) together with a series
of acid-mediated hydrolysis/cyclization products, fas-
cioquinols BD(122124), and strongylophorine-22 (125).
Additional co-metabolites include the new meroterpenes
fascioquinol E (126) and fascioquinol F (127), together with the
known sponge metabolite geranylgeranyl 1,4-hydroquinone.
By contrast, while the fascioquinols displayed little or no
inhibitory activity towards human cancer cell lines, fas-
cioquinols A and B displayed promising Gram-positive selec-
tive antibacterial activity towards S. aureus with IC
50
values
ranging from 0.9 to 2.5 mMandB. subtilis with IC
50
values
ranging from 0.3 to 7.0 mM.
164
This journal is © The Royal Society of Chemistry 2014 Nat. Prod. Rep.
Review NPR
Published on 29 May 2014. Downloaded by University of Wollongong on 03/07/2014 03:18:20.
View Article Online
10.3 Order Halichondrida
Three new bromopyrrolo-2-aminoimidazoles, 14-O-sulfate mas-
sadine (128), 14-O-methyl massadine (129), and 3-O-methyl
massadine chloride (130), together with the known metabolites
massadine chloride, massadine, stylissadine B, axinellamines A
C, hymenin, stevensine (also known as odiline), tauroacidin A,
hymenidin, taurodispacamide A, oroidin, debromohymenialdi-
sine, hymenialdisine, and aldisin, were isolated from a deep-sea
sponge Axinella sp. obtained at a depth of 85 m in the Great
Australian Bight.
165
Compound 130 displayed signicant growth
inhibitory activity against the Gram-positive bacteria S. aureus
and B. subtilis; Gram-negative bacteria E. coli and Pseudomonas
aeruginosa; and the fungus C. albicans. The massadines with
their complex architecture and interesting biological activities
have been the subject of several synthetic pursuits including an
enantioselective total synthesis of ()-palau'amine, ()-axinell-
amines, and ()-massadines from Baran's group,
166168
and by an
Ugi four-component coupling by Carreira's group.
169172
Wright and co-workers screened the extracts of 65 sponges,
gorgonians, hard corals and sponge-associated bacteria from
depths of 50 and 1000 m, giving rise to a 42% bioactivity hit rate
overall, and an impressive 72% for sponge and gorgonian
extracts.
15
From this screening, two sponges were chosen at
random for further investigation. The sponges Suberea sp.
(family Aplysinellidae) and Rhaphoxya sp. (family Halichon-
driidae), retrieved from a depth of 60 m and 90 m from the Black
Coral Kingdom, and Blue Hole, Guam, respectively, yieldeda vast
array of compounds including the novel theonellin isocyanate
(131) and novel bromotyrosine-containing psammaplysins I and
J(132 and 133), along with six previously reported compounds.
16
10.4 Order Haplosclerida
Two new marine-derived sesquiterpene benzoquinones, neo-
petrosiquinones A (134) and B (135), have been isolated from a
deep-water sponge Neopetrosia proxima collected at a depth of
140 m othe north coast of Jamaica, St. Ann's Bay. While both
compounds inhibited in vitro proliferation of the DLD-1 human
colorectal adenocarcinoma cell line with IC
50
values of 3.7 and
9.8 mM, respectively, and the PANC-1 human pancreatic carci-
noma cell line with IC
50
values of 6.1 and 13.8 mM, respectively,
neopetrosiquinone A also inhibited the in vitro proliferation of
the AsPC-1 human pancreatic carcinoma cell line with an IC
50
value of 6.1 mM.
173
Six linear acetylenes, ()-duryne (136) and ()-durynes BF
(137141) have been reported from the marine sponge
Nat. Prod. Rep. This journal is © The Royal Society of Chemistry 2014
NPR Review
Published on 29 May 2014. Downloaded by University of Wollongong on 03/07/2014 03:18:20.
View Article Online
Petrosia sp. collected by remotely operated vehicle (ROV) from a
depth of 415 m at Miyako sea-knoll, southwestern Japan. The
compounds (136137) exhibited cytotoxicity against HeLa cells
with IC
50
values between 80 and 500 nM.
174
An enantioselective
synthesis of (+)-duryne via a one-pot organocatalyzed hydroxyl-
ation/Ohira-Bestmann and Grubbs cross-metathesis/selective
cis-Wittig reaction has been reported, with the potential to
access other members of the family by this route.
175
Earlier
syntheses had established the geometry of the central double
bond and the absolute conguration of the chiral centres in (+)-
and ()-duryne.
176
Four new meroterpenes, alisiaquinones AC(142144)and
alisiaquinol (145), were isolated from a New Caledonian deep-
water sponge, Xestospongia sp., collected by trawling on a deep-sea
mount between depths of 250 and 400 m in the South of New
Caledonia, Norfolk Rise. The compounds exhibited micromolar
inhibitory activity towards plasmodial kinase Pfnek-1 and protein
farnesyl transferase, both important antimalarial targets.
Alisiaquinone C (144) displayed potent activity on P. falciparum
and competitive selectivity towards dierent plasmodial strains.
177
10.5 Order Homoscleropherida
The deep reef Caribbean sponges Plakortis angulospiculatus,
obtained by mixed gas scuba at a depth of 58 m from Little
Cayman Island, Bahamas, was found to produce a new
compound, 23-nor-spiculoic acid B (146) along with known
spiculoic acid B. Four other new compounds, zyggomphic
acid B (147), 27-nor-zyggomphic acid B (148), 22-nor-zyggom-
phic acid B (149) and 22,27-dinor-zyggomphic acid B (150), were
isolated from a second sample of the same sponge species
collected at 62 m from Exuma Cays, Bahamas, with compounds
146 and 148 found to inhibit NFkB activity with IC
50
values of
0.5 and 2.3 mM, respectively.
178
A third sample collected at a depth of 91 m from Exuma
Cays, Bahama, and identied as Plakortis halichondrioides
This journal is © The Royal Society of Chemistry 2014 Nat. Prod. Rep.
Review NPR
Published on 29 May 2014. Downloaded by University of Wollongong on 03/07/2014 03:18:20.
View Article Online
yielded three new aromatic compounds (151153), whereas
another deep-sea Plakortis sp., obtained at a depth of 96 m near
Blue Hole, Orote Peninsula, Guam, yielded a further six new
aromatic metabolites (154159), along with the known
compounds dehydrocurcuphenol and manoalide. The new
compounds were evaluated for antifungal and antibacterial
activity with the cyclic peroxides 154 and 155 showing weak
activity against S. aureus.
179
10.6 Order Lithistida
Bioassay-guided isolation of the deep-water sponge
Leiodermatium sp., collected at a depth of 618 m oWemyss
Bight in the Bahamas, furnished leiodermatolide (160), with a
previously unreported 16-membered macrolide skeleton. The
structurally unique compound exhibited potent antimitotic
activity (IC
50
< 10 nM) against human A549 lung adenocarci-
noma, PANC-1 pancreatic carcinoma, DLD-1 colorectal carci-
noma, and murine P388 leukemia cell lines.
180
The structurally
unique macrolide has attracted much interest and is the subject
of a patent by Wright and co-workers,
181
and several total
synthesis studies including by the research groups of Pater-
son,
182,183
Roush
184
and Maier.
185,186
The deep-sea sponges Theonella swinhoei and Theonella
cupola, obtained at a depth of 100120 m and 90 m, respectively,
yielded the new sulfated cyclic depsipeptide, mutremdamide A
(161), and six new highly N-methylated peptides, koshikamides
CH(162167). The cyclic koshikamides F and H were found to
inhibit HIV-1 entry at low micromolar concentrations, whereas
their linear counterparts were inactive.
187
The marine sponge T. swinhoei, obtained from Uchelbeluu
Reef in Palau at a depth of 100 m, was reported to produce three
new anabaenopeptin-like peptides, paltolides AC(168170).
188
The compounds were investigated for inhibition of HIV-1 entry
and cytotoxicity towards HCT-116, but were not active in either
assay.
10.7 Order Poecilosclerida
Three new polycyclic guanidine-containing mirabilins HJ
(171173), together with the known mirabilins C, F and G,
189,190
were isolated from a Southern Australian marine sponge
Clathria sp., retrieved by epibenthic sled at a depth of 60 m in
the Great Australian Bight.
191
Although the original n-BuOH
extract exhibited cytotoxicity against a range of human cancer
cell lines (HT-29, A549, MDA-MB-232), the puried mirabilins
displayed only modest activity (>30 mM). Mirabilins have also
been isolated from the marine sponges Batzella sp.
192
and
Monanchora unguifera,
193
and the synthesis of mirabilin B, along
with the a biosynthetic proposal, has been recently reported
from Snider's group.
194
A novel batzelline derivative featuring a benzoxazole moiety,
citharoxazole (174), along with the known batzelline C, was
isolated as a dark purple solid from the deep-sea Mediterranean
sponge Latrunculia (Biannulata) citharistae obtained by remotely
operated vehicle (ROV) at a 103 m depth oLa Ciotat, Banc de
Banquiere in France.
195
Bioassay- and LC-MS-guided fractionation of a new species
of deep-sea sponge belonging to the genus Latrunculia, collected
by dredging at a depth of 230 m othe Aleutian Islands, Alaska,
led to the isolation of two new brominated pyrroloiminoqui-
nones, dihydrodiscorhabdin B (175) as a dark green solid and
discorhabdin Y (176) as a purple solid, along with six known
pyrroloiminoquinone alkaloids, discorhabdins A, C, E, and L,
dihydrodiscorhabdin C, and a benzene derivative.
196
The abso-
lute conguration of 176 was assigned as 6Rfrom CD spec-
troscopy, but could not be assigned for 175 due to sample
decomposition during the collection of optical rotation and CD
data. The highly cytotoxic discorhabdins were rst reported
from the sponge Latrunculia sp. in 1986 by Blunt and
Munro.
197199
Their potent biological activity (including anti-
tumour, antimicrobial, and antiviral) and exquisite architecture
has attracted the attention of several research groups over the
years, with numerous synthetic endeavours reported including
by the groups of Kita,
200
Cava
201
and Heathcock,
202
and a recent
semi-synthesis by Copp and co-workers.
203
The discorhabdin
family of alkaloids have been reviewed by Molinski in 1993,
204
Harayama and Kita in 2005,
205
by Wada and co-workers in
2010
206
and by Hu and co-workers in 2011.
207
Although they
possess an impressive array of biological activities, the dis-
corhabdins have proven too non-selective for further drug
development.
On-going investigations of a large (1 tonne) collection of
the bright yellow deep-sea sponge Lissodendoryx sp. (family
Poecilosclerida), collected by trawling at a depth of 100 m
othe Kaikoura coast of New Zealand back in 1995 to supply
halichondrin B for earlier preclinical trials, has furnished
Nat. Prod. Rep. This journal is © The Royal Society of Chemistry 2014
NPR Review
Published on 29 May 2014. Downloaded by University of Wollongong on 03/07/2014 03:18:20.
View Article Online
four new variants of the halichondrin B skeleton,
halichondrin B-1140 (177), halichondrin B-1092 (178),
halichondrin B-1020 (179) and halichondrin B-1076 (180), with
comparable potency towards the P388 murine leukemia cell
line as halichondrin B.
208
Three novel diterpenyltaurines, phorbasins DF(181
183), together with the known phorbasins B and C, were
isolated by bioassay-guided fractionation of an Australian
deep-sea sponge, Phorbas sp., obtained by epibenthic sled at
a depth of 65 m in the Great Australian Bight.
209
Afurther
ve new members of the phorbasin family, phorbasins GK
(184188), were isolated from the same marine source,
although I and J are likely to be solvolysis artefacts.
210
The
phorbasins show low micromolar cytotoxicity towards a
range of human cancer cell lines including A549, HT29 and
MM96L cell lines.
This journal is © The Royal Society of Chemistry 2014 Nat. Prod. Rep.
Review NPR
Published on 29 May 2014. Downloaded by University of Wollongong on 03/07/2014 03:18:20.
View Article Online
11 Recent advances in the
development of deep-sea-derived
drugs
Natural product-derived drugs account for 50% of the drugs
used for the treatment of cancer and over 75% of the drugs used
for treating infectious diseases.
156,212,213
At the time of writing,
six marine-derived drugs have been approved for clinical use for
cancer, pain, and HIV (see Table 1), with tens more in dierent
phases of clinical trials, hundreds in preclinical trials and
thousands under development.
213,214
The six approved drugs are
the sponge-derived nucleosides cytarabine and vidarabine; the
cone snail peptide ziconotide; the complex ascidian alkaloid
trabectedin; the antibodydrug conjugate brentuximab vedotin
involving a synthetic derivative of the cyanobacterial-derived
molluscan metabolite dolastatin; and eribulin mesylate, a
synthetic macrocyclic ketone of the marine sponge natural
product halichondrin-B.
215,216
Halichondrin-B is a natural mitotic inhibitor with a unique
mechanism of action as a non-taxane microtubule dynamics
inhibitor
217,218
originally isolated by Hirata and Uemura from a
600-kg collection of the black shallow-water sponge Halichon-
dria okadai from coastal Japan in 1986.
219
Blunt and Munro later
isolated halichondrin-B and a series of other halichondrin
derivatives from a 200-kg collection of the unrelated bright
yellow, deep-sea Poecilosclerid sponge Lissodendoryx sp.,
220
from trawling at >100 m depth othe Kaikoura Peninsula, New
Zealand. The deep-sea sponge was found to produce halichon-
drins in a much greater amount (10-fold) than any of the
shallow-water halichondrin-producing sponge species, and a
massive 1-tonne scale collection of Lissodendoryx sp. was
undertaken in 1995 (under Government licence aer surveys
established there were approx. 300 tonnes in the area) to
furnish 200 mg of halichondrin B and 300 mg of isohomo-
halichondrin B for further biological investigation at the
time.
221,222
This, coupled with the pioneering total synthesis
of halichondrin-B reported by Kishi and co-workers in
1992,
223
enabled further drug development
224
and although the
natural product halichondrin-B eventually proved too toxic for
clinical use, eribulin mesylate E7389 (Halaven), a synthetic
truncated analogue of halichondrin-B was successfully brought
to market by Eisai in 2010 for the treatment of metastatic breast
cancer for patients who have received at least two relevant
chemotherapeutic regimens, including an anthracycline and a
taxane.
225
Today, halichondrins have been reported from a range of
both shallow- and deep-water sponge species, including by
Pettit and co-workers from an Eastern Indian Ocean shallow
reef sponge Phakellia carteri
226
and a Western Pacic marine
sponge Axinella sp. collected at 40 m depth,
227
raising the
possibility that these highly active compounds are of microbial
origin. Furthermore, the 1995 1-tonne collection of deep-sea
Lissodendoryx sp. continues to provide new halichondrin
derivatives as described herein (see section on Porifera).
208
The
halichondrin story, elegantly reviewed by Jackson and
colleagues in 2009,
228
exemplies the drug development
Nat. Prod. Rep. This journal is © The Royal Society of Chemistry 2014
NPR Review
Published on 29 May 2014. Downloaded by University of Wollongong on 03/07/2014 03:18:20.
View Article Online
potential of those deep-sea natural products bearing unusual
architectures and unique modes of action.
12 Conclusions
Deep-sea fauna have yielded an impressive array of novel
compounds (Table 2) with exquisite and complex structures and
potent (nanomolar) biological activities including the anti-
protozoal xenicane diterpenoid, cristaxenicin A (5) from the
Japanese cnidarian Acanthoprimnoa cristata (138 m depth);
85
the cytotoxic chlorinated pyrrolo[4,3,2-de]quinolones, ammo-
samides A (64) and B (65) from a Caribbean sediment-
derived Streptomyces sp. (1618 m depth);
121
the cytotoxic indole
diketopiperazines, luteoalbusins A (70) and B (71) from the
South China Sea fungus Acrostalagmus luteoalbus (2800 m
depth);
137
the highly cytotoxic and structurally unique macro-
lide, leiodermatolide (160) from the Caribbean sponge
Leiodermatium sp. (618 m depth);
180
and new cytotoxic dis-
corhabdin derivatives (175 and 176) from a new species of
Alaskan sponge belonging to the genus Latrunculia (230 m
depth).
196
There have also been new additions to some well
known natural product families that have already attracted
attention due to their structural complexity and range of bio-
logical activities including the rare actinomycete-derived abys-
somicins JL(6769) from 2733 m depth in the South China
Sea;
129131
the benzodiazepine alkaloids, circumdatins K and L
(77 and 78) from the Pacic sediment-derived fungus Aspergillus
versicolor (800 m depth);
139
new massadine derivatives (128130)
from the Australian sponge Axinella sp. (85 m depth);
165
and new
sponge-derived psammaplysin derivatives I and J (132133)
from 6090 m depth, Guam.
Most strikingly, deep-sea natural products appear to have a
particularly high hit rate regarding biological activity. Herein,
75% of the compounds were reported to possess bioactivity (i.e.
141 of 188 compounds), with almost half (i.e. 81 of 188
compounds) exhibiting low micromolar cytotoxicity towards a
range of human cancer cell lines, as found previously.
18
Under
18% of the compounds (33 from 188) were described as either
not active or only weakly or moderately active in the bioassays
This journal is © The Royal Society of Chemistry 2014 Nat. Prod. Rep.
Review NPR
Published on 29 May 2014. Downloaded by University of Wollongong on 03/07/2014 03:18:20.
View Article Online
utilised, while the remaining 7% of the compounds (14 of 188)
had no biological results reported.
Almost a quarter of the metabolites (24%) reported emanate
from Australia, as found previously. However, the main dier-
ence in the regional analysis of samples is the marked increase
in reports of metabolites from deep-sea sediment sampling
from the South China Sea (18%) and the Pacic Ocean (17%,
including Guam and Palau) (Fig. 3). Currently, the level of
access to manned submersibles and trawling operations in
dierent regions will be the greatest inuence on any regional
analysis, rather than an indication of the geographical distri-
bution of marine fauna (and their natural products) in deeper
water. In addition to using research-class deep-sea sampling
equipment, expanded access to submersibles, remotely oper-
ated vehicles and trawling technology through collaboration
with deep-sea industries is enabling researchers to further
explore deep-sea fauna and their natural products.
229,230
Compared to the previous review, where over 50% of the
metabolites were found in depths ranging from 100 to 400 m,
the depth prole of the metabolites in this review is more
polarised with 44% of the compounds obtained from organisms
inhabiting the twilight zone of 50200 m and 37% originating
from organisms found at depths of over 1000 m (Fig. 4, top
chart). The latter, which has increased from just 8% in the
previous review, may be a reection of expanded access to deep-
sea submersibles and other deep-sea research opportunities
enabling further exploration of these uncharted waters. Overall,
the depth prole of all reported deep-sea natural products
shows that depth is inversely correlated with the number of
novel compounds reported (Fig. 4, bottom chart).
Pleasingly there is typically more information provided in
recent papers regarding the collection and identication of the
organisms, although there is still no depth information
provided for a small number of papers. The deepest reported
sample, from which new natural products have been isolated, is
a 10 898 m deep ocean sediment from the Philippine Sea, from
which the marine bacterium Dermacoccus abyssi was cultured,
to give seven novel, cytotoxic compounds, the dermacozines A
G(2935).
Deep-sea sponges are the largest source of new deep-water
metabolites, accounting for over 45% of the metabolites
described, with specimens down to 400 m depth (Table 3).
Compared to the previous review, there has been a shito a
larger number of microbial metabolites (42% compared to 12%
previously), reecting the dierent degrees of diculty in
Table 1 Approved drugs derived from marine natural products
214
Year Compound Tradename Source Compound type Indication Company
1969 Cytarabine Cytosar-U
®
Sponge Nucleoside Cancer Bedford, Enzon
1976 Vidarabine Vira-A
®
Sponge Nucleoside Antiviral King Pharmaceuticals
2004 Ziconotide Prialt
®
Cone snail Peptide Pain Elan Corporation
2007 Trabectedin Yondelis
®
Tunicate Alkaloid Cancer Pharmamar
2010 Eribulin mesylate Halaven
®
Deep-sea sponge Macrocyclic ketone Cancer Eisai
2011 Brentuximab vedotin Adcetris
®
Mollusc Antibody drug conjugate
(MM auristatin E)
Cancer Seattle Genetics
Fig. 3 Geographic origins of deep-sea natural products reported
since 2008.
Fig. 4 Top chart: Depth prole of novel deep-sea natural products
reported since 2008; Bottom chart: All reported deep-sea natural
products.
Nat. Prod. Rep. This journal is © The Royal Society of Chemistry 2014
NPR Review
Published on 29 May 2014. Downloaded by University of Wollongong on 03/07/2014 03:18:20.
View Article Online
Table 2 Novel natural products isolated from deep-water marine sources
a
PHYLUM/Class/Order Species Natural product (or compound type) Depth/m Region Ref.
BRYOZOA
Ctenostomata Amathia tortusa Convolutamines I and J (1, 2) 63 Australia 68
CHORDATA
Ascidiacea
Enterogona Aplidium sp. Rossinones A and B (3, 4) 200 Antarctica 77
CNIDARIA
Anthozoa
Alcyonacea Acanthoprimnoa cristata Cristaxenicin A (5) 138 Japan 85
Convexella magelhaenica Dolabellane diterpenoids (6, 7) 93 Atlantic 86
Echinogorgia pseudossapo Pseudozoanthoxanthins IIIIV (8, 9) n.s. S. China Sea 87
Sesquiterpenes (10, 11)
ECHINODERMATA
Crinoidea
Cyrtocrinida Holopus rangii Gymnochromes E and F (12, 13) 358 Caribbean 88
7-Bromoemodic acid (14)
Proisocrinus ruberrimus Proisocrinins AF(1520) 1800 Japan 89
Holothuroidea
Elasipodida Achlionice violaecuspidata Achlioniceosides A
1
A
3
(2123) 1525 and 407 Weddell Sea 90
MICROORGANISMS
Bacteria Bacillus subtilis Lipoamicoumacins AD(2427) 1000 Red Sea 94
Bacilosarcin C (28)
Dermacoccus abyssi Dermacozines AG(2935) 10 898 Philippine Sea 95
Clone-derived E. coli Alkaloid (36) 3006 Indian Ocean 96
Marinactinospora
thermotolerans
Marinacarbolines AD(3740) 3865 S. China Sea 97
Indolactam alkaloid (41, 42)
Micromonospora sp. Levantilides A and B (43, 44) 4400 Mediterranean 100
Nocardiopsis sp. Nocardiopsins A and B (45, 46) 55 S. Molle Island 101
Nocardiopsis sp. Nocardioazines A and B (47, 48) 55 S. Molle Island 102
Pseudonocardia sp. Pseudonocardians AC(4951) 3258 S. China Sea 104
Serinicoccus profundi Alkaloid (52) n.s. Indian Ocean 106
Streptomyces lusitanus Grincamycins BF(5357) 3370 S. China Sea 107
Streptomyces sp. Spiroindimicins AD(5861) 3412 Indian Ocean 110
Streptomyces sp. Streptopyrrolidine (62) n.s. Ayu Trough 112
Streptomyces sp. Caboxamycin (63) 3814 Atlantic 118
Streptomyces sp. Ammosamides A and B (64, 65) 1618 Bahamas 121
Streptomyces sp. Benzoxacystol (66) 3814 Atlantic 128
Verrucosispora sp. Abyssomicins JL(6769) 2733 S. China Sea 129
Fungi Acrostalagmus luteoalbus Luteoalbusins A, B (70, 71) 2801 S. China Sea 137
Aspergillus sp. Waikialoid A (72); waikialide A (73) 50 Hawaii 138
Aspergillus versicolor Oxisterigmatocystin AC(7476) 800 Pacic Ocean 139
Aspergillus westerdijkiae Circumdatins K and L (77, 78) 2918 S. China Sea 22
5-Chlorosclerotiamide (79)
10-epi-Sclerotiamide (80)
Aspergilliamide B (81)
Penicillium crustosum Penilactones A and B (82, 83) 526 Antarctica 211
Penicillium paneum Penipanoids AC(8486) 201 S. China Sea 142
Penicillium rubrum Berkeleyones AC(8789) n.s. USA 143
Penicillium sp. Breviones FH(9092) 5115 E. Pacic 145
Sterolic acid (93)
Penicillium sp. Breviones IK(9496) 5115 E. Pacic 144
Penicillium sp. Penicilliumin A (97) 1300 S. China Sea 150
Phialocephala malorum Dihydrotrichodermolide (98) 5059 E. Pacic 151
Dihydrodemethylsorbicillin (99)
Phialofurone (100)
Trichoderma sp. Trichoderone (101) n.s. S. China Sea 152
MOLLUSCA
Bivalvia
Mytiloida Bathymodiolus thermophilus Bathymodiolamides A and B (102, 103) 1733 Mid-Atlantic
Ridge
153
This journal is © The Royal Society of Chemistry 2014 Nat. Prod. Rep.
Review NPR
Published on 29 May 2014. Downloaded by University of Wollongong on 03/07/2014 03:18:20.
View Article Online
sampling deep-sea macro-invertebrates compared to sampling
of deep-sea sediment and subsequent culturing of the microbial
ora at sea level. Deep-sea bacteria, accounting for over 25% of
the natural products reported, have been cultured from sedi-
ment obtained down to 10 898 m depth, whereas deep-sea
fungi, which account for over 17% of the reported metabolites,
have been cultured from sediment collected down to 5115 m
depth. Bryozoa, Cnidarians, Chordata, Echinodermata and
Mollusca make up the remainder of the Phyla, including
the rst examples of deep-sea bryozoan metabolites, the
brominated convolutamines I (1) and J (2) from Amathia tor-
tusa,
68
and the rst reported deep-sea molluscan metabolites,
the bathymodiolamides A (102) and B (103) from Bathymodiolus
thermophilus.
153
Deep-sea natural products represent just a fraction (<2%) of
the marine natural products reported to-date,
23
and yet there is
already a deep-sea natural product-derived drug (eribulin
mesylate) that has advanced to market. This, coupled with the
high hit rates (75%) from screening programs, indicates that
deep-sea natural products are a potentially rich source of
structurally diverse, biologically active compounds just waiting
to be explored.
13 Acknowledgements
We thank SEA SERPENT (Scientic and Environmental ROV
Partnership Using Existing Industrial Technology) for support.
Table 2 (Contd. )
PHYLUM/Class/Order Species Natural product (or compound type) Depth/m Region Ref.
PORIFERA
Demospongiae
Astrophorida Stelletta sp. Bistellettazines AC(104106) 90 Australia 158
Bistellettazole A (107)
Geodia sp. Franklinolide A (108) 105 Australia 159
Franklinolide A methyl ester (109)
Franklinolides B and C (110, 111)
Dictyoceratida Aplysinopsis digitata Aplysinoplides AC(112114) 150 Japan 160
Spongia sp. Heterobrins A1A3 and B1B3 (115120) 125 Australia 161
Fasciospongia sp. Fascioquinols AD(121124) 100 Australia 164
Strongylophorine-22 (125)
Fascioquinols E and F (126, 127)
Halichondrida Axinella sp. 14-O-Sulfate massadine (128) 85 Australia 165
14-O-Methyl massadine (129)
3-O-Methyl massadine chloride (130)
Halichondria sp. Franklinolides AC(108, 110, 111) 105 Australia 159
Rhaphoxya sp. Theonellin isocyanate (131) 90 Guam 16
Psammaplysins I, J (132,133)
Haplosclerida Neopetrosia proxima Neopetrosiquinones A, B (134, 135) 140 Jamaica 173
Petrosia sp. ()-Duryne (136) 415 Japan 174
()-Durynes BF(137141)
Xestospongia sp. Alisiaquinones AC(142144) 250400 Australia 177
Alisiaquinol (145)
Homosclerophorida Plakortis angulospiculatus 23-nor-Spiculoic acid B (146) 58 Caribbean 178
Zyggomphic acid B (147) 62 Bahamas
27-nor-Zyggomphic acid B (148)
22-nor-Zyggomphic acid B (149)
22,27-dinor-Zyggomphic acid B (150)
Plakortis halichondrioides Aromatic metabolites (151153) 91 Bahamas
Plakortis sp. Aromatic metabolites (154159) 96 Guam 179
Lithistida Leiodermatium sp. Leiodermatolide (160) 401 USA 180
Theonella swinhoei Mutremdamide A (161) 100120 Palau 187
Theonella cupola Koshikamides CH(162167)90
Theonella swinhoei Paltolides AC(168170) 101 Palau 188
Poecilosclerida Clathria sp. Mirabilins HJ(171173) 60 Australia 191
Latrunculia sp. Citharoxazole (174) 103 France 195
Latrunculia sp. Dihydrodiscorhabdin B (175) 230 Alaska 196
Discorhabdin Y (176)
Lissodendoryx sp. Halichondrin B-1140, 1092,
1020, 1076 (177180)
100 New Zealand 208
Phorbas sp. Phorbasins DF(181183) 65 Australian 209
Phorbas sp. Phorbasins GK(184188) 65 Australia 210
Verongida Suberea sp. Psammaplysins I, J (132, 133) 60 Guam 16
a
n.s. ¼not specied.
Nat. Prod. Rep. This journal is © The Royal Society of Chemistry 2014
NPR Review
Published on 29 May 2014. Downloaded by University of Wollongong on 03/07/2014 03:18:20.
View Article Online
14 Notes and references
1 J. F. Grassle and N. J. Maciolek, Am. Nat., 1992, 139, 313
341.
2 J. D. Gage, J. Exp. Mar. Biol. Ecol., 1996, 200, 257286.
3 L. A. Levin, R. J. Etter, M. A. Rex, A. J. Gooday, C. R. Smith,
et al.,Annu. Rev. Ecol. Syst., 2001, 32,5193.
4 P. V. R. Snelgrove and C. R. Smith, in Oceanography and
Marine Biology, Vol 40, ed. R. N. Gibson, M. Barnes and R.
J. A. Atkinson, 2002, vol. 40, pp. 311342.
5 A. Brandt, A. J. Gooday, S. N. Brandao, S. Brix, W. Brokeland,
et al.,Nature, 2007, 447, 307311.
6 J. C. Venter, K. Remington, J. F. Heidelberg, A. L. Halpern,
D. Rusch, et al.,Science, 2004, 304,6674.
7 W. Appeltans, S. T. Ahyong, G. Anderson, M. V. Angel,
T. Artois, et al.,Curr. Biol., 2012, 22, 21892202.
8 M. Tatian, C. Lagger, M. Demarchi and C. Mattoni, Zool.
Scr., 2011, 40, 603612.
9 A. Mecho, J. Aguzzi, J. B. Company, M. Canals, G. Lastras
and X. Turon, Deep-Sea Res., Part I, 2014, 83,5156.
10 K. W. Ockelmann and G. E. Dinesen, Mar. Biol. Res., 2011, 7,
7184.
11 J. Vacelet and N. Bouryesnault, Nature, 1995, 373, 333335.
12 W. L. Lee, H. M. Reiswig, W. C. Austin and L. Lundsten,
Invertebr. Biol., 2012, 131, 259284.
13 P. C. Wright, R. E. Westacott and A. M. Burja, Biomol. Eng.,
2003, 20, 325331.
14 A. T. Bull, A. C. Ward and M. Goodfellow, Microbiol. Mol.
Biol. Rev., 2000, 64, 573606.
15 P. J. Schupp, C. Kohlert-Schupp, S. Whiteeld,
A. Engemann, S. Rohde, T. Hemscheidt, J. M. Pezzuto,
T. P. Kondratyuk, E. J. Park, L. Marler, B. Rostama and
A. D. Wright, Nat. Prod. Commun., 2009, 4, 17171728.
16 A. D. Wright, P. J. Schupp, J. P. Schror, A. Engemann,
S. Rohde, D. Kelman, N. de Voogd, A. Carroll and
C. A. Motti, J. Nat. Prod., 2012, 75, 502506.
17 E. J. Dumdei, J. W. Blunt, M. H. G. Munro and L. K. Pannell,
J. Org. Chem., 1997, 62, 26362639.
18 D. Skropeta, Nat. Prod. Rep., 2008, 25, 11311166.
19 G. Szakacs, J. K. Paterson, J. A. Ludwig, C. Booth-Genthe
and M. M. Gottesman, Nat. Rev. Drug Discovery, 2006, 5,
219234.
20 C. A. Arias and B. E. Murray, N. Engl. J. Med., 2009, 360, 439
443.
21 M. Pidwirny, in Fundamentals of Physical Geography,
PhysicalGeography.net, 2nd Edition edn, 2006, p. 310.
22 J. Peng, X. Y. Zhang, Z. C. Tu, X. Y. Xu and S. H. Qi, J. Nat.
Prod., 2013, 76, 983987.
23 U.o.C. MarinLit Database, Department of Chemistry,
University of Canterbury, Christchurch,New Zealand,
http://www.chem.canterbury.ac.nz/marinlit/
marinlit.shtml.
24 J. M. Roberts, A. J. Wheeler and A. Freiwald, Science, 2006,
312, 543547.
25 Z. E. Wilson and M. A. Brimble, Nat. Prod. Rep., 2009, 26,
4471.
26 T. R. A. Thomas, D. P. Kavlekar and P. A. LokaBharathi,
Mar. Drugs, 2010, 8, 14171468.
27 C. C. Thornburg, T. M. Zabriskie and K. L. McPhail, J. Nat.
Prod., 2010, 73, 489499.
28 R. K. Pettit, Mar. Biotechnol., 2011, 13,111.
Table 3 Deep-sea marine species collected at dierent depths since 2008
Depth/m Phylum Species Depth/m Phylum Species
50 Bryozoa Amathia tortusa 200 Chordata Aplidium sp.
Cnidaria Convexella magelhaenica Porifera Latrunculia sp.
Bacteria Nocardiopsis sp. 300 Echinodermata Holopus rangii
Fungi Aspergillus sp. 400 Porifera Petrosia sp.
Porifera Stelletta sp. Porifera Leiodermatium sp.
Porifera Axinella sp. 500 Fungi Penicillium crustosum
Porifera Rhaphoxya sp. 800 Fungi Aspergillus versicolor
Porifera Theonella cupola 1000 Echinodermata Proisocrinus ruberrimus
Porifera Clathria Mollusca Bathymodiolus thermophilus
Porifera Phorbas sp. Bacteria Bacillus subtilis
Porifera Plakortis angulospiculatus Fungi Penicillium sp.
Porifera Plakortis halichondrioides 2000 Fungi Acrostalagmus luteoalbus
Porifera Plakortis sp. Bacteria Verrucosispora sp.
100 Cnidaria Acanthoprimnoa cristata 3000 Bacteria Escherichia coli
Porifera Geodia sp. Bacteria Marinactinospora thermotolerans
Porifera Spongia (Heterobria) sp. Bacteria Pseudonocardia sp.
Porifera Fasciospongia sp. Bacteria Streptomyces lusitanus
Porifera Halichondria sp. Bacteria Streptomyces sp.
Porifera Neopetrosia proxima 4000 Bacteria Micromonospora sp.
Porifera Theonella swinhoei 5000 Fungi Penicillium sp.
Porifera Latrunculia sp. Fungi Phialocephala malorum
Porifera Lissodendoryx sp. 10 000 Bacteria Dermacoccus abyssi
Porifera Aplysinopsis digitata
Porifera Aaptos ciliata
This journal is © The Royal Society of Chemistry 2014 Nat. Prod. Rep.
Review NPR
Published on 29 May 2014. Downloaded by University of Wollongong on 03/07/2014 03:18:20.
View Article Online
29 P. L. Winder, S. A. Pomponi and A. E. Wright, Mar. Drugs,
2011, 9, 26432682.
30 T. H. Silva, A. Alves, B. M. Ferreira, J. M. Oliveira, L. L. Reys,
R. J. F. Ferreira, R. A. Sousa, S. S. Silva, J. F. Mano and
R. L. Reis, Int. Mater. Rev., 2012, 57, 276307.
31 D. Thistle, in Ecosystems of the world: Ecosystems of the deep
oceans, ed. P. Tyler, Elsevier, Amsterdam, 2003, vol. 28, p. 5.
32 R. N. Glud, F. Wenzh¨
ofer, M. Middelboe, K. Oguri,
R. Turnewitsch, D. E. Caneld and H. Kitazato, Nat.
Geosci., 2013, 6, 284.
33 N. Le Bris, P. M. Sarradin and S. Pennec, Deep-Sea Res., Part
I, 2001, 48, 19411951.
34 K. Park, Science, 1966, 154, 1540.
35 H. L. Sanders, Am. Nat., 1968, 102, 243282.
36 H. L. Sanders and R. R. Hessler, Science, 1969, 163, 1419
1424.
37 H. L. Sanders, R. R. Hessler and G. R. Hampson, Deep-Sea
Res., 1965, 12, 845867.
38 K. S. McCann, Nature, 2000, 405, 228233.
39 J. D. Gage, J. Exp. Mar. Biol. Ecol., 1996, 200, 257286.
40 F. Abe, Biosci., Biotechnol., Biochem., 2007, 71, 23472357.
41 F. Abe and K. Horikoshi, Trends Biotechnol., 2001, 19, 102
108.
42 F. Abe, C. Kato and K. Horikoshi, Trends Microbiol., 1999, 7,
447453.
43 F. M. Lauro and D. H. Bartlett, Extremophiles, 2008, 12,1525.
44 D. H. Bartlett, Biochim. Biophys. Acta, Protein Struct. Mol.
Enzymol., 2002, 1595, 367381.
45 M. Gross and R. Jaenicke, Eur. J. Biochem., 1994, 221, 617
630.
46 R. Margesin and F. Schinner, Cold-adapted Organisms:
Ecology, Physiology, Enzymology and Molecular Biology,
Springer, Berlin, 1999.
47 G. Feller, Cell. Mol. Life Sci., 2003, 60, 648662.
48 G. Feller and C. Gerday, Cell. Mol. Life Sci., 1997, 53, 830
841.
49 J. G. Zeikus, Enzyme Microb. Technol., 1979, 1, 243252.
50 R. Sterner and W. Liebl, Crit. Rev. Biochem. Mol. Biol., 2001,
36,39106.
51 V. Tunniclie, Oceanograph. Mar. Biol., 1991, 29, 319407.
52 J. J. Childress and C. R. Fisher, Oceanograph. Mar. Biol.,
1992, 30, 337441.
53 C. Z. Fu, Y. F. Hu, F. Xie, H. Guo, E. J. Ashforth, S. W. Polyak,
B. L. Zhu and L. X. Zhang, Appl. Microbiol. Biotechnol., 2011,
90, 961970.
54 T. Kobayashi, K. Uchimura, S. Deguchi and K. Horikoshi,
Appl. Environ. Microbiol., 2012, 78, 24932495.
55 C. Murakami, E. Ohmae, S. Tate, K. Gekko, K. Nakasone
and C. Kato, J. Biochem., 2010, 147, 591599.
56 K. Uchimura, M. Miyazaki, Y. Nogi, T. Kobayashi and
K. Horikoshi, Mar. Biotechnol., 2010, 12, 526533.
57 J. Y. Yang and H. Y. Dang, FEMS Microbiol. Lett., 2011, 325,
7176.
58 In UNEP/GRID-Arendal Maps & Graphics Library, ed.
GRID-Arendal, February 2008, accessed 31 October 2013,
http://maps.grida.no/go/graphic/world-ocean-bathymetric-
map%3E.
59 D. J. Hughes, J. Mar. Biol. Assoc. U. K., 2001, 81, 987993.
60 A. Clarke and S. Lidgard, J. Anim. Ecol., 2000, 69, 799814.
61 J. E. Winston and S. E. Beaulieu, Proc. Biol. Soc. Wash., 1999,
112, 313318.
62 J. H. Sharp, M. K. Winson and J. S. Porter, Nat. Prod. Rep.,
2007, 24, 659673.
63 U. Anthoni, P. H. Nielsen, M. Pereira and
C. Christophersen, Comp. Biochem. Physiol. B, 1990, 96, 431.
64 C. Christophersen, Acta Chem. Scand., Ser. B, 1985, 39, 517
529.
65 J. Kortmansky and G. K. Schwartz, Cancer Invest., 2003, 21,
924936.
66 K. J. Hale, M. G. Hummersone, S. Manaviazar and
M. Frigerio, Nat. Prod. Rep., 2002, 19, 413453.
67 G. R. Pettit, C. L. Herald, D. L. Doubek, D. L. Herald,
E. Arnold and J. Clardy, J. Am. Chem. Soc., 1982, 104,
68466848.
68 R. A. Davis, M. Sykes, V. M. Avery, D. Camp and R. J. Quinn,
Bioorg. Med. Chem., 2011, 19, 66156619.
69 W. F. Wang and M. Namikoshi, Heterocycles, 2007, 74,53
88.
70 A. R. Davis and J. Bremner, in Recent Advances in Marine
Biotechnology Vol. III: Biolms, Bioadhesion, Corrosion and
Biofouling, ed. M. Fingerman, R. Nagabhushanam and M.
F. Thompson, Science Publishers Inc., New Hampshire,
USA, 1999, vol. 3, pp. 259308.
71 D. J. Newman and G. M. Cragg, J. Nat. Prod., 2004, 67, 1216
1238.
72 B. S. Davidson, Chem. Rev., 1993, 93, 17711791.
73 K. E. Sanamyan and N. P. Sanamyan, J. Nat. Hist., 2006, 40,
307344.
74 K. E. Sanamyan and N. P. Sanamyan, J. Nat. Hist., 2005, 39,
20052021.
75 K. E. Sanamyan and N. P. Sanamyan, J. Nat. Hist., 2002, 36,
305359.
76 B. R. Moser, J. Nat. Prod., 2008, 71, 487491.
77 D. R. Appleton, C. S. Chuen, M. V. Berridge, V. L. Webb and
B. R. Copp, J. Org. Chem., 2009, 74, 91959198.
78 Z.-Y. Zhang, J.-H. Chen, Z. Yang and Y.-F. Tang, Org. Lett.,
2010, 12, 55545557.
79 L. Nunez-Pons, M. Carbone, J. Vazquez, J. Rodriguez,
R. M. Nieto, M. M. Varela, M. Gavagnin and C. Avila, Mar.
Drugs, 2012, 10, 17411764.
80 J. W. Blunt, B. R. Copp, M. H. G. Munro, P. T. Northcote and
M. R. Prinsep, Nat. Prod. Rep., 2011, 28, 196268.
81 J. W. Blunt, B. R. Copp, R. A. Keyzers, M. H. G. Munro and
M. R. Prinsep, Nat. Prod. Rep., 2012, 29, 144222.
82 J. W. Blunt, B. R. Copp, R. A. Keyzers, M. H. G. Munro and
M. R. Prinsep, Nat. Prod. Rep., 2013.
83 G. L. Mariottini and L. Pane, Mar. Drugs, 2010, 8, 1122
1152.
84 F. Amir, Y. C. Koay and S. Wan, Trop. J. Pharm. Res., 2012,
11, 485498.
85 S.-T. Ishigami, Y. Goto, N. Inoue, S.-I. Kawazu,
Y. Matsumoto, Y. Imahara, M. Tarumi, H. Nakai,
N. Fusetani and Y. Nakao, J. Org. Chem., 2012, 77, 10962
10966.
Nat. Prod. Rep. This journal is © The Royal Society of Chemistry 2014
NPR Review
Published on 29 May 2014. Downloaded by University of Wollongong on 03/07/2014 03:18:20.
View Article Online
86 M. T. R. de Almeida, G. E. Siless, C. D. Perez, M. J. Veloso,
L. Schejter, L. Puricelli and J. A. Palermo, J. Nat. Prod.,
2010, 73, 17141717.
87 C. H. Gao, Y. F. Wang, S. Li, P. Y. Qian and S. H. Qi, Mar.
Drugs, 2011, 9, 24792487.
88 H. V. K. Wangun, A. Wood, C. Fiorillo, J. K. Reed,
P. J. McCarthy and A. E. Wrightt, J. Nat. Prod., 2010, 73,
712715.
89 K. Wolkenstein, W. Schoeerger, N. Muller and T. Oji,
J. Nat. Prod., 2009, 72, 20362039.
90 A. S. Antonov, S. A. Avilov, A. I. Kalinovsky, S. D. Anastyuk,
P. S. Dmitrenok, V. I. Kalinin, S. Taboada, A. Bosh, C. Avila
and V. A. Stonik, J. Nat. Prod., 2009, 72,3338.
91 G. M. Cragg, D. J. Newman and S. S. Yang, J. Nat. Prod.,
2006, 69, 488498.
92 W. Fenical, Chem. Rev., 1993, 93, 16731683.
93 L. X. Zhang, R. An, J. P. Wang, N. Sun, S. Zhang, J. C. Hu and
J. Kuai, Curr. Opin. Microbiol., 2005, 8, 276281.
94 Y. Li, Y. Xu, L. Liu, Z. Han, P. Y. Lai, X. Guo, X. Zhang,
W. Lin and P.-Y. Qian, Mar. Drugs, 2012, 10, 319328.
95 W. M. Abdel-Mageed, B. F. Milne, M. Wagner,
M. Schumacher, P. Sandor, W. Pathom-aree,
M. Goodfellow, A. T. Bull, K. Horikoshi, R. Ebel,
M. Diederich, H. P. Fiedler and M. Jaspars, Org. Biomol.
Chem., 2010, 8, 23522362.
96 L. Chen, X. X. Tang, M. Zheng, Z. W. Yi, X. Xiao, Y. K. Qiu
and Z. Wu, J. Asian Nat. Prod. Res., 2011, 13, 444448.
97 H. B. Huang, Y. L. Yao, Z. X. He, T. T. Yang, J. Y. Ma,
X. P. Tian, Y. Y. Li, C. G. Huang, X. P. Chen, W. J. Li,
S. Zhang, C. S. Zhang and J. H. Ju, J. Nat. Prod., 2011, 74,
21222127.
98 S. Tagawa, T. Choshi, A. Okamoto, T. Nishiyama,
S. Watanabe, N. Hatae and S. Hibino, Heterocycles, 2013,
87, 357367.
99 Q. Chen, C. Ji, Y. Song, H. Huang, J. Ma, X. Tian and J. Ju,
Angew. Chem., Int. Ed., 2013, 52, 99809984.
100 A. Gartner, B. Ohlendorf, D. Schulz, H. Zinecker, J. Wiese
and J. F. Imho,Mar. Drugs, 2011, 9,98108.
101 R. Raju, A. M. Piggott, M. Conte, Z. Tnimov, K. Alexandrov
and R. J. Capon, Chem. Eur. J., 2010, 16, 31943200.
102 R. Raju, A. M. Piggott, X.-C. Huang and R. J. Capon, Org.
Lett., 2011, 13, 27702773.
103 M. Wang, X. Feng, L. Cai, Z. Xu and T. Ye, Chem. Commun.,
2012, 48, 43444346.
104 S. Li, X. Tian, S. Niu, W. Zhang, Y. Chen, H. Zhang, X. Yang,
W. Zhang, W. Li, S. Zhang, J. Ju and C. Zhang, Mar. Drugs,
2011, 9, 14281439.
105 C. Zhang, S. Li, X. Tian, W. Zhang, H. Zhang, G. Zhang,
S. Zhang and J. Ju, Patent, CN102351859A, 2012.
106 X.-W. Yang, G.-Y. Zhang, J.-X. Ying, B. Yang, X.-F. Zhou,
A. Steinmetz, Y.-H. Liu and N. Wang, Mar. Drugs, 2012,
11,3339.
107 H. B. Huang, T. T. Yang, X. M. Ren, J. Liu, Y. X. Song,
A. J. Sun, J. Y. Ma, B. Wang, Y. Zhang, C. G. Huang,
C. S. Zhang and J. H. Ju, J. Nat. Prod., 2012, 75, 202208.
108 J. Ju, Y. Zhang, H. Huang, J. Liu and J. Ma, Patent,
CN103215281A, 2013.
109 Y. Zhang, H. Huang, Q. Chen, M. Luo, A. Sun, Y. Song, J. Ma
and J. Ju, Org. Lett., 2013, 15, 32543257.
110 W. J. Zhang, Z. Liu, S. M. Li, T. T. Yang, Q. B. Zhang, L. Ma,
X. P. Tian, H. B. Zhang, C. G. Huang, S. Zhang, J. H. Ju,
Y. M. Shen and C. S. Zhang, Org. Lett., 2012, 14, 33643367.
111 C. Zhang, W. Zhang, X. Tian, S. Li, Q. Zhang, L. Ma,
H. Zhang, S. Zhang and J. Ju, Patent, CN102643765A, 2012.
112 H. J. Shin, T. S. Kim, H. S. Lee, J. Y. Park, I. K. Choi and
H. J. Kwon, Phytochemistry, 2008, 69, 23632366.
113 D. K. Mohapatra, B. Thirupathi, P. P. Das and J. S. Yadav,
Beilstein J. Org. Chem., 2011, 7,3439.
114 A. Duris, A. Daich and D. Berkes, Synlett, 2011, 16311637.
115 W. Huang, J.-Y. Ma, M. Yuan, L.-F. Xu and B.-G. Wei,
Tetrahedron, 2011, 67, 78297837.
116 Z. Shaameri, S. H. S. Ali, M. F. Mohamat, B. M. Yamin and
A. S. Hamzah, J. Heterocycl. Chem., 2013, 50, 320325.
117 Y.-H. Wang, W. Ou, L. Xie, J.-L. Ye and P.-Q. Huang, Asian J.
Org. Chem., 2012, 1, 359365.
118 C. Hohmann, K. Schneider, C. Brunter, E. Irran,
G. Nicholson, A. T. Bull, A. L. Jones, R. Brown,
J. E. M. Stach, M. Goodfellow, W. Beil, M. Kr¨
amer,
J. F. Imho,R.D.S
¨
ussmuth and H.-P. Fiedler, J. Antibiot.,
2009, 62,99104.
119 Y. Tagawa, H. Koba, K. Tomoike and K. Sumoto,
Heterocycles, 2011, 83, 867874.
120 P. J. Smith and D. N. Ward, US Pat., WO2011047390A2,
2011.
121 S. Taboada, L. Nunez-Pons and C. Avila, Polar Biol., 2013,
36,1325.
122 C. C. Hughes, J. B. MacMillan, S. P. Gaudencio, W. Fenical
and C. J. J. La, Angew. Chem., Int. Ed., 2009, 48, 728732.
123 C. C. Hughes and W. Fenical, J. Am. Chem. Soc., 2010, 132,
25282529.
124 D. Zurwerra, C. W. Wullschleger and K.-H. Altmann, Angew.
Chem., Int. Ed., 2010, 49, 69366938.
125 (a) P. V. N. Reddy, B. Banerjee and M. Cushman, Org. Lett.,
2010, 12, 31123114; (b) Q. Wu, X. Jiao, L. Wang, Q. Xiao,
X. Liu and P. Xie, Tetrahedron Lett., 2010, 51, 48064807.
126 Y. Takayama, T. Yamada, S. Tatekabe and K. Nagasawa,
Chem. Commun., 2013, 49, 65196521.
127 P. V. N. Reddy, K. C. Jensen, A. D. Mesecar, P. E. Fanwick
and M. Cushman, J. Med. Chem., 2012, 55, 367377.
128 J. Nachtigall, K. Schneider, C. Bruntner, A. T. Bull,
M. Goodfellow, H. Zinecker, J. F. Imho, G. Nicholson,
E. Irran, R. D. Sussmuth and H. P. Fiedler, J. Antibiot.,
2011, 64, 453457.
129 Q. Wang, F. H. Song, X. Xiao, P. Huang, L. Li, A. Monte,
W. M. Abdel-Mageed, J. Wang, H. Guo, W. N. He, F. Xie,
H. Q. Dai, M. M. Liu, C. X. Chen, H. Xu, M. Liu,
A. M. Piggott, X. T. Liu, R. J. Capon and L. X. Zhang,
Angew. Chem., Int. Ed., 2013, 52, 12311234.
130 J. Riedlinger, A. Reicke, H. Zahner, B. Krismer, A. T. Bull,
L. A. Maldonado, A. C. Ward, M. Goodfellow, B. Bister,
D. Bischo, R. D. Sussmuth and H. P. Fiedler, J. Antibiot.,
2004, 57, 271279.
131 S. Keller, G. Nicholson, C. Drahl, E. Sorensen, H. P. Fiedler
and R. D. Sussmuth, J. Antibiot., 2007, 60, 391394.
This journal is © The Royal Society of Chemistry 2014 Nat. Prod. Rep.
Review NPR
Published on 29 May 2014. Downloaded by University of Wollongong on 03/07/2014 03:18:20.
View Article Online
132 B. Bister, D. Bischo, M. Strobele, J. Riedlinger, A. Reicke,
F. Wolter, A. T. Bull, H. Zahner, H. P. Fiedler and
R. D. Sussmuth, Angew. Chem., Int. Ed., 2004, 43, 25742576.
133 M. Goodfellow, J. E. M. Stach, R. Brown, A. N. V. Bonda,
A. L. Jones, J. Mexson, H. P. Fiedler, T. D. Zucchi and
A. T. Bull, Ant. Van Leeuwen. Int. J. Gen. Mol. Microbiol.,
2012, 101, 185193.
134 X. M. Niu, S. H. Li, H. Gorls, D. Schollmeyer, M. Hilliger,
S. Grabley and I. Sattler, Org. Lett., 2007, 9, 24372440.
135 Y. Igarashi, L. K. Yu, S. Miyanaga, T. Fukuda, N. Saitoh,
H. Sakurai, I. Saiki, P. Alonso-Vega and M. E. Trujillo,
J. Nat. Prod., 2010, 73, 19431946.
136 M. A. Abdalla, P. P. Yadav, B. Dittrich, A. Schuer and
H. Laatsch, Org. Lett., 2011, 13, 21562159.
137 F. Z. Wang, Z. Huang, X. F. Shi, Y. C. Chen, W. M. Zhang,
X. P. Tian, J. Li and S. Zhang, Bioorg. Med. Chem. Lett.,
2012, 22, 72657267.
138 X. R. Wang, J. L. You, J. B. King, D. R. Powell and
R. H. Cichewicz, J. Nat. Prod., 2012, 75, 707715.
139 S. X. Cai, T. J. Zhu, L. Du, B. Y. Zhao, D. H. Li and Q. Q. Gu,
J. Antibiot., 2011, 64, 193196.
140 G. W. Wu, A. Q. Lin, Q. Q. Gu, T. J. Zhu and D. H. Li, Mar.
Drugs, 2013, 11, 13991408.
141 J. T. J. Spence and J. H. George, Org. Lett., 2013, 15, 3891
3893.
142 C. S. Li, C. Y. An, X. M. Li, S. S. Gao, C. M. Cui, H. F. Sun and
B. G. Wang, J. Nat. Prod., 2011, 74, 13311334.
143 D. B. Stierle, A. A. Stierle, B. Patacini, K. McIntyre,
T. Girtsman and E. Bolstad, J. Nat. Prod., 2011, 74, 2273
2277.
144 Y. Li, D. Z. Ye, X. L. Chen, X. H. Lu, Z. Z. Shao, H. Zhang and
Y. S. Che, J. Nat. Prod., 2009, 72, 912916.
145 Y. Li, D. Ye, Z. Shao, C. Cui and Y. Che, Mar. Drugs, 2012, 10,
497508.
146 K. Shishido, Chem. Pharm. Bull., 2013, 61, 781798.
147 H. Yokoe, C. Mitsuhashi, Y. Matsuoka, T. Yoshimura,
M. Yoshida and K. Shishido, J. Am. Chem. Soc., 2011, 133,
88548857.
148 F. A. Macias, C. Carrera, N. Chinchilla, F. R. Fronczek and
J. C. G. Galindo, Tetrahedron, 2010, 66, 41254132.
149 H. Takikawa, Biosci., Biotechnol., Biochem., 2006, 70, 1082
1088.
150 X. Lin, X. Zhou, F. Wang, K. Liu, B. Yang, X. Yang, Y. Peng,
J. Liu, Z. Ren and Y. Liu, Mar. Drugs, 2012, 10, 106115.
151 D. H. Li, S. X. Cai, T. J. Zhu, F. P. Wang, X. Xiao and
Q. Q. Gu, Chem. Biodiversity, 2011, 8, 895901.
152 J. L. You, H. Q. Dai, Z. H. Chen, G. J. Liu, Z. X. He,
F. H. Song, X. Yang, H. A. Fu, L. X. Zhang and X. P. Chen,
J. Ind. Microbiol. Biotechnol., 2010, 37, 245252.
153 E. H. Andrianasolo, L. Haramaty, K. L. McPhail, E. White,
C. Vetriani, P. Falkowski and R. Lutz, J. Nat. Prod., 2011,
74, 842846.
154 W. E. G. M¨
uller, Sponges (Porifera), Springer, Berlin, 2003.
155 D. Skropeta, N. Pastro and A. Zivanovic, Mar. Drugs, 2011, 9,
21312154.
156 D. J. Newman and G. M. Cragg, J. Nat. Prod., 2012, 75, 311
335.
157 P. Proksch, Toxicon, 1994, 32, 639655.
158 M. El-Naggar, A. M. Piggott and R. J. Capon, Org. Lett., 2008,
10, 42474250.
159 H. Zhang, M. M. Conte and R. J. Capon, Angew. Chem., Int.
Ed., 2010, 49, 99049906.
160 R. Ueoka, Y. Nakao, S. Fujii, R. W. M. van Soest and
S. Matsunaga, J. Nat. Prod., 2008, 71, 10891091.
161 A. A. Salim, J. Rae, F. Fontaine, M. M. Conte, Z. Khalil,
S. Martin, R. G. Parton and R. J. Capon, Org. Biomol.
Chem., 2010, 8, 31883194.
162 J. Rae, F. Fontaine, A. A. Salim, H. P. Lo, R. J. Capon,
R. G. Parton and S. Martin, PLoS One, 2011, 6, e22868.
163 A. Zivanovic, N. J. Pastro, J. Fromont, M. Thomson and
D. Skropeta, Nat. Prod. Commun., 2011, 6, 19211924.
164 H. Zhang, Z. G. Khalil and R. J. Capon, Tetrahedron, 2011,
67, 25912595.
165 H. Zhang, Z. Khalil, M. M. Conte, F. Plisson and R. J. Capon,
Tetrahedron Lett., 2012, 53, 37843787.
166 I. B. Seiple, S. Su, I. S. Young, A. Nakamura, J. Yamaguchi,
L. Jorgensen, R. A. Rodriguez, D. P. O'Malley, T. Gaich,
M. Kock and P. S. Baran, J. Am. Chem. Soc., 2011, 133,
1471014726.
167 S. Su, R. A. Rodriguez and P. S. Baran, J. Am. Chem. Soc.,
2011, 133, 1392213925.
168 S. Su, I. B. Seiple, I. S. Young and P. S. Baran, J. Am. Chem.
Soc., 2008, 130, 1649016491.
169 G. M. Chinigo, A. Breder and E. M. Carreira, Org. Lett., 2011,
13,7881.
170 A. Breder, G. M. Chinigo, A. W. Waltman and
E. M. Carreira, Chem. Eur. J., 2011, 17, 1240512416,
S12405/12401-S12405/12126.
171 G. M. Chinigo, A. Breder, A. W. Waltman and
E. M. Carreira, Abstracts of Papers, 238th ACS National
Meeting, Washington, DC, United States, August 1620,
2009.
172 A. Breder, G. M. Chinigo, A. W. Waltman and
E. M. Carreira, Angew. Chem., Int. Ed., 2008, 47, 85148517.
173 P. L. Winder, H. L. Baker, P. Linley, E. A. Guzman,
S. A. Pomponi, M. C. Diaz, J. K. Reed and A. E. Wright,
Bioorg. Med. Chem., 2011, 19, 65996603.
174 Y. Hitora, K. Takada, S. Okada, Y. Ise and S. Matsunaga, J.
Nat. Prod., 2011, 74, 12621267.
175 G. Kumaraswamy, K. Sadaiah and N. Raghu, Tetrahedron:
Asymmetry, 2012, 23, 587593.
176 B. W. Gung and A. O. Omollo, J. Org. Chem., 2008, 73, 1067
1070.
177 D. Desoubzdanne, L. Marcourt, R. Raux, S. Chevalley,
D. Dorin, C. Doerig, A. Valentin, F. Ausseil and
C. Debitus, J. Nat. Prod., 2008, 71, 11891192.
178 S. Ankisetty, D. J. Gochfeld, M. C. Diaz, S. I. Khan and
M. Slattery, J. Nat. Prod., 2010, 73, 14941498.
179 E. Manzo, M. L. Ciavatta, D. Melck, P. Schupp, N. J. de
Voogd and M. Gavagnin, J. Nat. Prod., 2009, 72, 15471551.
180 I. Paterson, S. M. Dalby, J. C. Roberts, G. J. Naylor,
E. A. Guzman, R. Isbrucker, T. P. Pitts, P. Linley,
D. Divlianska, J. K. Reed and A. E. Wright, Angew. Chem.,
Int. Ed., 2011, 50, 32193223.
Nat. Prod. Rep. This journal is © The Royal Society of Chemistry 2014
NPR Review
Published on 29 May 2014. Downloaded by University of Wollongong on 03/07/2014 03:18:20.
View Article Online
181 A. E. Wright, J. K. Reed, J. Roberts and R. E. Longley, US
Pat., US20080033035A1, 2008.
182 K. K. Ng, S. Williams and I. Paterson, 2013.
183 I. Paterson, T. Paquet and S. M. Dalby, Org. Lett., 2011, 13,
43984401.
184 R. L. Stowe and W. R. Roush, 245th ACS National Spring
Meeting, New Orleans, Apr 711 2013, Abstract 199-
ORGN, 2013.
185 V. Navickas, C. Rink and M. E. Maier, Synlett, 2011, 191
194.
186 C. Rink, V. Navickas and M. E. Maier, Org. Lett., 2011, 13,
23342337.
187 A. Plaza, G. Bifulco, M. Masullo, J. R. Lloyd, J. L. Keer,
P. L. Colin, J. N. A. Hooper, L. J. Bell and C. A. Bewley, J.
Org. Chem., 2010, 75, 43444355.
188 A. Plaza, J. L. Keer, J. R. Lloyd, P. L. Colin and C. A. Bewley,
J. Nat. Prod., 2010, 73, 485488.
189 R. A. Barrow, L. M. Murray, T. K. Lim and R. J. Capon, Aust.
J. Chem., 1996, 49, 767773.
190 R. J. Capon, M. Miller and F. Rooney, J. Nat. Prod., 2001, 64,
643644.
191 M. El-Naggar, M. Conte and R. J. Capon, Org. Biomol. Chem.,
2010, 8, 407412.
192 A. D. Patil, A. J. Freyer, P. Oen, M. F. Bean and
R. K. Johnson, J. Nat. Prod., 1997, 60, 704707.
193 H.-m. Hua, J. Peng, F. R. Fronczek, M. Kelly and
M. T. Hamann, Bioorg. Med. Chem., 2004, 12, 64616464.
194 M. Yu, S. S. Pochapsky and B. B. Snider, J. Org. Chem., 2008,
73, 90659074.
195 G. Genta-Jouve, N. Francezon, A. Puissant, P. Auberger,
J. Vacelet, T. Perez, A. Fontana, A. Al Mourabit and
O. P. Thomas, Magn. Reson. Chem., 2011, 49, 533536.
196 M. K. Na, Y. Q. Ding, B. Wang, B. L. Tekwani, R. F. Schinazi,
S. Franzblau, M. Kelly, R. Stone, X. C. Li, D. Ferreira and
M. T. Hamann, J. Nat. Prod., 2010, 73, 383387.
197 N. B. Perry, J. W. Blunt, J. D. McCombs and M. H. G. Munro,
J. Org. Chem., 1986, 51, 54765478.
198 N. B. Perry, J. W. Blunt and M. H. G. Munro, Tetrahedron,
1988, 44, 17271734.
199 N. B. Perry, J. W. Blunt, M. H. G. Munro, T. Higa and
R. Sakai, J. Org. Chem., 1988, 53, 41274128.
200 Y. Kita, H. Tohma, M. Inagaki, K. Hatanaka and T. Yakura,
J. Am. Chem. Soc., 1992, 114, 21752180.
201 E. V. Sadanandan, S. K. Pillai, M. V. Lakshmikantham,
A. D. Billimoria, J. S. Culpepper and M. P. Cava, J. Org.
Chem., 1995, 60, 18001805.
202 K. M. Aubart and C. H. Heathcock, J. Org. Chem., 1999, 64,
1622.
203 C. F. C. Lam, A. C. Giddens, N. Chand, V. L. Webb and
B. R. Copp, Tetrahedron, 2012, 68, 31873194.
204 T. F. Molinski, Chem. Rev., 1993, 93, 18251838.
205 Y. Harayama and Y. Kita, Curr. Org. Chem., 2005, 9, 1567
1588.
206 Y. Wada, H. Fujioka and Y. Kita, Mar. Drugs, 2010, 8, 1394
1416.
207 J. F. Hu, H. Fan, J. Xiong and S. B. Wu, Chem. Rev., 2011,
111, 54655491.
208 S. J. H. Hickford, J. W. Blunt and M. H. G. Munro, Bioorg.
Med. Chem., 2009, 17, 21992203.
209 H. Zhang and R. J. Capon, Org. Lett., 2008, 10, 19591962.
210 H. Zhang, J. M. Major, R. J. Lewis and R. J. Capon, Org.
Biomol. Chem., 2008, 6, 38113815.
211 G. W. Wu, H. Y. Ma, T. J. Zhu, J. Li, Q. Q. Gu and D. H. Li,
Tetrahedron, 2012, 68, 97459749.
212 G. M. Cragg, P. G. Grothaus and D. J. Newman, Chem. Rev.,
2009, 109, 30123043.
213 M. S. Butler, Nat. Prod. Rep., 2005, 22, 162195.
214 A. M. Mayer, K. B. Glaser, C. Cuevas, R. S. Jacobs, W. Kem,
R. D. Little, J. M. McIntosh, D. J. Newman, B. C. Potts and
D. E. Shuster, Trends Pharmacol. Sci., 2010, 31, 255265.
215 T. F. Molinski, D. S. Dalisay, S. L. Lievens and J. P. Saludes,
Nat. Rev. Drug Discovery, 2009, 8,6985.
216 T. L. Simmons, E. Andrianasolo, K. McPhail, P. Flatt and
W. H. Gerwick, Mol. Cancer Ther., 2005, 4, 333342.
217 S. L. Scarpace, Clin. Ther., 2012, 34, 14671473.
218 R. Bai, K. D. Paull, C. L. Herald, L. Malspeis, G. R. Pettit and
E. Hamel, J. Biol. Chem., 1991, 266, 1588215889.
219 Y. Hirata and D. Uemura, Pure Appl. Chem., 1986, 58, 701
710.
220 M. Litaudon, S. J. H. Hickford, R. E. Lill, R. J. Lake,
J. W. Blunt and M. H. G. Munro, J. Org. Chem., 1997, 62,
18681871.
221 J. B. Hart, R. E. Lill, S. J. H. Hickford, J. W. Blunt and
M. H. G. Munro, in Drugs from the Sea, ed. N. Fusetani, S.
Karger Ag, Basel, 2000, pp. 134153.
222 D. Garcia, P. M. S. A. Gravalos, R. J. Lake, J. W. Blunt,
M. H. G. Munro and M. S. P. Litaudon, Eur. Pat., 0572109
(A1), 1993.
223 T. D. Aicher, K. R. Buszek, F. G. Fang, C. J. Forsyth,
S. H. Jung, Y. Kishi, M. C. Matelich, P. M. Scola,
D. M. Spero and S. K. Yoon, J. Am. Chem. Soc., 1992, 114,
31623164.
224 M. J. Towle, K. A. Salvato, J. Budrow, B. F. Wels,
G. Kuznetsov, et al.,Cancer Res., 2001, 61, 10131021.
225 D. A. Dabydeen, J. C. Burnett, R. L. Bai, P. Verdier-Pinard,
S. J. H. Hickford, G. R. Pettit, J. W. Blunt,
M. H. G. Munro, R. Gussio and E. Hamel, Mol.
Pharmacol., 2006, 70, 18661875.
226 G. R. Pettit, R. Tan, F. Gao, M. D. Williams, D. L. Doubek,
M. R. Boyd, J. M. Schmidt, J. C. Chapuis, E. Hamel,
R. Bai, J. N. A. Hooper and L. P. Tackett, J. Org. Chem.,
1993, 58, 25382543.
227 G. R. Pettit, C. L. Herald, M. R. Boyd, J. E. Leet, C. Dufresne,
D. L. Doubek, J. M. Schmidt, R. L. Cerny, J. N. A. Hooper
and K. C. Rutzler, J. Med. Chem., 1991, 34, 33393340.
228 K. L. Jackson, J. A. Henderson and A. J. Phillips, Chem. Rev.,
2009, 109, 30443079.
229 N. K. Gulavita, S. P. Gunasekera, S. A. Pomponi and
E. V. Robinson, J. Org. Chem., 1992, 57, 17671772.
230 D. O. B. Jones, B. D. Wigham, I. R. Hudson and B. J. Bett,
Mar. Biol., 2007, 151, 17311741.
This journal is © The Royal Society of Chemistry 2014 Nat. Prod. Rep.
Review NPR
Published on 29 May 2014. Downloaded by University of Wollongong on 03/07/2014 03:18:20.
View Article Online
... One biochemical adaptation to these conditions is the production of secondary metabolites. 2 These compounds have unusual and diverse structures that confer a competitive advantage to the organisms but, incidentally, also exhibit high rates of affinity to biological targets implicated in human disease. 2 Natural products from the deep sea constitute less than 2% of known natural products; however, the rate of bioactivity from deep-sea compounds is estimated to be as high as 75%. 2 Across the world's oceans, the phylum Cnidaria is second only to Porifera in the number of new natural products reported annually from invertebrates. 3 Comprising over 3000 species, Octocorallia are a particularly rich source of natural product exploration; roughly 80% of bioactive compounds from corals have been isolated from this subclass. 4 The Nephtheidae family comprises 20 genera and about 500 species, including Duva f lorida. ...
... 2 These compounds have unusual and diverse structures that confer a competitive advantage to the organisms but, incidentally, also exhibit high rates of affinity to biological targets implicated in human disease. 2 Natural products from the deep sea constitute less than 2% of known natural products; however, the rate of bioactivity from deep-sea compounds is estimated to be as high as 75%. 2 Across the world's oceans, the phylum Cnidaria is second only to Porifera in the number of new natural products reported annually from invertebrates. 3 Comprising over 3000 species, Octocorallia are a particularly rich source of natural product exploration; roughly 80% of bioactive compounds from corals have been isolated from this subclass. 4 The Nephtheidae family comprises 20 genera and about 500 species, including Duva f lorida. ...
... 2 These compounds have unusual and diverse structures that confer a competitive advantage to the organisms but, incidentally, also exhibit high rates of affinity to biological targets implicated in human disease. 2 Natural products from the deep sea constitute less than 2% of known natural products; however, the rate of bioactivity from deep-sea compounds is estimated to be as high as 75%. 2 Across the world's oceans, the phylum Cnidaria is second only to Porifera in the number of new natural products reported annually from invertebrates. 3 Comprising over 3000 species, Octocorallia are a particularly rich source of natural product exploration; roughly 80% of bioactive compounds from corals have been isolated from this subclass. 4 The Nephtheidae family comprises 20 genera and about 500 species, including Duva f lorida. ...
Article
Full-text available
Cold water benthic environments are a prolific source of structurally diverse molecules with a range of bioactivities against human disease. Specimens of a previously chemically unexplored soft coral, Duva florida, were collected during a deep-sea cruise that sampled marine invertebrates along the Irish continental margin in 2018. Tuaimenal A (1), a cyclized merosesquiterpenoid representing a new carbon scaffold with a highly substituted chromene core, was discovered through exploration of the soft coral secondary metabolome via NMR-guided fractionation. The absolute configuration was determined through vibrational circular dichroism. Functional biochemical assays and in silico docking experiments found tuaimenal A selectively inhibits the viral main protease (3CLpro) of SARS-CoV-2.
... Deep-sea sediments are considered an important source of structurally diverse secondary metabolites with wide biological activities [1]. To adapt to extreme environments of higher pressure, darkness, lower temperature and lack of oxygen, microorganisms have gradually evolved unique metabolic mechanisms to maintain their living [2]. ...
Article
Full-text available
Deep-sea sediment-derived bacterium may make full use of self-genes to produce more bioactive metabolites to adapt to extreme environment, resulting in the discovery of novel metabolites with unique structures and metabolic mechanisms. In the paper, we systematically investigated the metabolites in structurally diversity and their biosynthesis from the deep-sea sediment-derived bacterium Agrococcus sp. SCSIO 52902 based on OSMAC strategy, Molecular Networking tool, in combination with bioinformatic analysis. As a result, three new compounds and one new natural product, including 3R-OH-1,6-diene-cyclohexylacetic acid (1), linear tetradepsipeptide (2), N1,N5-di-p-(EE)-coumaroyl-N10-acetylspermidine (3) and furan fatty acid (4), together with nineteen known compounds (5–23) were isolated from the ethyl acetate extract of SCSIO 52902. Their structures were elucidated by comprehensive spectroscopic analysis, single-crystal X-ray diffraction, Marfey’s method and chiral-phase HPLC analysis. Bioinformatic analysis revealed that compounds 1, 3, 9 and 13–22 were closely related to the shikimate pathway, and compound 5 was putatively produced by the OSB pathway instead of the PKS pathway. In addition, the result of cytotoxicity assay showed that compound 5 exhibited weak cytotoxic activity against the HL-60 cell line.
... Whilst no auxiliary ecological parameters were monitored during the experiment, the deep sea (>1000 m) has a salinity of ~35 (parts per thousand), an average pH between 7.8 and 7.9, and consists of low oxygen levels (200-300 μmol/kg) and low temperatures (~1-3 • C) that are less volatile than the terrestrial environment or sea surface (McGrath Skropeta and Wei, 2014;Zhang et al., 2018). As each substrate was attached to a lander, these environmental conditions would have been identical for the colonising communities between substrates. ...
Article
Full-text available
Plastic pollution has now been found within multiple ecosystems across the globe. Characterisation of microbial assemblages associated with marine plastic, or the so-called ‘plastisphere’, has focused predominantly on plastic in the epipelagic zone. Whether this community includes taxa that are consistently enriched on plastic compared to surrounding non plastic surfaces is unresolved, as are the ecological implications. The deep sea is likely a final sink for most of the plastic entering the ocean, yet there is limited information on microbial colonisation of plastic at depth. The aim of this study was to investigate deep-sea microbial communities associated with polystyrene (PS) and polyurethane (PU) with Bath stone used as a control. The substrates (n = 15) were deployed in the Rockall Trough (Atlantic), and recovered 420 days later from a depth of 1796 m. To characterise the bacterial communities, 16S rRNA genes were sequenced using the Illumina MiSeq platform. A dominant core microbiome (taxa shared across all substrates) comprised 8% of total ASVs (amplicon sequence variant) and accounted for 92% of the total community reads. This suggests that many commonly reported members of the plastisphere are simply opportunistic which freely colonise any hard surface. Transiently associated species consisted of approximately 7% of the total community. Thirty genera were enriched on plastic (P < 0.05), representing 1% of the total community. The discovery of novel deep-sea enriched taxa included Aurantivirga, Algivirga, IheB3-7, Spirosoma, HTCC5015, Ekhidna and Calorithrix on PS and Candidatus Obscuribacter, Haloferula, Marine Methylotrophic Group 3, Aliivibrio, Tibeticola and Dethiosulfatarculus on PU. This small fraction of the microbiome include taxa with unique metabolic abilities and show how bacterial communities can be shaped by plastic pollution at depth. This study outlines a novel approach in categorising the plastisphere to elucidate the ecological implications of enriched taxa that show an affinity for colonising plastic.
Article
Two new (cladosporioles A and B, 1 and 2) and fourteen known (3–16) compounds were isolated from the deep‐sea‐derived fungus Cladosporium cladosporioides 170056. The relative structures of the new compounds were elucidated mainly by detailed analysis of their NMR and HR‐ESI‐MS spectroscopic data. Their absolute configurations were determined by comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. All isolates were tested for antimicrobial activity against Vibrio parahaemolyticus. Compound 15 exhibited weak effect with the MIC value of 156.25 μg/mL.
Article
Two new antimicrobial cytochalasin derivatives, 6 β , 7 β ‐epoxydeoxaphomin C ( 1 ) and 12‐hydroxydeoxaphomin C ( 2 ), a new natural occurring product 24‐nor‐cytochalasin B ( 3 ), together with two related known analogues ( 4 – 5 ) were isolated and identified from an endozoic fungus Curvularia verruculosa CS‐129, isolated from the deep‐sea squat lobster Shinkaia crosnieri which was collected in cold seep region of south China sea. The structures of new compounds were elucidated on the basis of detailed spectroscopic analysis and ECD calculation. The spectroscopic data of 24‐nor‐cytochalasin B ( 3 ) were reported for the first time. All compounds were tested for their antibacterial activities against human and aquatic pathogenic bacteria.
Article
Full-text available
Four unusual steckwaic acids E–H (1–4), possessing a rarely described acrylic acid unit at C-4 (1–3) or a double bond between C-12 and C-13 (4) are reported for the first time, along with four new analogues (5–8) and two known congeners (9 and 10). They were purified from the organic extract of Penicillium steckii AS-324, an endozoic fungus obtained from a deep-sea coral Acanthogorgiidae sp., which was collected from the Magellan Seamount at a depth of 1458 m. Their structures were determined by the interpretation of NMR and mass spectroscopic data. The relative and absolute configurations were determined by NOESY correlations, X-ray crystallographic analysis, and ECD calculations. All compounds were tested for their antimicrobial activities against human- and aquatic-pathogenic bacteria and plant-related pathogenic fungi.
Article
Full-text available
Microbes in marine ecosystems are known to produce secondary metabolites. One of which are carotenoids, which have numerous industrial applications, hence their demand will continue to grow. This review highlights the recent research on natural carotenoids produced by marine microorganisms. We discuss the most recent screening approaches for discovering carotenoids, using in vitro methods such as culture-dependent and culture independent screening, as well as in silico methods, using secondary metabolite Biosynthetic Gene Clusters (smBGCs), which involves the use of various rule-based and machine-learning-based bioinformatics tools. Following that, various carotenoids are addressed, along with their biological activities and metabolic processes involved in carotenoids biosynthesis. Finally, we cover the application of carotenoids in health and pharmaceutical industries, current carotenoids production system, and potential use of synthetic biology in carotenoids production.
Article
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive neoplastic diseases of the pancreas with fatal proliferation and metastasis and no medicine available for treatment. From an Antarctica sponge-derived fungus, Aspergillus insulicola HDN151418, four new nitrobenzoyl sesquiterpenoids, namely, insulicolides D-G (1-4), were isolated. Compounds 3 and 4 exhibited selective inhibition against human PDAC cell lines. Further studies indicated that compound 4 could significantly suppress cell proliferation to induce apoptosis and blocked migration and invasion of PDAC cells. Compound 4 could also avoid resistance and improved the therapeutic effect of the chemotherapy drug gemcitabine. A preliminary mechanism study showed that compound 4 can significantly inhibit the expression of EGFR and XIAP in PDAC cells. Altogether, 4 is a potential lead compound for anti-PDAC drug research.
Article
Full-text available
Aspergillus is well-known as the second-largest contributor of fungal natural products. Based on NMR guided isolation, three nitrogen-containing secondary metabolites, including two new compounds, variotin B (1) and coniosulfide E (2), together with a known compound, unguisin A (3), were of isolated from the ethyl acetate (EtOAc) extract of the deep-sea fungus Aspergillus unguis IV17-109. The planar structures of 1 and 2 were elucidated by an extensive analysis of their spectroscopic data (HRESIMS, 1D and 2D NMR). The absolute configuration of 2 was determined by comparison of its optical rotation value with those of the synthesized analogs. Compound 2 is a rare, naturally occurring substance with an unusual cysteinol moiety. Furthermore, 1 showed moderate anti-inflammatory activity with an IC50 value of 20.0 µM. These results revealed that Aspergillus unguis could produce structurally diverse nitrogenous secondary metabolites, which can be used for further studies to find anti-inflammatory leads.
Article
Full-text available
The genus Nephthea is a member of the family Acyonaceae, subfamily Nephtheidae, and is distributed throughout the world mainly in the Indo-Pacific region. The genus Nephthea has been studied for its phytochemical constituents and these studies have resulted in the discovery of over a hundred compounds comprising amides, sesquiterpenes, diterpenes and steroids. Corresponding biological activities such as anti-inflammatory and cytotoxic activities have also been observed for some of the isolated constituents. Among the isolated constituents, steroids are the most abundant followed by diterpenes and sesqui biological activities reported for twelve species of the genus Nephthea, namely,. chabrolii and N. sinulata. The purpose of the review is to draw greater attention to the potentials of soft corals as a source of new drugs and secondary metabolites.
Sponges (phylum Porifera) are known to be very rich sources for bioactive compounds, mainly secondary metabolites. Main efforts are devoted to cell- and mariculture of sponges to assure a sustainable exploitation of bioactive compounds from biological starting material. These activities are flanked by improved technologies to cultivate bacteria and fungi which are associated with the sponges. It is the hope that by elucidating the strategies of interaction between microorganisms and their host (sponge), by modern cell and molecular biological methods, a more comprehensive cultivation of the symbiotic organisms will be possible. The next step in the transfer of knowledge to biotechnological applications is the isolation, characterization and structural determination of the bioactive compounds by sophisticated chemical approaches.
Book
Major parts of the oceans and lands of our planet are permanently, or temporarily, exposed to temperatures below 10 C. Microorganisms, plants and animals living under these conditions have adapted to their environments in such a way that metabolic processes, reproduction and survival strategies are optimal for their natural biotopes. This book presents the most recent knowledge of the ecology and the physiology of cold-adapted microorganisms, plants and animals, and explains the mechanisms of cold-adaptation on the enzymatic and molecular level, including results from the first crystal structures of enzymes of cold-adapted organisms.
Article
Striatodoma dorothea, a new genus and species of cheilostomate bryozoan, is described from material found attached to hexactinellid sponges and pogonophoran tubes at an abyssal station (4100 m depth) off central California. Members of this new genus can be distinguished from other members of the family Tessaradomidae by the presence of biserial, rather than quadriserial branches, and a peristomial sinus, rather than an enclosed spiramen. Two other Pacific species, Diplonotos striatum Canu and Bassler, 1930, and Tessaradoma bifax Cheetham, 1972, are transferred to Striatodoma.
Article
The first total syntheses of dichotomide I (1), and marinacarbolines A-D (3-6) were achieved in four steps from methyl 1-chloro-beta-carboline-3-carboxlyate (9), which was previously used as a synthetic intermediate of dichotomine C. The required compound 9 was prepared in a six-step sequence including a microwave-assisted thermal electrocyclic reaction of a 1-azahexatriene system.
Article
The synthesis of three key fragments of the novel 16-membered macrolide leiodermatolide is described. The stereotetrad-containing building block was prepared via a Marshall-Tamaru reaction on an aldehyde obtained by organocatalysis. For a second building block, a Marshall-Tamaru reaction was used as well. The side-chain fragment containing a hydroxy delta-lactone could be obtained by intramolecular Reformatsky reaction.
Article
A brief and efficient approach for the synthesis of (±)-5-benzyl-4-hydroxy-2-pyrrolidine (1) from phenylalanine racemate is described. The key step is the stereocontrolled reduction of the keto functionality of benzylated pyrrolidinone intermediate (6) via sodium borohydride in carboxylic acid medium furnishing both (R,R)- and (S,S)-configured diastereomers. The natural (R,R) enantiomer (2), however, crystallized out from its racemic mixture. Structure of 2 was confirmed by NMR, IR, elemental analyzer, and single crystal X-ray crystallographic techniques.
Article
Oceans not only cover the major part of the earth’s surface but also reach into depths exceeding the height of the Mt Everest. They are populated down to the deepest levels (≈11800 m), which means that a significant proportion of the global biosphere is exposed to pressures of up to 120 MPa. Although this fact has been known for more than a century, the ecology of the ‘abyss’ is still in its infancy. Only recently, barophilic adaptation, i.e. the requirement of elevated pressure for viability, has been firmly established. In non-adapted organisms, increased pressure leads to morphological anomalies or growth inhibition, and ultimately to cell death. The detailed molecular mechanism of the underlying ‘metabolic dislocation’ is unresolved.
Article
The first synthesis of the title compound (IV) via an oxidation including an easy work-up and with environmentally benign materials is presented.