marine drugs
Review
Secondary Metabolites from Polar Organisms
Yuan Tian 1, *, Yan-Ling Li 1 and Feng-Chun Zhao 2
1
2
*
College of Life Science, Taishan Medical University, Taian 271016, Shandong, China; [email protected]
College of Life Science, Shandong Agricultural University, Taian 271018, Shandong, China;
[email protected]
Correspondence: [email protected]; Tel.: +86-358-623-5778
Academic Editor: Orazio Taglialatela-Scafati
Received: 7 January 2017; Accepted: 29 January 2017; Published: 23 February 2017
Abstract: Polar organisms have been found to develop unique defences against the extreme
environment environment, leading to the biosynthesis of novel molecules with diverse bioactivities.
This review covers the 219 novel natural products described since 2001, from the Arctic and the
Antarctic microoganisms, lichen, moss and marine faunas. The structures of the new compounds and
details of the source organism, along with any relevant biological activities are presented. Where
reported, synthetic and biosynthetic studies on the polar metabolites have also been included.
Keywords: natural products; secondary metabolism; structure elucidation; biological activity;
biosynthesis; chemical synthesis
1. Introduction
Organisms from special ecosystems such as the polar regions are a rich source of various chemical
scaffolds and novel natural products with promising bioactivities. Polar regions, which refer to the
Arctic, the Antarctic and their subregions, are remote and challenging areas on the earth. To survive
under the constant influence of low temperatures, strong winds, low nutrient and high UV radiation
or combinations of these factors [1], polar organisms require a diverse array of biochemical and
physiological adaptations that are essential for survival. These adaptations are often accompanied by
modifications to both gene regulation and metabolic pathways, increasing the possibility of finding
unique functional metabolites of pharmaceutical importance.
Polar regions are complex ecosystems that harbor diverse groups of fauna and microorganisms
including bacteria, actinomycetes and fungi. Physiological adaptations have enabled psychrophilic
organisms to thrive in the polar regions, especially microorganisms which are high in number and
usually uncharacterized [2–5]. However, when compared to the large number of polar microorganisms
which have been reported, very few have been screened for the production of interesting secondary
metabolites. The advent of modern techniques provides the opportunity to find novel metabolites.
From 2001 to 2016, a vast amount of new biological natural compounds with various activities,
such as anti-bacteria, anti-tumor, anti-virus and so on, have been isolated from polar organisms
including microorganisms, lichen, moss, bryozoans, cnidarians, echinoderms, molluscs, sponges and
tunicates. Natural products from the Arctic or the Antarctic organisms have been the subject of several
review articles. In 2007, Lebar et al. reviewed the studies on structure and bioactivity of cold-water
marine natural products, including many polar examples [6]. In 2009, Wilson and Brimble reviewed
molecules derived from the extremes of life, including some polar examples [7]. In 2011, advances
in the chemistry and bioactivity of arctic sponge were reviewed by Hamann and his co-workers [8].
In 2013, Liu et al. reviewed a number of new secondary metabolites with various activities derived
from both Antarcitc and Arctic organisms [9], while in 2014, Skropeta and Wei published a review on
natural products isolated from deep-sea sources, which included some polar organisms [10]. Moreover,
Mar. Drugs 2017, 15, 28; doi:10.3390/md15030028
www.mdpi.com/journal/marinedrugs
Mar. Drugs 2017, 15, 28 2 of 30 published a review on natural products isolated from deep‐sea sources, which included some polar organisms [10]. Moreover, Blunt and his co‐workers published periodical reviews on the Mar.characteristics of various marine natural products with some polar examples [11–13]. Drugs 2017, 15, 28
2 of 30
However, comprehensive reviews of natural products from polar regions were rare; therefore, we describe here the source, chemistry, and biology of the newly discovered biomolecules from the polar We also summarize the chemical and the biosynthetic relationship of Blunt
andorganisms. his co-workers
published
periodical
reviewssynthesis on the characteristics
of various
marine natural
metabolites. The Metabolites Name Index in combination with the Source Index, the Biological products
with some
polar examples
[11–13].
Activity Index and the References on isolation in the accompanying tables, will help understand the However, comprehensive reviews of natural products from polar regions were rare; therefore, we
fascinating chemistry and biology of natural products derived from polar organisms. describe
here the source, chemistry, and biology of the newly discovered biomolecules from the polar
organisms. We also summarize the chemical synthesis and the biosynthetic relationship of metabolites.
2. Microorganisms The Metabolites Name Index in combination with the Source Index, the Biological Activity Index and
The microbial diversity of polar environments is a fertile ground for new bioactive compounds, the References
on isolation in the accompanying tables, will help understand the fascinating chemistry
genes, proteins, microorganisms and other products with potential for commercial use [14]. and biology of natural products derived from polar organisms.
2.1. Unicellular Bacteria 2. Microorganisms
TheThe culture broth of the marine bacterium Bacillus sp., isolated from the sea mud near the Arctic microbial diversity of polar environments is a fertile ground for new bioactive compounds,
pole, was found to yield three and
new other
cyclic acylpeptides as for
mixirins A (1), B (2) [14].
and C (3) genes, proteins,
microorganisms
products
with named potential
commercial
use
(Figure 1) [15]. All of the three compounds were found to display significant cytotoxicity against 50) values of 0.68, 2.1.human colon tumor cells (HCT‐116) with half maximal inhibitory concentration (IC
Unicellular Bacteria
1.6, 1.3 μg/mL, respectively. TheFour culture
broth of the marine bacterium Bacillus sp., isolated from the sea mud near the Arctic
new aromatic nitro compounds (4–7) (Figure 1) along with fifteen known ones were pole,
was found to yield three new cyclic acylpeptides named as mixirins A (1), B (2) and C (3)
reported from the Salegentibacter strain T436, isolated from a bottom section of a sea ice floe collected (Figure
[15].
All Ocean. of the three
compounds
found
to display
cytotoxicity
against
from 1)
the Arctic The new natural were
products showed weak significant
antimicrobial and cytotoxic human
colon
tumor
cells
(HCT-116)
with
half
maximal
inhibitory
concentration
(IC
)
values
of 0.68,
50
activities [16]. Further study of the same bacterium isolate yielded another seven new aromatic nitro 1.6,compounds (8–14) (Figure 1) [17]. 1.3 µg/mL, respectively.
Figure 1. Secondary metabolites derived from the Arctic bacteria (compounds 1–14). Figure
1. Secondary metabolites derived from the Arctic bacteria (compounds 1–14).
A novel diketopiperazine, named cyclo‐(D‐pipecolinyl‐L‐isoleucine) (15) (Figure 2), and two Four
newpeptides aromatic(16, nitro
compounds
(Figure
1) along
withdiketopiperazines fifteen known ones
were
reported
new linear 17) (Figure 2), (4–7)
along with seven known were isolated from
the
Salegentibacter
strain
T436,
isolated
from
a
bottom
section
of
a
sea
ice
floe
collected
from
from the cell‐free culture supernatant of the Antarctic psychrophilic bacterium Pseudoalteromonas thehaloplanktis TAC125 [18]. Peptide 17 and a known phenyl‐containing diketopiperazine showed free Arctic Ocean. The new natural products showed weak antimicrobial and cytotoxic activities [16].
Further
study of the same bacterium isolate yielded another seven new aromatic
nitro compounds
radical scavenging properties, with the phenyl group essential for activity. (8–14) (Figure 1) [17].
A novel diketopiperazine, named cyclo-(D-pipecolinyl-L-isoleucine) (15) (Figure 2), and two
new linear peptides (16, 17) (Figure 2), along with seven known diketopiperazines were isolated
from the cell-free culture supernatant of the Antarctic psychrophilic bacterium Pseudoalteromonas
haloplanktis TAC125 [18]. Peptide 17 and a known phenyl-containing diketopiperazine showed free
radical scavenging properties, with the phenyl group essential for activity.
Mar. Drugs 2017, 15, 28
Mar. Drugs 2017, 15, 28 3 of 30
3 of 30 Figure 2. Secondary metabolites derived from the Antarctic bacteria (compounds 15–22). Figure 2. Secondary metabolites derived from the Antarctic bacteria (compounds 15–22).
From the Antarctic cyanobacterium Nostoc CCC 537, an antibacterial lead molecule (18) (Figure 2) From
the Antarctic
cyanobacterium
CCC 537,
an antibacterial
molecule
(Figure 2)
was obtained. Compound 18 exhibited Nostoc
antibacterial activity against two lead
Gram positive (18)
pathogenic wasstrains obtained.
Compound negative strains 18 exhibited antibacterial
activity
against resistant strains two Gram positive
pathogenic
and seven Gram including three multi‐drug of Escherichia strains
and seven Gram negative strains including three multi-drug resistant strains of Escherichia
coli,
coli, with minimal inhibition concentration (MIC) values in the range of 0.5–16.0 μg/mL [19]. Two pigments named violacein (MIC)
(19) and flexirubin (20) (Figure 2) were isolated with minimal
inhibition
concentration
values
in the range
of 0.5–16.0
µg/mL
[19]. from two Antarctic bacterial strains. The two displayed antibacterial activities against some Two pigments
named
violacein
(19)compounds and flexirubin
(20) (Figure
2) were isolated
from
two Antarctic
mycobacteria with low MIC values (ranging from 2.6 to 34.4 μg/mL), and might be valuable natural bacterial
strains. The two compounds displayed antibacterial activities against some mycobacteria
lead compounds for new antimycobacterial drugs used for tuberculosis chemotherapy [20]. with
low MIC values (ranging from 2.6 to 34.4 µg/mL), and might be valuable natural lead compounds
purification of for
Antarctic strain chemotherapy
Pseudomonas BNT1 for newBioassay‐guided antimycobacterial
drugs used
tuberculosis
[20]. extracts produced three rhamnolipids including two new ones (21, 22). Compound 21 was effective against the tested human Bioassay-guided purification of Antarctic strain Pseudomonas BNT1 extracts produced three
pathogens strains Burkholderia cepacia, B. metallica, B. seminalis, B. latens and Staphylococcus aureus with rhamnolipids including two new ones (21, 22). Compound 21 was effective against the tested human
low MIC and minimun bacteriocidal concentration (MBC) values, while compound 22 only had pathogens strains Burkholderia cepacia, B. metallica, B. seminalis, B. latens and Staphylococcus aureus
moderate antimicrobial effect against S. aureus with an MBC value of 100 μg/mL [21]. with low MIC and minimun bacteriocidal concentration (MBC) values, while compound 22 only had
moderate
antimicrobial effect against S. aureus with an MBC value of 100 µg/mL [21].
2.2. Actinomycetes In this century, actinomyces derived from polar regions have yielded an array of interesting 2.2. Actinomycetes
new metabolites. Three new pyrrolosesquiterpenes, glyciapyrroles A (23), B (24), and C (25) (Figure In this century, actinomyces
derived
from polar regions have yielded an array of interesting new
3), along with three known ones, iketopiperazines cyclo(leucyl‐prolyl), cyclo(isoleucyl‐prolyl), and metabolites.
Three new pyrrolosesquiterpenes,
glyciapyrroles
A (23), B (24), and
C (25) (Figure
cyclo(phenylalanyl‐prolyl), were isolated from the Streptomyces sp. NPS008187 originating from a 3),
along
with
three
known
ones,
iketopiperazines
cyclo(leucyl-prolyl),
cyclo(isoleucyl-prolyl),
and
marine sediment collected in Alaska near the Arctic [22]. cyclo(phenylalanyl-prolyl), were isolated from the Streptomyces sp. NPS008187 originating from
a marine sediment collected in Alaska near the Arctic [22].
Mar. Drugs 2017, 15, 28
Mar. Drugs 2017, 15, 28 4 of 30
4 of 30 Figure 3. Secondary metabolites derived from the Arctic actinomyces (compounds 23–27, 30, 31). Figure
3. Secondary metabolites derived from the Arctic actinomyces (compounds 23–27, 30, 31).
The Arctic seaweed‐associated actinomycete Nocardiopsis sp. 03N67 was found to produce a Thebioactive Arctic seaweed-associated
actinomycete
Nocardiopsis
sp. 03N67
foundtumor to produce
a rare
rare diketopiperazine, cyclo‐(
L‐Pro‐L‐Met) (26) (Figure 3). It was
inhibited necrosis bioactive
diketopiperazine,
cyclo-(
L
-ProL
-Met)
(26)
(Figure
3).
It
inhibited
tumor
necrosis
factor-α
factor‐α (TNF‐α)‐induced tube formation and invasion at 10 μM, a concentration at which no (TNF-α)-induced
tube formation and invasion at 10 µM, a concentration at which no cytotoxicity was
cytotoxicity was observed. Anti‐angiogenesis activity against human umbilical vein endothelial cells observed.
Anti-angiogenesis activity against human umbilical vein endothelial cells (HUVECs) of
(HUVECs) of compound 26 is an encouraging bioprobe to develop new anticancer therapeutics from compound
26 is an encouraging bioprobe to develop
new anticancer therapeutics from such type of
such type of small molecules in near future [23]. The marine actinomycete small molecules
in near
future [23].Nocardia dassonvillei BM‐17, obtained from a sediment sample collected in the Arctic Ocean, has furnished a new secondary metabolite, N‐(2‐hydroxyphenyl)‐ The marine
actinomycete
Nocardia
dassonvillei
BM-17,
obtained
from a sediment
sample collected
2‐phenazinamine (27) (Figure 3), and six known antibiotics. The new compound showed weak in the Arctic Ocean, has furnished a new secondary metabolite, N-(2-hydroxyphenyl)-2-phenazinamine
antifungal activity against Candida albicans, with a MIC value of 64 μg/mL and low cancer against
cell (27) (Figure 3), and six known antibiotics. The new compound showed weak antifungal activity
cytotoxicity against HepG2, A549, HCT‐116 and COC1 cells, with IC
50 values of 40.33, 38.53, 27.82 Candida albicans, with a MIC value of 64 µg/mL and low cancer cell cytotoxicity against HepG2, A549,
and 28.11 μg/mL, respectively [24]. HCT-116
and COC1 cells, with IC50 values of 40.33, 38.53, 27.82 and 28.11 µg/mL, respectively [24].
Chemical examination from the Arctic actinomycete Streptomyces nitrosporeus CQT14‐24 Chemical examination from the Arctic actinomycete Streptomyces nitrosporeus CQT14-24 resulted
resulted in the isolation of two new alkaloids, named as nitrosporeusines A (28) and B (29) (Scheme in the isolation of two new alkaloids, named as nitrosporeusines A (28) and B (29) (Scheme 1), with
1), with an unprecedented skeleton containing benzenecarbothioc cyclopenta[c]pyrrole‐1,3‐dione. an unprecedented skeleton containing benzenecarbothioc cyclopenta[c]pyrrole-1,3-dione. Both 28
Both 28 and 29 showed inhibitory activity against the influenza WSN virus (H1N1) in Madin–Darby and 29 showed inhibitory activity against the influenza WSN virus (H1N1) in Madin–Darby canine
canine kidney (MDCK) cells with the dose of 50 μM. In an in vitro plaque reduction assay, 29 kidney (MDCK) cells with the dose of 50 µM. In an in vitro plaque reduction assay, 29 exhibited
exhibited dose‐dependent reduction of the production of the viral progeny which was produced by dose-dependent
reduction
of the
production
of thevirus. viral The progeny
which was
produced(EC
by50) the
the infected MDCK cells with influenza A/WSN/33 half effective concentration infected
MDCK
cells
with
influenza
A/WSN/33
virus.
The
half
effective
concentration
(EC50 )
value of 29 for the inhibition of viral plaque formation was quite comparable to that of the positive value
of 29
for the inhibition
viral [25]. plaque
formation
was
quite have comparable
tointerest that ofto the
control oseltamivir phosphate of
(Osv‐P) Their biological activities attracted positive
control
oseltamivir
phosphate
(Osv-P)
[25].
Their
biological
activities
have
attracted
interest
synthesize these compounds. Efficient stereoselective synthesis of the natural enantiomer of to synthesize
these compounds. Efficient stereoselective
synthesis of the natural enantiomer of
nitrosporeusines A and B was performed by Reddy’s groups. An overall five‐step process starting nitrosporeusines
A and B was performed by Reddy’s groups. An overall five-step process starting
from 5,6‐dihydrocyclopenta[c]pyrrole‐1,3(2H,4H)‐dione and p‐hydroxybenzoic acid is summarized in Scheme 1 [26]. from
5,6-dihydrocyclopenta[c]pyrrole-1,3(2H,4H)-dione and p-hydroxybenzoic acid is summarized in
new secondary metabolites, arcticoside (30) and C‐1027 chromophore‐V (31) (Figure 3), SchemeTwo 1 [26].
from 3),
were isolated along with three kown compounds, C‐1027 chromophore‐III, fijiolides A and B Two new secondary metabolites, arcticoside (30) and C-1027 chromophore-V (31) (Figure
the isolated
culture along
of an Arctic marine actinomycete Streptomyces strain. Compounds 30 and 31 inhibited were
with three
kown
compounds,
C-1027 chromophore-III,
fijiolides
A and
B from
Candida albicans isocitrate lyase, an enzyme that plays an important role in the pathogenicity of C. the culture of an Arctic marine actinomycete Streptomyces strain. Compounds 30 and 31 inhibited
albicans. Furthermore, 31 exhibited significant cytotoxicity against breast carcinoma MDA‐MB231 Candida
albicans isocitrate lyase, an enzyme that plays an important role in the pathogenicity of
cells and colorectal carcinoma HCT‐116 cells, with IC50 values of 0.9 and 2.7 μM, respectively [27]. C. albicans. Furthermore, 31 exhibited significant cytotoxicity against breast carcinoma MDA-MB231
cells and colorectal carcinoma HCT-116 cells, with IC50 values of 0.9 and 2.7 µM, respectively [27].
Mar. Drugs 2017, 15, 28
5 of 30
Mar. Drugs 2017, 15, 28 O
5 of 30 O
AcO
Mar. Drugs 2017, 15, 28 NH
O
O
NH
a
a
NH
O
O
NH
O
b
HO
NH
O
AcO
O
NH
b
O
O
O
O
HO
c
NH
O
HO
O
NH
SH
c
O
OH
O
O
HO
e
HO
O
OH
d
e
O
SH
HO
OH
d
OH
O
H
N
S
H
N
O
O
Nitrosporeusine
S A (28)
+
H
N
OO
Nitrosporeusine A (28)
+ S
H
N
O
O
Nitrosporeusine
S B (29)
5 of 30 O
H
O
OH
H
OH
O
H
O
OH
H
OH
Scheme 1. Synthesis of natural products nitrosporeusines A (28) and B (29). Reagents and conditions: O conditions:
Scheme
1. Synthesis of natural products nitrosporeusines AOH(28) and B (29). Reagents and
OH
Nitrosporeusine
B
(29)
(a) SeO2, 1,4‐dioxane, microwave, 110 °C, 61%; (b) Amano PS lipase, THF, CH2=CHOAc, 38%; (c) (a) SeO2 , 1,4-dioxane, microwave, 110 ◦ C, 61%; (b) Amano PS lipase, THF, CH2 =CHOAc, 38%; Amano PS lipase, phosphate buffer, 92%; (d) Lawessonʹs reagent, acetonitrile, microwave, 100 °C, ◦
Scheme 1. Synthesis of natural products nitrosporeusines A (28) and B (29). Reagents and conditions: (c) Amano
PS lipase, phosphate buffer, 92%; (d) Lawesson's reagent, acetonitrile, microwave, 100 C,
53%; (e) H
2O, room temperature (rt), 65%. (a) (e)
SeO
1,4‐dioxane, microwave, °C, 61%; (b) Amano PS lipase, THF, CH2=CHOAc, 38%; (c) 53%;
H22, O,
room temperature
(rt),110 65%.
Amano PS lipase, phosphate buffer, 92%; (d) Lawessonʹs reagent, acetonitrile, microwave, 100 °C, A Streptomyces griseus strain NTK 97, recovered from an Antarctic terrestrial sample, yielded a 53%; (e) H
2O, room temperature (rt), 65%. A Streptomyces griseus strainfrigocyclinone NTK 97, recovered
from 4), consisting an Antarctic of terrestrial
sample, moiety yielded a
new angucyclinone antibiotic (32) (Figure a tetrangomycin new
angucyclinone
antibiotic
frigocyclinone
(32)
(Figure
4),
consisting
of
a
tetrangomycin
moiety
attached through a C‐glycosidic linkage with the aminodeoxysugar ossamine. Frigocyclinone A Streptomyces griseus strain NTK 97, recovered from an Antarctic terrestrial sample, yielded a revealed good inhibitory activities against Bacillus subtilis and Staphylococcus aureus [28]. Another attached
through
a
C-glycosidic
linkage
with
the
aminodeoxysugar
ossamine.
Frigocyclinone
revealed
new angucyclinone antibiotic frigocyclinone (32) (Figure 4), consisting of a tetrangomycin moiety Antarctic Streptomyces griseus strain NTK14 was and
shown to contain the novel‐type angucyclinone good
inhibitory
activities
against
Bacillus
subtilis
Staphylococcus
aureus
[28]. Another
Antarctic
attached through a C‐glycosidic linkage with the aminodeoxysugar ossamine. Frigocyclinone gephyromycin (33) (Figure 4), and two known compounds, fridamycin E and dehydrorabelomycin. Streptomyces
griseus
strain NTK14
was shownBacillus to contain
the novel-type
angucyclinone
gephyromycin
revealed good inhibitory activities against subtilis and Staphylococcus aureus [28]. Another Gephyromycin, an unprecedented intramolecular ether bridge, displayed angucyclinone glutaminergic Streptomyces griseus strain NTK14 was shown contain the novel‐type (33)Antarctic (Figure 4),
and with two known
compounds,
fridamycin
E to and
dehydrorabelomycin.
Gephyromycin,
activity (agonist) towards neuronal cells. In addition, 33 exhibited no acute cytostatic activities, and gephyromycin (33) (Figure 4), and two known compounds, fridamycin E and dehydrorabelomycin. with an unprecedented intramolecular ether bridge, displayed glutaminergic activity (agonist) towards
the lack of cytotoxicity made its neuroprotective properties even more valuable [29]. glutaminergic Gephyromycin, with an 33unprecedented intramolecular ether bridge, displayed neuronal
cells. In addition,
exhibited no acute
cytostatic activities,
and the
lack of cytotoxicity
made
A new sulphur‐containing natural alkaloid named microbiaeratin (34) (Figure 4) was activity (agonist) towards neuronal cells. In addition, 33 exhibited no acute cytostatic activities, and its neuroprotective properties even more valuable [29].
characterized, together with the known bacillamide from the culture of Microbispora aerata strain the lack of cytotoxicity made its neuroprotective properties even more valuable [29]. A new sulphur-containing natural alkaloid named microbiaeratin (34) (Figure 4) was
IMBAS‐11A, isolated from the Antarctic Livingston Island. A low antiproliferative and cytotoxic A new together
sulphur‐containing natural alkaloid named microbiaeratin (34) (Figure 4) was characterized,
with the known
bacillamide
from the
culture of Microbispora
aerata
strain
effects of 34 was determined with L‐929 bacillamide mouse fibroblast cells, K‐562 of human leukemia cells and characterized, together with the known from the culture Microbispora aerata strain IMBAS-11A, isolated from the Antarctic Livingston Island. A low antiproliferative and cytotoxic effects
HeLa human cervix carcinoma cells [30]. IMBAS‐11A, isolated from the Antarctic Livingston Island. A low antiproliferative and cytotoxic of 34 was
determined with L-929 mouse fibroblast cells, K-562 human leukemia cells and HeLa human
The Nocardiopsis sp. SCSIO KS107 was isolated from Antarctic seashore sediment. Fermentation effects of 34 was determined with L‐929 mouse fibroblast cells, K‐562 human leukemia cells and cervix
carcinoma cells [30].
and isolation of this strain provided two new α‐pyrones germicidin H (35), 4‐hydroxymucidone (36), HeLa human cervix carcinoma cells [30]. TheThe Nocardiopsis sp. SCSIO KS107 was isolated from Antarctic seashore sediment. Fermentation sp. SCSIO
KS107 was isolated
from
seashore sediment.
Fermentation
and a Nocardiopsis
known compound 7‐hydroxymucidone. Only the Antarctic
known compound showed antibacterial andand isolation of this strain provided two new α‐pyrones germicidin H (35), 4‐hydroxymucidone (36), isolation
of
this
strain
provided
two
new
α-pyrones
germicidin
H
(35),
4-hydroxymucidone
(36),
activity against Micrococcus luteus with an MIC value of 16 μg/mL [31]. andand a known
compound
7-hydroxymucidone.
Only the the known knowncompound compoundshowed showed
antibacterial
a known compound 7‐hydroxymucidone. Only antibacterial activity
against
Micrococcus
luteus
with
an
MIC
value
of
16
µg/mL
[31].
activity against Micrococcus luteus with an MIC value of 16 μg/mL [31]. Figure 4. Secondary metabolites derived from the Antarctic actinomyces (compounds 32–36). 2.3. Fungi Figure 4. Secondary metabolites derived from the Antarctic actinomyces (compounds 32–36). Figure
4. Secondary metabolites derived from the Antarctic actinomyces (compounds 32–36).
The rapid growth and ability to metabolize a wide variety of substrates have enabled fungi to 2.3. Fungi 2.3.become the predominant components of the microorganisms in polar regions. The psychrotolerant Fungi
fungus Penicillium algidum, collected from soil under a Ribes sp. in Greenland near the Arctic, The rapid growth and ability to metabolize a wide variety of substrates have enabled fungi to The
rapid
growth and ability to metabolize a wide variety of substrates have enabled fungi to
yielded the new cyclic nitropeptide, psychrophilin D (37) (Figure 5), together with two known cyclic become the predominant components of the microorganisms in polar regions. The psychrotolerant become
thePenicillium predominant
components
the soil microorganisms
insp. polar
regions. The
psychrotolerant
fungus algidum, collected of
from under a Ribes in Greenland near the Arctic, yielded the new cyclic nitropeptide, psychrophilin D (37) (Figure 5), together with two known cyclic Mar. Drugs 2017, 15, 28
6 of 30
Mar. Drugs 2017, 15, 28 fungus
Penicillium algidum, collected from soil under a Ribes sp. in Greenland near the Arctic, 6 of 30 yielded
the new cyclic nitropeptide, psychrophilin D (37) (Figure 5), together with two known cyclic peptides,
peptides, cycloaspeptide A and cycloaspeptide D. The compounds were tested in antimicrobial, cycloaspeptide A and cycloaspeptide D. The compounds were tested in antimicrobial, antiviral,
antiviral, anticancer and antiplasmodial assays. Psychrophilin D exhibited a moderate activity with anticancer
and antiplasmodial
Psychrophilin
D in exhibited
a moderate
withcell half assay. infective
half infective dose (ID50) assays.
value of 10.1 μg/mL the P388 murine activity
leukaemia dose
(ID
)
value
of
10.1
µg/mL
in
the
P388
murine
leukaemia
cell
assay.
Cycloaspeptide
A
and D
50
50 = 3.5 and 4.7 μg/mL, respectively) against Cycloaspeptide A and D exhibited moderate activity (IC
exhibited
moderate activity (IC50 = 3.5 and 4.7 µg/mL, respectively) against Plasmodium falciparum [32].
Plasmodium falciparum [32]. O
HN
H
O NO2
H
N
HN
HN
HO
O
O
O
O
HN
HO
O
OH
O
Cytochalasins Z25 (39)
Cytochalasins Z24 (38)
Psychrophilin D (37)
O
O
HO
O
H
O
HN
HO
O
O
O
O
O
HO
O
O
OH
O
OH
Cytochalasins Z26 (40)
O
Libertellenone H (42)
Libertellenone G (41)
OH
O
N
O
O
OH
OH
O
O
O
O
O
OH
Eutypenoid A (43)
OH
Eutypenoid A (45)
Eutypenoid A (44)
OH
O
O
OH
O
O
O
O
HN
O
HN
O
H
O
H
Lindgomycin (46)
H
O
H
O
H
O
O
(48)
H
Ascosetin (47)
Figure 5. Secondary metabolites derived from the Arctic fungi (compounds 37–48). Figure 5. Secondary metabolites derived from the Arctic fungi (compounds 37–48).
Three new cytochalasins Z24, Z25, Z26 (38–40) (Figure 5) and one known compound, scoparasin B, Three
new cytochalasins
Z24 , fungus Z25 , Z26Eutypella (38–40) (Figure
5) These and one
known compound,
scoparasin
were isolated from the Arctic sp. D‐1. compounds were evaluated for B,
were
isolatedactivities from theagainst Arctic fungus
sp. D-1.
These
were
evaluated38 forshowed cytotoxic
cytotoxic several Eutypella
human tumor cell lines. compounds
Among them, compound activities
against several human tumor cell lines. Among them, compound
38 showed moderate
moderate cytotoxicity toward human breast cancer MCF‐7 cell line with IC
50 value of 9.33 mΜ [33]. Further investigation of Eutypella sp. D‐1 led to the discovery of two new diterpenes, libertellenone cytotoxicity
toward human breast cancer MCF-7 cell line with IC50 value of 9.33 mM [33]. Further
G (41) and oflibertellenone 5), together with new
two diterpenes,
known pimarane diterpenes. investigation
Eutypella sp. H D-1(42) led(Figure to the discovery
of two
libertellenone
G (41)
Compound 41 exhibited antibacterial activity against Escherichia coli, Bacillus subtilis and and libertellenone H (42) (Figure 5), together with two known pimarane diterpenes. Compound
Staphylococcus aureus. Compound 42 showed slight coli,
cytotoxicity toward most cell lines, with 41 exhibited
antibacterial
activity against
Escherichia
Bacillus subtilis
and
Staphylococcus
aureus.
half‐maximal inhibitory concentration values ranging from 3.31 to 44.1 μM. In addition, the Compound 42 showed slight cytotoxicity toward most cell lines, with half-maximal
inhibitory
cytotoxicity of 42 is most likely dependent on the presence of its cyclopropane ring as deduced from concentration
values ranging from 3.31 to 44.1 µM. In addition, the cytotoxicity of 42 is most likely
the inactivity of other similar compounds [34]. Recently, three pimarane diterpenoids, Eutypenoids dependent on the presence of its cyclopropane ring as deduced from the inactivity of other similar
A–C (43–45), were also isolated from the culture of Eutypella (E.) sp. D‐1. Using a ConA‐induced compounds [34]. Recently, three pimarane diterpenoids, Eutypenoids A–C (43–45), were also isolated
splenocyte proliferation model, compound 44 exhibited potent immunosuppressive activities [35]. from the culture of Eutypella (E.) sp. D-1. Using a ConA-induced splenocyte proliferation model,
An unusual polyketide with a new carbon skeleton, lindgomycin (46) (Figure 5) [36], and the compound
44 exhibited potent immunosuppressive activities [35].
recently described ascosetin (47) (Figure 5) [37] were extracted from different Lindgomycetaceae strains, which were isolated from an Arctic sponge. Both the compounds exhibited strong antibiotic Mar. Drugs 2017, 15, 28
7 of 30
An unusual polyketide with a new carbon skeleton, lindgomycin (46) (Figure 5) [36], and the
recently described ascosetin (47) (Figure 5) [37] were extracted from different Lindgomycetaceae
strains, which were isolated from an Arctic sponge. Both the compounds exhibited strong antibiotic
activities against the clinically relevant Gram-positive bacteria (including methicillin-resistant
Staphylococcus
aureus) and human pathogenic yeast Candida albicans.
Mar. Drugs 2017, 15, 28 7 of 30 Trichoderma polysporum strain OPU1571, recovered from a moss, Sanionia uncinata, growing
against the clinically relevant Gram‐positive bacteria (including methicillin‐resistant in the activities high arctic
wetlands
on Spitsbergen
Island, Svalbard,
Norway,
yielded
eleven compounds,
Staphylococcus aureus) and human pathogenic yeast Candida albicans. including a new one (48) (Figure 5). The in vitro investigation suggested that compound 48 showed
Trichoderma polysporum strain OPU1571, recovered from a moss, Sanionia uncinata, growing in a concentration-dependent growth-inhibitory effect on snow rot pathogen Pythium iwayamai at
the high arctic wetlands on Spitsbergen Island, Svalbard, Norway, yielded eleven compounds, including 5 daysa [38].
new one (48) (Figure 5). The in vitro investigation suggested that compound 48 showed a Fermentation
of the Antarctic ascomycete fungus Geomyces sp. yielded five new asterric
acid
concentration‐dependent growth‐inhibitory effect on snow rot pathogen Pythium iwayamai at 5 days [38].
derivatives,
ethyl asterrate
n-butyl
asterrate
(50), Geomyces and geomycins
A–C
(51–53)
(Figure
6). The
Fermentation of the (49),
Antarctic ascomycete fungus sp. yielded five new asterric acid derivatives, ethyl asterrate (49), n‐butyl asterrate (50), and geomycins A–C (51–53) (Figure new metabolites
were tested for their antibacterial and antifungal activities. Geomycin B 6). The (52) showed
new metabolites were tested for their antibacterial and antifungal activities. Geomycin B (52) significant antifungal activity against Aspergillus fumigatus ATCC 10894, with IC50 /MIC
values of
showed significant antifungal activity against Aspergillus fumigatus ATCC 10894, with IC
50/MIC 0.86/29.5 µM (the positive control fluconazole showed IC50 /MIC values of 7.35/163.4 µM). Geomycin
values of 0.86/29.5 μM (the positive control fluconazole showed IC50/MIC values of 7.35/163.4 μM). C (53) displayed moderate antimicrobial activities against the Gram-positive bacteria (Staphylococcus
Geomycin C (53) displayed moderate antimicrobial activities against the Gram‐positive bacteria aureus (Staphylococcus aureus ATCC 6538 and Streptococcus pneumoniae CGMCC 1.1692) and Gram‐negative ATCC 6538 and Streptococcus pneumoniae CGMCC 1.1692) and Gram-negative bacterium
(Escherichia
coli CGMCC 1.2340) [39].
bacterium (Escherichia coli CGMCC 1.2340) [39].
Figure 6. Secondary metabolites derived from the Antarctic fungi (compounds 49–59). Figure 6. Secondary metabolites derived from the Antarctic fungi (compounds 49–59).
Chemical investigation of the marine‐derived fungus Trichoderma asperellum, collected from the Chemical
investigation
the marine-derived
fungus
Trichoderma
asperellum,
collected
sediment of the Antarctic of
Penguin Island, resulted in the isolation of six new peptaibols named from
the sediment
of
the
Antarctic
Penguin
Island,
resulted
in
the
isolation
of
six
new
peptaibols
asperelines A–F (54–59) (Figure 6), which are characterized by an acetylated N‐terminus and a residue. The compounds by
were against N-terminus
fungi containing an uncommon namedC‐terminus asperelines
A–F (54–59)
(Figure prolinol 6), which
are characterized
an tested acetylated
bacteria, but they showed weak inhibitory activity toward The
the early blight pathogen and aand C-terminus
containing
an only uncommon
prolinol
residue.
compounds
were tested
againstAlternaria solani, the rice blast Pyricularia oryzae, and the bacteria Staphylococcus aureus and Escherichia fungi and bacteria, but they showed only weak inhibitory activity toward the early blight
coli [40]. Further study on the same fungus strain determined thirty‐eight short peptaibols, including pathogen Alternaria solani, the rice blast Pyricularia oryzae, and the bacteria Staphylococcus aureus and
thirty‐two new compounds namely asperelines G–Z13 [41]. Mar. Drugs 2017, 15, 28
8 of 30
Escherichia coli [40]. Further study on the same fungus strain determined thirty-eight short peptaibols,
including thirty-two new compounds namely asperelines G–Z13 [41].
Mar. Drugs 2017, 15, 28 8 of 30 Two
new epipolythiodioxopiperazines, named chetracins B (60) and C (61), and
five new
diketopiperazines,
named
chetracin
D
(62)
and
oidioperazines
A–D
(63–66)
(Figure
7),
were
obtained
Two new epipolythiodioxopiperazines, named chetracins B (60) and C (61), and five new from the
Antarctic
fungus
Oidiodendron
truncatum
GW3-13.
An
in
vitro
3-(4,
5-dimethylthiazol-2-yl)
2,
diketopiperazines, named chetracin D (62) and oidioperazines A–D (63–66) (Figure 7), were Mar. Drugs 2017, 15, 28 8 of 30 obtained from the Antarctic fungus Oidiodendron An in vitro 3‐(4, 5-diphenyl
tetrazolium
bromide
(MTT)
cytotoxicity
assaytruncatum revealed GW3‐13. potent biological
activity
for 60 in
5‐dimethylthiazol‐2‐yl) 2, 5‐diphenyl tetrazolium bromide (MTT) cytotoxicity assay revealed potent the nanomolar
range
against
a
panel
of
five
human
cancer
lines,
HCT-8,
BEL-7402,
BGC-823,
A-549
and
Two new epipolythiodioxopiperazines, named chetracins B (60) and C (61), and five new biological activity for 60 in the nanomolar range against a panel of five human cancer lines, HCT‐8, diketopiperazines, D (62) significant
and oidioperazines A–D at
(63–66) (Figure 7), concentration,
were A-2780. New
metabolitesnamed 61 andchetracin 62 displayed
cytotoxicity
a micromolar
BEL‐7402, BGC‐823, A‐549 and A‐2780. New metabolites 61 and 62 displayed significant cytotoxicity at from the fungus Oidiodendron truncatum GW3‐13. An 3‐(4, whereas obtained 63–66 showed
no Antarctic significant
cytotoxicity
at 10
µM. Comparison
of in thevitro bioactivity
data
a micromolar concentration, whereas 63–66 showed no significant cytotoxicity at 10 μM. Comparison 5‐dimethylthiazol‐2‐yl) 2, 5‐diphenyl tetrazolium bromide (MTT) cytotoxicity assay revealed potent suggested
that
the
sulfide
bridge
was
a
determinant
factor
for
their
cytotoxicity,
while
the
number
of
of the bioactivity data suggested that the sulfide bridge was a determinant factor for their cytotoxicity, biological activity for 60 in the nanomolar range against a panel of five human cancer lines, HCT‐8, sulfur atoms
in the bridge did not seem to influence activity [42].
while the number of sulfur atoms in the bridge did not seem to influence activity [42]. BEL‐7402, BGC‐823, A‐549 and A‐2780. New metabolites 61 and 62 displayed significant cytotoxicity at a micromolar concentration, whereas 63–66 showed no significant cytotoxicity at 10 μM. Comparison of the bioactivity data suggested that the sulfide bridge was a determinant factor for their cytotoxicity, while the number of sulfur atoms in the bridge did not seem to influence activity [42]. Figure 7. Secondary metabolites derived from the Antarctic fungi (compounds 60–68). Figure 7. Secondary metabolites derived from the Antarctic fungi (compounds 60–68).
In 2012, two highly oxygenated polyketides, penilactones A and B (67 and 68) (Figure 7) of Figure 7. Secondary metabolites derived from the Antarctic fungi (compounds 60–68). In related structure but opposite absolute stereochemistry, were isolated from the Antarctic deep‐sea 2012, two highly
oxygenated polyketides, penilactones A and B (67 and 68) (Figure 7) of related
structure
but opposite absolute stereochemistry, were isolated from the Antarctic deep-sea derived
derived fungus Penicillium crustosum PRB‐2. The nuclear factor‐κB (NF‐κB) inhibitory activities of 67 In 2012, two highly oxygenated polyketides, penilactones A and B (67 and 68) (Figure 7) of fungus and 68 were tested by means of transient transfection and reporter gene expression assay, and only Penicillium
crustosum PRB-2. The nuclear factor-κB (NF-κB) inhibitory activities of 67 and 68
related structure but opposite absolute stereochemistry, were isolated from the Antarctic deep‐sea A plausible 67 showed weak with an inhibitory rate reporter
of 40% at a concentration 10 μM.
were tested
by means ofactivity transient
transfection
and
gene
expression of assay,
and
only 67 showed
derived fungus Penicillium crustosum PRB‐2. The nuclear factor‐κB (NF‐κB) inhibitory activities of 67 The penilactones biosynthetic pathway for 67 and 68 was proposed as shown in Scheme 2 [43].
and 68 were tested by means of transient transfection and reporter gene expression assay, and only weak activity
with an inhibitory rate of 40% at a concentration of 10 µM. A plausible biosynthetic
contain a new carbon skeleton formed from rate two of 3,5‐dimethyl‐2,4‐diol‐acetophenone units and a weak activity with an inhibitory 40% at a 2concentration of 10 μM. A plausible pathway67 forshowed 67 and
68 was
proposed
as shown
in Scheme
[43]. The penilactones
contain a new
γ‐butyrolactone moiety, and have been prepared by a biomimetic synthesis reported the following biosynthetic pathway for 67 and 68 was proposed as shown in Scheme 2 [43]. The penilactones carbon year as shown in Scheme 3 [44]. skeleton
formed from two 3,5-dimethyl-2,4-diol-acetophenone units and a γ-butyrolactone
contain a new carbon skeleton formed from two 3,5‐dimethyl‐2,4‐diol‐acetophenone units and a moiety, and
have been prepared by a biomimetic synthesis reported the following year as shown in
γ‐butyrolactone moiety, and have been prepared by a biomimetic synthesis reported the following Scheme 3year as shown in Scheme 3 [44]. [44].
Scheme 2. Proposed biosynthesis of penilactones A (67) and B (68). Scheme 2. Proposed biosynthesis of penilactones A (67) and B (68). Scheme 2. Proposed biosynthesis of penilactones A (67) and B (68).
Mar. Drugs 2017, 15, 28
9 of 30
Mar. Drugs 2017, 15, 28 9 of 30 Mar. Drugs 2017, 15, 28 9 of 30 Scheme 3. Synthesis of ent‐penilactone A (ent‐67) and penilactone B (68). Reagents and conditions: (a) Scheme
3. Synthesis of ent-penilactone A (ent-67) and penilactone B (68). Reagents and conditions: ◦ 71%; (b) HCHO, NaOAc, AcOH, 80 °C, ◦ 75%; (c) HCHO, NaOAc, AcOH, AcOH, 90 °C, (a) Scheme 3. Synthesis of ent‐penilactone A (ent‐67) and penilactone B (68). Reagents and conditions: (a) AcOH, BF
BF33.Et
.Et2O, 2 O, 90 C, 71%; (b) HCHO, NaOAc, AcOH, 80 C, 75%; (c) HCHO, NaOAc, AcOH,
90 °C, then 110 °C, 46%; (d) toluene, 110 °C, 93%; (e) Ph
3P=C=C=O, toluene, 110 °C, 52%; (f) H
, PD/C, ◦
◦
◦
90 AcOH, C, thenBF
110
(d)71%; toluene,
110 C, 93%;
(e) Ph
toluene,
110 ◦ C, 52%;
(f) 2H
3 P=C=C=O,
2 , PD/C,
3.Et2C,
O, 46%;
90 °C, (b) HCHO, NaOAc, AcOH, 80 °C, 75%; (c) HCHO, NaOAc, AcOH, MeOH, rt, 99%; (g) dioxane, 110 °C, 86%. ◦
MeOH,
rt, 99%; (g) dioxane, 110 C, 86%.
90 °C, then 110 °C, 46%; (d) toluene, 110 °C, 93%; (e) Ph
3P=C=C=O, toluene, 110 °C, 52%; (f) H2, PD/C, MeOH, rt, 99%; (g) dioxane, 110 °C, 86%. A new chloro‐trinoreremophilane sesquiterpene (69) (Figure 8), three new chlorinated A new chloro-trinoreremophilane sesquiterpene (69) (Figure 8), three new chlorinated
eremophilane sesquiterpenes (70–72) (Figure 8), together with a known compound, eremofortine C A new chloro‐trinoreremophilane sesquiterpene (69) (Figure 8), three new chlorinated eremophilane
sesquiterpenes (70–72) (Figure 8), together with a known compound, eremofortine
(73) (Scheme 4), were isolated from the Antarctic deep‐sea derived fungus, Penicillium sp. PR19N‐1 eremophilane sesquiterpenes (70–72) (Figure 8), together with a known compound, eremofortine C C (73)
(Scheme 4), were isolated from the Antarctic deep-sea derived fungus, Penicillium sp. PR19N-1
in 2013. Compound 69 showed moderate cytotoxic activity against HL‐60 and A549 cancer cell lines. (73) (Scheme 4), were isolated from the Antarctic deep‐sea derived fungus, Penicillium sp. PR19N‐1 in 2013.
Compound
showedmetabolic moderate network cytotoxic of activity
HL-60
and A549
cell lines.
In addition, the 69
plausible these against
isolated products was cancer
proposed as in 2013. Compound 69 showed moderate cytotoxic activity against HL‐60 and A549 cancer cell lines. demonstrated in Scheme 4 [45]. Further investigation of this was
strain yielded five new In addition,
the plausible
metabolic
network
of these
isolated products
proposed
as demonstrated
In addition, the plausible metabolic network of these isolated products was proposed as eremophilane‐type sesquiterpenes (74–78) and a new rare lactam‐type eremophilane (79) (Figure 8). in Scheme
4
[45].
Further
investigation
of
this
strain
yielded
five
new
eremophilane-type
sesquiterpenes
demonstrated in Scheme 4 [45]. Further investigation of this strain yielded five new Their cytotoxities against HL‐60 and A‐549 human cancer cell lines were valuated, and 78 was the (74–78)
and a new rare lactam-type eremophilane (79) (Figure 8). Their cytotoxities against HL-60 and
eremophilane‐type sesquiterpenes (74–78) and a new rare lactam‐type eremophilane (79) (Figure 8). most active one with IC
50 value of 5.2 μM against the A‐549 cells [46]. A-549
human cancer cell lines
were valuated, and 78 was the most active one with IC50 value of 5.2 µM
Their cytotoxities against HL‐60 and A‐549 human cancer cell lines were valuated, and 78 was the against
the
A-549
cells
[46].
most active one with IC50 value of 5.2 μM against the A‐549 cells [46]. OH
OH
OH
PPO
farnesyl
diphosphate
hydroxylation
PPO
farnesyl
diphosphate
hydroxylation
isomerization
OH
[O]
OH
O
O
O
O
73a
HO
O
73a
Cl
HO
O
O
O
O
Cl O
O
O
O
H2O
O
[O]
H
HCl O
O
H2O
isomerization
H
HCl O
O
OH
O
O
O
O
OH
OH
O
OH
O
OH
OH
O
O
O
O
OH
73b
degradation
H 2O
73b
acetylation
69
70
[O]
deacetylation
degradation
H 2O
acetylation
69
70
[O]
deacetylation
hydroxylation
epoxidation
O
O
O
acetylation
[H]
O
HO
acetylation
[H]
O
HO
HCl
methylation
HCl
methylation
72
72
O
O
O
71
71
O
H
H
O
O
O
hydroxylation
[O] epoxidation
O
HO
[O]
O
O
O
HO
O
HCl
O
O
epoxidation
O
HCl
Scheme 4. Proposed biogenetic network for compounds 69–73. O
epoxidation
Scheme 4. Proposed biogenetic network for compounds 69–73. Scheme 4. Proposed biogenetic network for compounds 69–73.
Two new meroterpenoids, named chrodrimanins I and J (80 and 81) (Figure 8), together with five known biosynthetically related chrodrimanins, were isolated from the culture of the Antarctic Two new meroterpenoids, named chrodrimanins I and J (80 and 81) (Figure 8), together with moss‐derived fungus Penicillium funiculosum GWT2‐24. Distinguished from all of reported Two new meroterpenoids,
named
chrodrimanins
I and
J (80 and 81)
(Figure
8),the together
with
five known biosynthetically related chrodrimanins, were isolated from the culture of the Antarctic chrodrimanins, compounds 80 and 81 possess a unique cyclohexanone (E ring) instead of a δ‐lactone fivemoss‐derived known biosynthetically
related
chrodrimanins,
were
isolated
from
the
culture
of
the
Antarctic
fungus Penicillium funiculosum GWT2‐24. Distinguished from all of the reported moss-derived
fungus Penicillium funiculosum GWT2-24. Distinguished from all of the reported
chrodrimanins, compounds 80 and 81 possess a unique cyclohexanone (E ring) instead of a δ‐lactone chrodrimanins, compounds 80 and 81 possess a unique cyclohexanone (E ring) instead of a δ-lactone
Mar. Drugs 2017, 15, 28
10 of 30
Mar. Drugs 2017, 15, 28 10 of 30 ring.
However, only the known compounds exhibited inhibitory activities against influenza
virus
Mar. Drugs 2017, 15, 28 10 of 30 ring. However, only the known compounds exhibited inhibitory activities against influenza virus A A (H1N1)
[47].
(H1N1) [47]. ring. However, only the known compounds exhibited inhibitory activities against influenza virus A Cl
Cl
Cl
Cl
(H1N1) [47]. O
O
O
Cl
69
HO
O
O
OH
HO
OH
HO
O
O
HO
OH
70
O
O
O
HO
Cl
O
O
HO
O
71
OH
O
OH
69
O
Cl
Cl
O
O
HO
O
O
O
72
O
O
OH
O
70
71
O
O
O
O
HO
72
O
O
O
O
OH
OH
HO
O
HO
74
HO
75
76
75
76
77
HO
OH
74
O
O
O
O
O
O
O
O
78
O
O
O
O
O
H
N
O
H
N
O
O
O
Chrodrimanin J 81
O
OH
O
O
O
HO
NO2
OH
HO
O
OH
O
OH
CO2Me
I 80
Pseudogymnoascins AChrodrimanin
(82) R =
OH
OR
O
O
O
O
OR
O
OH
O
Chrodrimanin I 80
O
79
O
O
O
O
79
OH
78
OH
O
O
O
O
77
O
OH
CO
CO22Me
H
Pseudogymnoascins A
B (82)
(83) R =
O
Pseudogymnoascins B
C (83)
(84) R
R ==
O
Pseudogymnoascins
C (85)
(84) R
R ==
3-Nitroasterric acid
CO H
CO22H
H
CO2H
NO2 O
Chrodrimanin J 81
Figure 8. Secondary metabolites derived from the Antarctic fungi (compounds 69–72, 74–85). 3-Nitroasterric
acid (85) R69–72,
=
H
Figure
8. Secondary metabolites derived from the Antarctic fungi
(compounds
74–85).
Figure 8. Secondary metabolites derived from the Antarctic fungi (compounds 69–72, 74–85). Fermentation of a Pseudogymnoascus sp. fungus isolated from an Antarctic marine sponge, Fermentation of a Pseudogymnoascus sp. fungus isolated from an Antarctic marine sponge, yielded
yielded four new nitroasterric acid derivatives, pseudogymnoascins A–C (82–84) and 3‐nitroasterric Fermentation a along Pseudogymnoascus sp. fungus isolated from an and Antarctic marine sponge, four
new
nitroasterric
acid
derivatives,
pseudogymnoascins
A–C
(82–84)
and pyriculamide. 3-nitroasterric
acid (85)
acid (85) (Figure of 8), with two known compounds questin These yielded four new nitroasterric acid derivatives, pseudogymnoascins A–C (82–84) and 3‐nitroasterric (Figure
8), along with two known compounds questin and pyriculamide. These compounds
are the
compounds are the first nitro derivatives of the known fungal metabolite asterric acid [48]. acid (85) (Figure 8), along with two known compounds questin and pyriculamide. These first nitro
derivatives
of the
known fungal
metabolite
asterric acid [48].ochraceopones A–E (86–90) Five new highly oxygenated α‐pyrone merosesquiterpenoids, compounds are the first nitro derivatives of the known fungal metabolite asterric acid [48]. (Scheme 5), together with one new double bond isomer of asteltoxin, isoasteltoxin (91) (Figure 9), Five new highly oxygenated α-pyrone merosesquiterpenoids, ochraceopones A–E
(86–90)
Five new highly oxygenated α‐pyrone merosesquiterpenoids, ochraceopones A–E (86–90) and two known asteltoxin derivatives, asteltoxin and asteltoxin B, were isolated from the Antarctic (Scheme
5), together with one new double bond isomer of asteltoxin, isoasteltoxin (91) (Figure 9),
(Scheme 5), together with one new double bond isomer of asteltoxin, isoasteltoxin (91) (Figure 9), Aspergillus ochraceopetaliformis SCSIO 05702. Ochraceopones A–D (86–89) were andsoil‐derived fungus two known asteltoxin
derivatives, asteltoxin and asteltoxin B, were isolated from the Antarctic
and two known asteltoxin derivatives, asteltoxin and asteltoxin B, were isolated from the Antarctic the first examples of α‐pyrone merosesquiterpenoids possessing a linear tetracyclic carbon skeleton. soil-derived
fungus Aspergillus ochraceopetaliformis SCSIO 05702. Ochraceopones A–D (86–89) were
soil‐derived fungus Aspergillus ochraceopetaliformis SCSIO 05702. Ochraceopones A–D (86–89) were All isolated compounds were tested for their antiviral, cytotoxic, antibacterial, and the firstthe examples
of α-pyrone
merosesquiterpenoids
possessing
a linear
tetracyclic
carbon skeleton.
the first examples of α‐pyrone merosesquiterpenoids possessing a linear tetracyclic carbon skeleton. antitubercular activities. Among the new compounds, 86 and 91 exhibited promising antiviral AllAll the isolated
compounds
were tested
for
theirfor antiviral,
cytotoxic,
antibacterial,
and antitubercular
the isolated compounds were tested their antiviral, cytotoxic, antibacterial, and viruses. In addition, a possible biosynthetic activities against the H1N1 and H3N2 influenza activities.
Among
the
new
compounds,
86
and
91
exhibited
promising
antiviral
activities
against the
antitubercular activities. Among the new compounds, 86 and 91 exhibited promising antiviral pathway for ochraceopones A–E was proposed in Scheme 5 [49]. H1N1
and H3N2
influenza
viruses.
In addition,
a possible
biosynthetic
pathway
for ochraceopones
viruses. In addition, a possible biosynthetic activities against the H1N1 and H3N2 influenza A–E
was proposed in Scheme 5 [49].
pathway for ochraceopones A–E was proposed in Scheme 5 [49]. Figure 9. The structure of isoasteltoxin (91) derived from the Antarctic fungus Aspergillus ochraceopetaliformis SCSIO 05702. Figure 9. The structure of isoasteltoxin (91) derived from the Antarctic fungus Aspergillus Figure
9. The structure of isoasteltoxin (91) derived from the Antarctic fungus Aspergillus
ochraceopetaliformis SCSIO 05702. ochraceopetaliformis SCSIO 05702.
Mar. Drugs 2017, 15, 28
11 of 30
Mar. Drugs 2017, 15, 28 11 of 30 Scheme 5. Postulated biogenetic pathway for ochraceopones A–E (86–90). Scheme 5. Postulated biogenetic pathway for ochraceopones A–E (86–90).
3. Lichen 3. Lichen
Lichens are symbiotic associations of fungi and algae and/or cyanobacteria that produce unique Lichens are secondary symbiotic associations
of fungi
and algae
and/or
cyanobacteria
produce
unique
characteristic metabolites by comparison to those of higher plants. that
Several species of characteristic
secondary
metabolites
by
comparison
to
those
of
higher
plants.
Several
species
lichens have been used for various remedies in folk medicine since ancient time and variety of of lichens
haveactive been used
various remedies
in antimycobacterial, folk medicine since
ancientantioxidant time and variety
biologically lichen for
metabolites, including antiviral, and of biologically
active lichen metabolites,
including antimycobacterial,
antiviral,evolved unique antioxidant and
antiherbivore properties, have been described [50,51]. Antarctic lichens may have antiherbivore
properties, have been described [50,51]. Antarctic lichens may have evolved unique
secondary metabolites to help in surviving the extreme environment in which they live [52–54]. Professor Oh’s group has made great efforts in discovery of new metabolites from the Antarctic secondary metabolites to help in surviving the extreme environment in which they live [52–54].
lichens. From the MeOH of the Antarctic lichen of
Stereocaulon alpinum, a new cyclic Professor
Oh’s
group
has extract made great
efforts
in discovery
new metabolites
from
the Antarctic
depsipeptide A (92) (Figure 10) [55], together with three new a usnic acid derivatives lichens.
From thestereocalpin MeOH extract
of the
Antarctic
lichen
Stereocaulon
alpinum,
new cyclic
depsipeptide
usimines A
A–C (Figure 10) [56], with
were isolated by various chromatographic methods. stereocalpin
(92) (93–95) (Figure 10)
[55], together
three
new usnic
acid derivatives
usimines A–C
(93–95)
Compound 92 incorporated an unprecedented 5‐hydroxy‐2,4‐dimethyl‐3‐oxo‐octanoic acid in the an
(Figure 10) [56], were isolated by various chromatographic methods. Compound 92 incorporated
structure, and showed marginal levels of cytotoxicity against three human tumor cell lines, HT‐29, unprecedented
5-hydroxy-2,4-dimethyl-3-oxo-octanoic acid in the structure, and showed marginal
B16/F10 and HepG2. In addition, compounds 92–95 moderately inhibited the activity of protein levels of cytotoxicity against three human tumor cell lines, HT-29, B16/F10 and HepG2. In addition,
tyrosine phosphatase 1B (PTP1B) in a dose‐dependent manner. Inhibition of PTP1B is predicted to compounds 92–95 moderately inhibited the activity of protein tyrosine phosphatase 1B (PTP1B) in
be an excellent, novel therapy to target type 2 diabetes and obesity [57]. Furher investigation of this a dose-dependent manner. Inhibition of PTP1B is predicted to be an excellent, novel therapy to
Antarctic lichen recovered seven phenolic lichen metabolites. Among the compounds, the target
type 2 diabetes and obesity [57]. Furher investigation of this Antarctic lichen recovered seven
depsidone‐type compound, lobaric acid (96) (Figure 10) and two pseudodepsidone‐type phenolic
lichen metabolites. Among the compounds, the depsidone-type compound, lobaric acid
compounds, 97 and 98 (Figure 10), exhibited potent inhibitory activity against PTP1B with low IC50 (96)values in a non‐competitive manner [58]. In 2013, a new pseudodepsidone‐type metabolite, lobastin (Figure 10) and two pseudodepsidone-type compounds, 97 and 98 (Figure 10), exhibited potent
inhibitory
activity against PTP1B with low IC50 values in a non-competitive manner [58]. In 2013, a
(99) (Figure 10), with antioxidant and antibacterial activity was also reported from this strain [59]. new pseudodepsidone-type
metabolite,
lobastin (99)A–D (Figure
10), with
antioxidant
and
antibacterial
Four new diterpene furanoids, hueafuranoids (100–103) (Figure 10) have been isolated activity
was also reported from this strain [59].
from the MeOH extract of the Antarctic lichen Huea sp. Compound 100 showed inhibitory activity against therapeutically targeted protein, PTP1B with an IC50 value of 13.9 μM [60]. Four new diterpene furanoids, hueafuranoids A–D (100–103) (Figure 10) have been isolated from
From the Antarctic lichen Ramalina terebrata, the novel compound ramalin (104) (Figure 10) was the MeOH
extract of the Antarctic lichen Huea sp. Compound 100 showed inhibitory activity against
isolated. The experimental data showed that ramalin displayed potent antioxidant activity and can therapeutically
targeted protein, PTP1B with an IC50 value of 13.9 µM [60].
be a strong therapeutic candidate for controlling oxidative stress in cells [61]. Mar. Drugs 2017, 15, 28
12 of 30
From the Antarctic lichen Ramalina terebrata, the novel compound ramalin (104) (Figure 10) was
isolated. The experimental data showed that ramalin displayed potent antioxidant activity and can be
a strong
therapeutic candidate for controlling oxidative stress in cells [61].
Mar. Drugs 2017, 15, 28 12 of 30 O
O
O
NH
Mar. Drugs 2017, 15, 28 OO
O
OH
N
O
O
O
HO
O
OH
O
Stereocalpin A (92)
O
OH
O
O
N
O
OH
O
H3CO
H3CO
Lobaric acid (96)
HO
O
Hueafuranoids A (100)
14
Hueafuranoids C (102)
Usimine C (95)
HO
14
(98) R =COOH
14
Hueafuranoids B (101)
O
Hueafuranoids
HO D (103)
O
HO
OCH3
(99)
O
HO
14
OH
HO
OCH3
O
(99)
OH
O
O
O
O
O
OH
R
O
O
R
O OCH
3
(97) O
R=H
HO
COOH
O
O
O
O
14
O
COOH
Usimine CH(95)
HO
OH
OCH3
(97) R = H
14
(98) R =COOH
OH
N
O
OH
O HO
OH
O
Lobaric acid (96)
COOH
O
OOH
Usimine A (93) R = CH3
O
Usimine O
B (94) R = H
12 of 30 COOH
H
OH
HO
OR
HO
H3CO
N
O
OH
OH
H
O
HO
OH
OR
O OH
Usimine A (93) ROH
= CH3
Usimine B (94) R = H
Stereocalpin
AN(92)
O
OO
O
O
OO
H3CO
N
O
OH
NH
OO
OH
H
O
O
OH
OH
O
N
H
H
N
OH
NH2
O (104) OH
Ramalin
H
O
N
HO
N
H
HO
HO
O
NH
2
Figure 10. Secondary metabolites derived from the Antarctic lichen (compounds 92–104). Hueafuranoids B (101) 14
Hueafuranoids Ametabolites
(100) 14
Ramalin (104)
Figure
10. Secondary
derived
from the Antarctic lichen (compounds
92–104).
Hueafuranoids D (103)
Hueafuranoids C (102)
O
4. Mosses Figure 10. Secondary metabolites derived from the Antarctic lichen (compounds 92–104). 4. Mosses
Mosses represent a relatively untapped natural source to be explored for new bioactive 4. Mosses Mosses
represent a relatively untapped natural source to be explored for new bioactive
metabolites. Chemical studies of Antarctic moss Polytrichastrum alpinum led to the isolation of two metabolites.
Chemical
studies
of ohioensins Antarctic
moss
alpinum
lednew to the
isolation
Mosses represent a relatively untapped source to 106) be explored bioactive new benzonaphthoxanthenones, F natural and Polytrichastrum
G (105 and (Figure for 11), along with two of
two new
benzonaphthoxanthenones,
ohioensins
andfour G (105
and 106)showed (Figurepotent 11), along
with two
metabolites. Chemical studies of Antarctic moss Polytrichastrum alpinum led to the isolation of two known compounds ohioensins A and C. All of F the compounds inhibitory new benzonaphthoxanthenones, F and G compounds
(105 and 106) showed
(Figure 11), along with two activity
activity against therapeutically targeted protein tyrosine phosphatase 1B (PTP1B). Kinetic analysis of known
compounds
ohioensins A andohioensins C. All of the
four
potent
inhibitory
known compounds ohioensins and C. All of the four compounds showed potent inhibitory PTP1B inhibition by targeted
ohioensin F A (105) suggested that benzonaphthoxanthenones inhibited PTP1B against
therapeutically
protein
tyrosine
phosphatase
1B (PTP1B).
Kinetic
analysis
of PTP1B
activity against therapeutically targeted protein tyrosine phosphatase 1B (PTP1B). Kinetic analysis of activity in a non‐competitive manner [62]. inhibition by ohioensin F (105) suggested that benzonaphthoxanthenones inhibited PTP1B activity in a
PTP1B inhibition by ohioensin F (105) suggested that benzonaphthoxanthenones inhibited PTP1B non-competitive
manner [62].
activity in a non‐competitive manner [62]. Figure 11. Secondary metabolites derived from the Antarctic moss (compounds 105, 106). Figure 11. Secondary metabolites derived from the Antarctic moss (compounds 105, 106). Figure 11. Secondary metabolites derived from the Antarctic moss (compounds 105, 106).
5. Bryozoans 5. Bryozoans Bryozoans (moss animals and lace corals) have yielded a significant number of bioactive 5. Bryozoans
Bryozoans (moss animals and lace corals) have a significant number of bioactive metabolites and have been reviewed elsewhere [63]. yielded However, there is only a single report on metabolites and have been a reviewed elsewhere [63]. However, there is only single report on Bryozoans
(moss
animals
and
corals)In have
yielded
a significant
number
of of bioactive
secondary metabolites from polar lace
bryozoan. 2011, an investigation into a the chemistry the secondary metabolites from a polar bryozoan. In However,
2011, an investigation into the chemistry of the metabolites
and
have
been
reviewed
elsewhere
[63].
there
is
only
a
single
report
on
secondary
Arctic bryozoan Tegella cf. spitzbergensis resulted in the isolation and structural determination of Arctic bryozoan Tegella cf. spitzbergensis resulted in the isolation and structural determination of metabolites
from a polar bryozoan. In 2011, an investigation into the chemistry of the Arctic bryozoan
ent‐eusynstyelamide B (107) and three new derivatives, eusynstyelamides D–F (108–110) (Figure 12) ent‐eusynstyelamide B (107) and three new derivatives, eusynstyelamides D–F (108–110) (Figure 12) Ent‐eusynstyelamide is the enantiomer of determination
the known brominated tryptophan B
Tegella[64]. cf.
spitzbergensis
resultedB in (107) the isolation
and structural
of ent-eusynstyelamide
[64]. Ent‐eusynstyelamide B (107) is the enantiomer of the known brominated tryptophan metabolite eusynstyelamide B [65]. Antimicrobial activities were reported for 107–110, with MIC (107) and
three new
derivatives, eusynstyelamides
D–F
(108–110)
12)
[64].
Ent-eusynstyelamide
metabolite eusynstyelamide B [65]. Antimicrobial activities were (Figure
reported for 107–110, with MIC Mar. Drugs 2017, 15, 28
13 of 30
B (107) is the enantiomer of the known brominated tryptophan metabolite eusynstyelamide B [65].
Mar. Drugs 2017, 15, 28 Antimicrobial
activities were reported for 107–110, with MIC values as low as 6.25 µg/mL13 of 30 for 107 and
110 against
Staphylococcus aureus. Eusynstyelamides were generally more active against Gram-positive
values as low as 6.25 μg/mL for 107 and 110 against Staphylococcus aureus. Eusynstyelamides were bacteriagenerally more active against Gram‐positive bacteria than Gram‐negative bacteria [64]. than Gram-negative bacteria [64].
Figure 12. Secondary metabolites derived from the Arctic bryozoan (compounds 107–110). Figure 12. Secondary metabolites derived from the Arctic bryozoan (compounds 107–110).
6. Cnidarians 6. Cnidarians
Cnidarians are the second largest source (after sponges) of new marine natural products Cnidarians
are the second largest source (after sponges) of new marine natural products reported
reported each year, with a predominance of terpenoids [11–13] and are also well represented in the polar regions. In 2003, fractionation of the bioactive extract from the chemically defended Antarctic each year,
with a predominance of terpenoids [11–13] and are also well represented in the polar regions.
In 2003,gorgonian coral Ainigmaptilon antarcticus yielded two sesquiterpenes, ainigmaptilones A (111) and B fractionation of the bioactive extract from the chemically defended Antarctic gorgonian coral
(112) (Figure 13). Ainigmaptilone A has broad spectrum bioactivity toward sympatric predatory and Ainigmaptilon
antarcticus yielded two sesquiterpenes, ainigmaptilones A (111) and B (112) (Figure 13).
fouling organisms, including antibiotic activity [66]. Ainigmaptilone
A has broad spectrum bioactivity toward sympatric predatory and fouling organisms,
The ethereal extract of another Antarctic gorgonian Dasystenella acanthina was found to contain including
antibiotic
activity [66].
three main nonpolar and relatively transient sesquiterpene metabolites, including a new compound, The
ethereal extract(113) of another
gorgonian
Dasystenella
found
to contain
furanoeudesmane (Figure Antarctic
13). Compound 113 was toxic at 46 acanthina
μM in a was
Gambusia affinis ichthyotoxicity this result, an involvement of these molecules in the defensive three main
nonpolar test. and According relativelyto transient
sesquiterpene
metabolites,
including
a new
compound,
mechanisms of the animal could be suggested [67]. furanoeudesmane
(113) (Figure 13). Compound 113 was toxic at 46 µM in a Gambusia affinis
Seven new steroids, compounds 114–120 (Figure 13), were isolated from the Antarctic octocoral ichthyotoxicity test. According to this result, an involvement of these molecules in the defensive
Anthomastus bathyproctus. The in vitro cytotoxicity has been tested against three human tumor cell mechanisms
of the animal could be suggested [67].
lines MDA‐MB‐231 (breast adenocarcinoma), A‐549 (lung carcinoma), and HT‐29 (colon Seven
new
steroids, compounds 114–120 (Figure 13), were isolated from the Antarctic octocoral
adenocarcinoma). Compounds 115–118 displayed weak activity as inhibitors of cell growth [68]. AnthomastusChemical investigation of the lipophilic extract of the Antarctic soft coral Alcyonium grandis led bathyproctus. The in vitro cytotoxicity has been tested against three human tumor cell lines
to the finding nine unreported sesquiterpenoids, compounds and
121–129 (Figure 13) adenocarcinoma).
[69]. These MDA-MB-231
(breastof adenocarcinoma),
A-549 (lung carcinoma),
HT-29
(colon
molecules are members of the illudalane class and in particular belong to the group of Compounds 115–118 displayed weak activity as inhibitors of cell growth [68].
alcyopterosins. Similar illudalanes have been isolated from the sub‐Antartic deep sea soft coral Chemical investigation of the lipophilic extract of the Antarctic soft coral Alcyonium grandis
Alcyonium paessleri [70]. Repellency experiments conducted using the omnivorous Antarctic sea star led to the
finding of nine unreported sesquiterpenoids, compounds 121–129 (Figure 13) [69]. These
Odontaster validus revealed a strong activity in the lipophilic extract of A. grandis against predation molecules
members of the illudalane class and in particular belong to the group of alcyopterosins.
The total synthesis of some members of the alcyopterosin family has been reported already by [69].are
Similar many research groups [71–75]. illudalanes have been isolated from the sub-Antartic deep sea soft coral Alcyonium paessleri [70].
More recently, the isolation and of two new tricyclic sesquiterpenoids, Repellency experiments
conducted
using
thecharacterization omnivorous Antarctic
sea star
Odontaster
validus revealed
shagenes A (130) and B (131) (Figure 13) were presented. The two compounds were isolated from an a strong activity in the lipophilic extract of A. grandis against predation [69]. The total synthesis of
undescribed soft coral collected from the Scotia Arc in the Southern Ocean. Exploration of the some members of the alcyopterosin family has been reported already by many research groups [71–75].
bioactivity found that shagenes A was active against the visceral leishmaniasis causing parasite, More
recently, the isolation and characterization of two new tricyclic sesquiterpenoids, shagenes
Leishmania donovani (IC50 value = 5 μM), with no cytotoxicity against the mammalian host [76]. A (130) and In 2012, two halogenated natural products breitfussin A (132) and breitfussin B (133) (Figure 13) B (131) (Figure 13) were presented. The two compounds were isolated from an undescribed
soft coral
collected
theArctic Scotiahydrozoan Arc in the
Southern Ocean. Exploration
the Island) bioactivity
were isolated from
from the Thuiria breitfussi collected at Bjørnøya of(Bear [77]. found
Recently, Hedberg and co‐workers synthesized breitfussins A and B firstly using Suzuki coupling that shagenes A was active against the visceral leishmaniasis causing parasite, Leishmania donovani
(IC50 value = 5 µM), with no cytotoxicity against the mammalian host [76].
In 2012, two halogenated natural products breitfussin A (132) and breitfussin B (133) (Figure 13)
were isolated from the Arctic hydrozoan Thuiria breitfussi collected at Bjørnøya (Bear Island) [77].
Mar. Drugs 2017, 15, 28
14 of 30
Mar. Drugs 2017, 15, 28 Recently,
Hedberg and co-workers synthesized breitfussins A and B firstly using Suzuki14 of 30 coupling
Mar. Drugs 2017, 15, 28 14 of 30 reactions to join the heteroaromatic rings, thus confirming the assigned structure of these
natural
reactions to join the heteroaromatic rings, thus confirming the assigned structure of these natural products
(Scheme
6) [78].
Soon after, a conceptually
distinct synthesis
of breitfussin of B through
late-stage
reactions to join the rings, thus confirming the assigned these natural products (Scheme 6) heteroaromatic [78]. Soon after, a conceptually distinct synthesis structure of breitfussin B through bromination
of
the
breitfussin
core
was
reported
by
Khan
and
Chen
[79].
products (Scheme 6) [78]. Soon after, a conceptually distinct synthesis of breitfussin B through late‐stage bromination of the breitfussin core was reported by Khan and Chen [79]. late‐stage bromination of the breitfussin core was reported by Khan and Chen [79]. O
H
O
H
O
H
H
O
OH
Ainigmaptilones A (111)
OH
Ainigmaptilones A (111)
OH
Ainigmaptilones B (112)
OH
Ainigmaptilones B (112)
O
R
CO2Me
O
R
CO2Me
H
HH H
Furanoeudesmane (113)
O
Furanoeudesmane (113)
H
O
(114)
Cl
R2O
Cl
R1O
(121) R1 = COCH2CH2CH3; R2 = COCH 2CH2CH3
R1O
(122)
R2 CH
= COCH
3
(121) R
R11 =
= COCH
COCH32;CH
2
3; R2 = COCH 2CH2CH3
(123)
(122) R
R1 =
= COCH
COCH3;; R
R2 =
= COCH
COCH2CH2CH3
1
3
2
O
O(124)
O
(115)
O
(115)
(124)
3
1
3
2
2
2
(117)
H
R1
HH H
CO2Me
OAc
O
CO2Me
H
H
(119) R1 = OH, R2 = H
(120) R
R1==OH,
H, RR2 ==OH
(119)
H
O
OH
1
OH
2
(120) R1 = H, R2 = OH
3
H O
H O
O
NH
N
OO
O O
HN
O
O
HN
N
O
O
N
H
N
H
Br
O
Br
Shagenes A (130)
Shagenes B (131)
Shagenes A (130)
Shagenes B (131)
Breitfussin A (132)
HH
Br
NH
O
Breitfussin A (132)
HH
R2
R2
R1
(129) R = COCH2CH2CH3
3
(127) R1 = H, R2 = H
H O
O
H O
(117)
RO
(128) R = COCH3
RO
(129) R
R=
= COCH
COCH2CH2CH3
(128)
H
(118)
(118)
CO2Me
Cl
Cl
H
OAc
(116)
Cl
R1O
(125) R1 = COCH 3, R2 = COCH 3
R1O
(126)
R
=
COCH
(125) R11 = COCH33,, R
R22 =
= COCH
COCH23CH2CH3
(127)
R2 = ,HR = COCH CH CH
(126) R
R1 =
= H,
COCH
O
CO2Me
(116)
(123) R1 = COCH3; R2 = COCH2CH2CH3
R 2O
ClR2O
O
CO2Me
(114)
R2O
H
HH H
H
CO2Me
Br
NH
O
NH
NO
N
O
H
H
H
H
HH
HH
OH
OH
H
Br
Breitfussin B (133)
HH
HH
Br
O
Breitfussin B (133)
HO
OH
GersemiolOH
A (134)
GersemiolOH
B (135)
H
Gersemiol C OH
(136)
Gersemiol A (134)
Gersemiol B (135)
Gersemiol C (136)
HO
OH
OH
Eunicellol A (137)
Eunicellol A (137)
Figure 13. Secondary metabolites derived from the polar cnidarians (compounds 111–137). Figure
13. Secondary metabolites derived from the polar cnidarians (compounds 111–137).
Figure 13. Secondary metabolites derived from the polar cnidarians (compounds 111–137). Br
Br
133
133
OH
OH Me
a
Me
a
NO2
Br
NO2
Br
j
j
Br
Br
I
I
OMe
OMe
N
N
OMe
OMe Me
b
Me
b
Br
NO2
Br
NO2
O
O
N
TIPS
N
TIPS
Br
N
Br
Boc
N
i
Boc
i
Br
Br
OMe
OMe
N
H
N
H
132
132
h
h N
I
N
I
O
OMe
O
OMe
N
TIPS
N
TIPS
c
c
OMe
OMe
I
I
O
OB
OB
O
d
d
N
TIPS
N
TIPS
Br
Br
O
O
B(OH)2
N
Boc B(OH)2
N
I
Boc
N
I
N
I
N
I
Boc g
O
OMe
N
Boc g
O
OMe
Br
Br
N
TIPS
N
TIPS
N
N
TIPS
N
TIPS
TIPS
TIPS OMe N O
O
OMe
N
TIPS
N
TIPS
Br
Br
e
e
f
f
Br
Br
OMe
OMe
N
N
O
O
N
TIPS
N
TIPS
Scheme 6. Synthesis of Breitfussin A (132) and B (133). Reagents and conditions: (a) MeI, Cs2CO3, Scheme 6. Synthesis of Breitfussin A (132) and B (133). Reagents and conditions: (a) MeI, Cs2CO3, DMF, 82%; (b) ofDimethylformamide acetal Reagents
(DMFDMA), DMF, then Cs
Zn, Scheme
6. rt, Synthesis
Breitfussin A (132)dimethyl and B (133).
andPyrrolidine, conditions:
(a) MeI,
2 CO3 ,
DMF, rt, 82%; (b) Dimethylformamide dimethyl acetal (DMFDMA), Pyrrolidine, DMF, then Zn, AcOH/H2O, 80 °C, 61%; (c) Iodine chloride, Pyridine (ICl, Py), CH
2Cl2, then NaH, Three isopropyl DMF, rt, 82%; (b) Dimethylformamide dimethyl acetal (DMFDMA), Pyrrolidine, DMF, then Zn,
AcOH/H2O, 80 °C, 61%; (c) Iodine chloride, Pyridine (ICl, Py), CH2Cl2, then NaH, Three isopropyl silicon alkyl chloride (TIPSCl), THF, 81%; (ICl,
(d) Py),
1,1′‐Bis(diphenylphosphino)ferrocene] AcOH/H2O,
80 ◦ C, 61%;
(c) Iodine
chloride,
Pyridine
CH2 Cl2 , then NaH, Three isopropyl
silicon alkyl chloride (TIPSCl), THF, 81%; (d) 1,1′‐Bis(diphenylphosphino)ferrocene] dichloropalladium (Pd(dppf)Cl2), K3PO4, Toluene/H
2O, 80 °C; (e) 10% aq HCl, THF, 0 °C, 89%; (f) 0 -Bis(diphenylphosphino)ferrocene]dichloropalladium
silicondichloropalladium alkyl chloride (TIPSCl),
THF,
81%;
(d)
1,1
(Pd(dppf)Cl(LiHMDS), 2), K3PO4, Toluene/H2O, 80 °C; (e) 10% aq HCl, THF, 0 °C, 89%; (f) Lithium hexamethyldisilazide −78 then I2, −78 °C, 15%; (g) Pd(dppf)Cl
2CO3, ◦ C; °C, ◦ C, 89%;2, Cs
(Pd(dppf)Cl
K3 PO4 , Toluene/H
(e) then 10%I2, aq
THF,
(f)2CO
Lithium
Lithium hexamethyldisilazide (LiHMDS), °C, −78 HCl,
°C, 15%; (g) 0Pd(dppf)Cl
2, Cs
3, 2 ),
2 O, 80 −78 Dioxane/H2O, rt, 61%; (h) Trimethylsilyl trifluoromethanesulfonate (TMSOTf), Et
3N, CH2Cl2, 0 °C to ◦ C, then I , −78 ◦ C, 15%; (g) Pd(dppf)Cl , Cs CO ,
hexamethyldisilazide
(LiHMDS),
−
78
Dioxane/H2O, rt, 61%; (h) Trimethylsilyl trifluoromethanesulfonate (TMSOTf), Et
3N, CH2Cl2, 0 °C to 2
2
2
3
rt, then Tetrabutylammonium fluoride (TBAF), THF, 0 °C, 64%; (i) N‐Bromosuccinimide (NBS), THF, rt, then Tetrabutylammonium fluoride (TBAF), THF, 0 °C, 64%; (i) N‐Bromosuccinimide (NBS), THF, Dioxane/H
(TMSOTf), Et3 N, CH2 Cl2 , 0 ◦ C
2 O, rt, 61%; (h) Trimethylsilyl trifluoromethanesulfonate
−78 °C to rt, 57%; (j) Trifluoroacetic acid (TFA), CH
2Cl2, 0 °C to rt, then TBAF, THF, 0 °C, 67%. 2, 0 °C to rt, then TBAF, THF, 0 °C, 67%. to rt, −78 °C to rt, 57%; (j) Trifluoroacetic acid (TFA), CH
then Tetrabutylammonium fluoride (TBAF), 2Cl
THF,
0 ◦ C, 64%; (i) N-Bromosuccinimide (NBS),
◦
THF, −78 C to rt, 57%; (j) Trifluoroacetic acid (TFA), CH2 Cl2 , 0 ◦ C to rt, then TBAF, THF, 0 ◦ C, 67%.
Mar. Drugs 2017, 15, 28
Mar. Drugs 2017, 15, 28 15 of 30
15 of 30 From the Arctic soft coral Gersemia fruticosa, three new diterpenes named gersemiols A–C (134–136)
togetherFrom withthe a new
eunicellane
eunicellol
A (137),
been obtained.
All compounds
Arctic soft coral diterpene,
Gersemia fruticosa, three new have
diterpenes named gersemiols A–C were
tested for
their antimicrobial
activity against
several
bacteriaA and
fungi.
Only
was
(134–136) together with a new eunicellane diterpene, eunicellol (137), have been eunicellol
obtained. A
All found
to
exhibit
moderate
anti-bacterial
activity
against
methicillin
resistant
Staphylococcus
aureus
compounds were tested for their antimicrobial activity against several bacteria and fungi. Only (MRSA)
with A MIC
value
of 24–48
µg/mL
[80]. anti‐bacterial activity against methicillin resistant eunicellol was found to exhibit moderate Staphylococcus aureus (MRSA) with MIC value of 24–48 μg/mL [80]. 7. Echinoderms
7. Echinoderms Echinoderms are well known producers of bioactive glycosylated metabolites [11–13], and many
Echinoderms well known producers of the
bioactive glycosylated [11–13], and new natural
productsare have
been
described
from
polar examples.
In metabolites 2001, two new
trisulfated
many new natural liouvillosides
products have Abeen from the polar examples. In from
2001, the
two new triterpene
glycosides,
(138)described and B (139)
(Figure
14), were
isolated
Antarctic
seatrisulfated triterpene glycosides, liouvillosides A (138) and B (139) (Figure 14), were isolated from cucumber Staurocucumis liouvillei. Liouvillosides A and B are two new examples of a small number
the Antarctic sea cucumber Staurocucumis liouvillei. Liouvillosides A and B are two new examples of of trisulfated
triterpene glycosides from sea cucumbers belonging to the family Cucumariidae. Both
a small number of trisulfated triterpene glycosides from sea virus
cucumbers the family glycosides
were found
to be virucidal
against
herpes simplex
type 1 belonging (HSV-1) atto concentrations
type 1 Cucumariidae. Both glycosides were found to be virucidal against herpes simplex virus below 10 µg/mL [81]. A novel triterpene holostane disulfated tetrasaccharide olygoglycoside,
(HSV‐1) at concentrations below 10 μg/mL [81]. A novel triterpene holostane disulfated turquetoside A (140) (Figure 14), having a rare terminal 3-O-methyl-D-quinovose, was isolated from
tetrasaccharide olygoglycoside, turquetoside A (140) (Figure 14), having a rare terminal the Antarctic sea cucumber Staurocucumis turqueti [82]. The occurrence of 3-O-methyl-D-quinovose in
3‐O‐methyl‐D‐quinovose, was isolated from the Antarctic sea cucumber Staurocucumis turqueti [82]. triterpene glycosides in S. turqueti and in the congeneric Antarctic sea cucumber S. liouvillei suggests
The occurrence of 3‐O‐methyl‐D‐quinovose in triterpene glycosides in S. turqueti and in the congeneric that the presence of this sugar in carbohydrate chains of triterpene glycosides is a taxonomical character
Antarctic sea cucumber S. liouvillei suggests that the presence of this sugar in carbohydrate chains of of the
genus Staurocucumis [81,82].
triterpene glycosides is a taxonomical character of the genus Staurocucumis [81,82]. Subsequently,
another three new triterpene glycosides, achlioniceosides A1 (141), A2 (142),
Subsequently, another three new triterpene glycosides, achlioniceosides A1 (141), A2 (142), and andA3 A3(143) (143)(Figure (Figure14), 14),were wereobtained obtainedfrom fromthe theAntarctic Antarcticsea seacucumber cucumber
Achlionice
violaecuspidata.
Achlionice violaecuspidata. Glycosides
141–143
are
the
first
triterpene
glycosides
isolated
from
a
sea
cucumber
belonging
to the
Glycosides 141–143 are the first triterpene glycosides isolated from a sea cucumber belonging to the order
Elasipodida [83].
order Elasipodida [83]. Figure 14. Secondary metabolites derived from the Antarctic sea cucumbers (compounds 138–143). Figure 14. Secondary metabolites derived from the Antarctic sea cucumbers (compounds 138–143).
8. Molluscs 8. Molluscs
The nudibranch Austrodoris kerguelenensis is distributed widely around the Antarctic coast and The nudibranch
kerguelenensis
is distributed
widely around
the (144) Antarctic
continental shelves. Austrodoris
In 2003, two unprecedented nor‐sesquiterpenes, austrodoral and coast
its andoxidised continental
shelves.
In 2003, acid two unprecedented
nor-sesquiterpenes,
(144)
and its
derivative austrodoric (145) (Figure 15), were isolated from austrodoral
the skin of the marine oxidised
derivative austrodoric acid (145) (Figure 15), were isolated from the skin of the marine dorid
dorid A. kerguelenensis, collected in the Antarctic. A role of stress‐metabolites could be suggested for A. kerguelenensis,
collected
inshort the Antarctic.
A role
of stress-metabolites
be suggested
for these
these compounds [84]. A and efficient synthesis of 144 and 145 could
was reported as shown in compounds [84]. A short and efficient synthesis of 144 and 145 was reported as shown in Scheme 7 [85].
Mar. Drugs 2017, 15, 28
16 of 30
Mar. Drugs 2017, 15, 28 Mar. Drugs 2017, 15, 28 Mar. Drugs 2017, 15, 28 16 of 30 16 of 30 16 of 30 Further
chemical
study
of this chemical Antarctic study nudibranch
yielded
two novel
2-monoacylglycerols
(146) and
Scheme 7 [85]. Further of this Antarctic nudibranch yielded two novel Scheme 7 7 [85]. [85]. Further Further chemical chemical study study of this Antarctic nudibranch yielded two novel Scheme this Antarctic nudibranch yielded two novel (147)
(Figure
15),
along
with
two
known
1,2-diacyl
glyceryl
esters
[86].
2‐monoacylglycerols (146) and (147) (Figure 15), along with two known 1,2‐diacyl glyceryl esters [86]. 2‐monoacylglycerols (146) and (147) (Figure 15), along with two known 1,2‐diacyl glyceryl esters [86]. 2‐monoacylglycerols (146) and (147) (Figure 15), along with two known 1,2‐diacyl glyceryl esters [86]. Austrodoris Figure 15. Secondary metabolites derived from the Antarctic nudibranch Figure
15. Secondary
metabolites
derived
from the
Antarctic
nudibranch
Austrodoris
kerguelenensis
Figure 15. Secondary metabolites derived from the Antarctic nudibranch Austrodoris kerguelenensis (compounds 144–147). Figure 15. Secondary metabolites derived from the Antarctic nudibranch Austrodoris (compounds
144–147).
kerguelenensis (compounds 144–147). kerguelenensis (compounds 144–147). Scheme 7. Synthesis of austrodoral (144) and austrodoric acid (145). Reagents and conditions: (a) Scheme 7. Synthesis of austrodoral (144) and austrodoric acid (145). Reagents and conditions: (a) Scheme
7. Synthesis of austrodoral4, H
(144)
and austrodoric acid (145). Reagents and conditions: (a) four
four steps, 59% [87,88]; (b) OsO
2O, t‐BuOH, trimethylamine N‐oxide, pyridine, reflux, 24 h, 87%; Scheme 7. Synthesis of austrodoral (144) and austrodoric acid (145). Reagents and conditions: (a) four steps, 59% [87,88]; (b) OsO4, H2O, t‐BuOH, trimethylamine N‐oxide, pyridine, reflux, 24 h, 87%; steps,(c) BF
59%3∙OEt
[87,88];
OsO4 , H2 O, t-BuOH, trimethylamine
N-oxide, pyridine, reflux,
242Cl
h,2, 87%;
2, CH2(b)
Cl2, 0 °C to rt, 20 min, 95%; (d) NaBH
4, EtOH, rt, 15 min, 97%; (e) Pb(OAc)
4, CH
four steps, 59% [87,88]; (b) OsO
4, H2O, t‐BuOH, trimethylamine N‐oxide, pyridine, reflux, 24 h, 87%; (c) BF3∙OEt2, CH2Cl2, 0 °C to rt, 20 min, 95%; (d) NaBH
4, EtOH, rt, 15 min, 97%; (e) Pb(OAc)4, CH2Cl2, ◦ C to
4
, t‐BuOH–H
2
O, reflux, 12 h, 91%. (c) BFrt, 45 min, 92%; (f) NaIO
OEt
,
CH
Cl
,
0
rt,
20
min,
95%;
(d)
NaBH
,
EtOH,
rt,
15
min,
97%;
(e)
Pb(OAc)
,
CH
·
3
2
2 2
4
4
2 Cl2 ,
(c) BF
3∙OEt2, CH2Cl2, 0 °C to rt, 20 min, 95%; (d) NaBH
4, EtOH, rt, 15 min, 97%; (e) Pb(OAc)4, CH2Cl2, rt, 45 min, 92%; (f) NaIO
4, t‐BuOH–H2O, reflux, 12 h, 91%. rt, 45 min, 92%; (f) NaIO4 , t-BuOH–H2 O, reflux, 12 h, 91%.
rt, 45 min, 92%; (f) NaIO4, t‐BuOH–H2O, reflux, 12 h, 91%. Investigation of the nudibranch A. kerguelenensis collected near the Antarctic Peninsula Investigation of the nudibranch A. kerguelenensis collected near the Antarctic Peninsula resulted in the isolation of three A.
new diterpenes, palmadorins A–C (148–150) (Figure 16) [89].
Investigation
the
nudibranch
kerguelenensis
collected
near
the
Antarctic
Peninsula
resulted
resulted in the ofisolation of three new diterpenes, palmadorins A–C (148–150) (Figure 16) [89].
Investigation of the nudibranch A. kerguelenensis collected near the Antarctic Peninsula Detailed investigation of this Antarctic nudibranch led to the discovery of a diverse suite of Detailed
new in the
isolation
of
three
new
diterpenes,
palmadorins
A–C
(148–150)
(Figure
16)
[89].
Detailed of of this Antarctic to the discovery of a diverse suite of new resulted in investigation the isolation three new nudibranch diterpenes, led palmadorins A–C (148–150) (Figure 16) [89]. diterpenoid glyceride esters, palmadorins D–S (151–166) (Figure 16), including one (palmadorin L) investigation
of
this
Antarctic
nudibranch
led
to
the
discovery
of
a
diverse
suite
of
new
diterpenoid
diterpenoid glyceride esters, palmadorins D–S (151–166) (Figure 16), including one (palmadorin L) Detailed investigation of this diterpene Antarctic from nudibranch led to the nudibranch. discovery of Palmadorin a diverse suite of new that is the first halogenated this well‐studied A (148), B that is the first halogenated D–S
diterpene from (Figure
this well‐studied nudibranch. Palmadorin A glyceride
esters,
palmadorins
(151–166)
16), including
one (palmadorin
L)(148), that B is the
diterpenoid glyceride esters, palmadorins D–S (151–166) (Figure 16), including one (palmadorin L) (149), D (151), M (160), N (161), and O (162) inhibit human erythroleukemia (HEL) cells with low (149), D (151), M (160), N (161), and O (162) inhibit human erythroleukemia (HEL) cells with low firstthat halogenated
diterpene
from
this
well-studied
nudibranch.
Palmadorin
A
(148),
B
(149),
D
is the first halogenated diterpene from this well‐studied nudibranch. Palmadorin A (148), B micromolar IC50, and palmadorin M inhibits Jak2, STAT5, and Erk1/2 activation in HEL cells and (151),
micromolar IC
50, and palmadorin M inhibits Jak2, STAT5, and Erk1/2 activation in HEL cells and (149), D (151), M (160), N (161), and O (162) inhibit human erythroleukemia (HEL) cells with low M (160),
N (161), and O (162)
inhibit
human
erythroleukemia
(HEL) cells with low micromolar IC50 ,
causes apoptosis at 5 mM [90].
causes apoptosis at 5 mM [90].
IC50
palmadorin M inhibits Jak2, STAT5, and Erk1/2 activation in causes
HEL cells and andmicromolar palmadorin
M, and inhibits
Jak2, STAT5,
and Erk1/2
activation
in HEL
cells and
apoptosis
O
O
O
OR
O4
R
20
at 5causes apoptosis at 5 mM [90].
mM [90].
20 17
H
H
R1
R1
20
3
3
R1
H
19
18 19
18
3
Palmadorin R1
Palmadorin R
191
A (148)
H
18 H
A
B (148)
(149)
H
Palmadorin
RH
B
1
C (149)
(150)
H
AC
(148)
D (150)
(151) HH
H
(151) H=O
H
BD
(149)
E (152)
(152) H=O
CE
(150)
F
(153)
H
(153)
H
DF
(151)
G
(154) H=O
(154) =O
=O
EG
(152)
H (155)
H
H
(155) H=O
H
F (153)
I (156)
(156) =O
=O
G IJ(154)
(157)
=O
(157)
H JK
(155)
(158) H=O
=O
K (158)
=O
I (156)
=O
J (157)
=O
K (158)
=O H
H
4
HO 4H
HO 18
Cl
Cl 18
4
17
17
16
16
R2
16R2
4
O
R4
R3
R3
OH
ROH
3
OH
RR
R3
R4
Other
2 2
R2
R
R
Other
4,18
H
CH23OH H4
4,18
OH H
H
CH2OAc
4,18
H CH
H
2
4,18
RH
R
R4
Other
CH
3,4
2
OH
CH322OAc
OH H
H
3,4
4,18
OH
CH
OH CH
HH OH
H
4,18
22OH
H CH
H
2
4,18
4,18
H CH2H
3,4
H
H2OH
OH
HOAc CH
CH
2OH
3,4
3,4
OH
H
CH
OH
3,4
OH
H22OH
2OH CH
OH CHH
3,4
4,18
OH
H
CH22OH
OH
3,4
H
HH
CH
H
CH
2OH
3,4
3,4
H
H
CH
OH
3,4
2
OH
H 2OAcCH2HOH
OH CH
3,4
3,4
OH
3,4
OH
HH2OAcCH
OH
=O CH
CH2H
OH
2
3,4
CHH
3,4
3,4
2OH
H=O
HH2OH CH
OH CH
2OH
3,4
OH
CH
OH
H
3,4
3,4
2OH
OH
HH
=O CH
CH22OAc
3,4
=O CH2OH
H
3,4
=O
H
CH2OH
3,4
OH CH2OHO
H
O
3,4
=O CH2OH
H
O
OH
O
OH
OOH
OH
O L (159)
Palmadorin
OH
Palmadorin L (159)
OH
20
20
9
9
5 20
5
R3
R3
R4
RR4
O
O
R1
R1
O
OR2O OH
R1
R2
OH
3
O
R2
OH
R4
Palmadorin
R1
R2
R3
R4
H
Palmadorin
R=CH
R4
3
M (160)
CHR21OH R
H2
2
19 OH
M
(160) 18 CH
=CH
N (161)
H2
CHH2OH
=CH22
N
=CH
Palmadorin
R1 CHH2ROH
R3 22 R4
2
O (161)
(162)
CHH
=CH
2OAc
O
(162)
CH
H OH
=CH
2OAc
2 CH
M(163)
(160)
CH
=CH
P
H
2OHCH2H
2 3
P
HH CH
CH
CH3
2OH
N (163)
(161)
CH
=CHCH
Q
(164)
H
2OH
2 3
2OH
Q
H OAcCH2H
OH
O (164)
(162)
CH
=CHCH
2
2 3
P (163)
H
CH2OH O
CH3
Q (164)
H
CH2OH O
CH3
O
O
OH
O
O
O OH
OR
OR
H
O
O
H
Palmadorin R (165) R = Ac OH
Palmadorin
(165) R
ROR
=H
Ac
Palmadorin R
S (166)
=
Palmadorin S (166) R = H
H
H 9
18 19H
18 195
Palmadorin R (165) R = Ac O
H
Palmadorin S (166) R = HH O
Granuloside (167)
Granuloside (167)
H
Other
Other
5
55
5 Other
5
5 5
5
5 5
5
5 5
5
5
O
O
OH O
OH
O
Figure 16. Secondary metabolites derived from the Antarctic nudibranch (compounds 148–167). HO
Figure 16. Secondary metabolites derived from the Antarctic nudibranch (compounds 148–167). Cl
18
Palmadorin L (159)
Granuloside (167)
OH
Figure 16. Secondary metabolites derived from the Antarctic nudibranch (compounds 148–167). Figure
16. Secondary metabolites derived from the Antarctic nudibranch (compounds 148–167).
Mar. Drugs 2017, 15, 28
17 of 30
Mar. Drugs 2017, 15, 28 17 of 30 Recently, a new homosesterterpene named granuloside (167) (Figure 16), was characterized from
the Antarctic
nudibranch
Charcotia granulosa.
Granuloside
was
the(Figure first linear
homosesterterpene
Recently, a new homosesterterpene named granuloside (167) 16), was characterized from ever
the reported
Antarctic and,
nudibranch granulosa. Granuloside was structure
the first linear skeleton
despite theCharcotia low molecular
complexity,
its chemical
poses
many
homosesterterpene skeleton ever reported and, despite the low molecular complexity, its chemical questions
about its biogenesis and origin in the nudibranch [91].
structure poses many questions about its biogenesis and origin in the nudibranch [91]. 9. Sponges
9. Sponges Marine sponges are the largest source of new marine natural products reported annually [11–13]
Marine sponges are the of
largest source of new marine natural [92].
products reported annually and have
provided
a rich
array
biologically
important
compounds
There
are a large
number
[11–13] and have provided a rich array of biologically important compounds [92]. There are a large of studies on sponges from warm or tropical waters, whereas little is known about the chemistry of
number of studies on or
sponges from warm Actually,
or tropical waters, whereas little is known can
about the sponges
from
the Arctic
Antarctic
waters.
polar
species
of marine
sponges
also
be a
chemistry of sponges from the Arctic or Antarctic waters. Actually, polar species of marine sponges rich source of biologically and structurally interesting molecules.
can also be a rich source of biologically and structurally interesting molecules. Pyridinium alkaloids are widely distributed in marine sponges of different genera. In 2003,
Pyridinium alkaloids are widely distributed in marine sponges of different genera. In 2003, chemical investigation of the Arctic sponge Haliclona viscosa led to the isolation of a new trimeric
chemical investigation of the Arctic sponge Haliclona viscosa led to the isolation of a new trimeric 3-alkyl pyridinium alkaloid, viscosamine (168) (Figure 17) [93]. Further investigation of this sponge
3‐alkyl pyridinium alkaloid, viscosamine (168) (Figure 17) [93]. Further investigation of this sponge yielded
one new 3-alkyl pyridinium alkaloid, viscosaline (169) (Figure 17) [94], and two new
yielded one new 3‐alkyl pyridinium alkaloid, viscosaline (169) (Figure 17) [94], and two new 3-alkyltetrahy-dropyridine
alkaloids, haliclamines C (170) and D (171) (Figure 17) [95]. In 2009, new
3‐alkyltetrahy‐dropyridine alkaloids, haliclamines C (170) and D (171) (Figure 17) [95]. In 2009, new haliclamines
E (172)
and
F (173)
(Figure
17)17) were
subsequently
obtained
from
this
Arctic
sponge
[96].
haliclamines E (172) and F (173) (Figure were subsequently obtained from this Arctic sponge Compound
169
showed
activity
in
the
feeding
deterrence
assay
against
the
amphipod
Anonyx
nugax
[96]. Compound 169 showed activity in the feeding deterrence assay against the amphipod Anonyx andnugax and the starfish Asterias rubens from the North Sea [97]. Compounds 169 and 170 showed a the starfish Asterias rubens from the North Sea [97]. Compounds 169 and 170 showed a strong
inhibition
against two bacterial strains isolated from the vicinity of the sponge [95,97]. The synthesis
strong inhibition against two bacterial strains isolated from the vicinity of the sponge [95,97]. The synthesis of the Arctic sponge alkaloids were also achieved by two groups [97,98]. of the
Arctic sponge alkaloids were also achieved by two groups [97,98].
Figure 17. Secondary metabolites derived from the Arctic sponge Haliclona viscosa (compounds 168–173). Figure
17. Secondary metabolites derived from the Arctic sponge Haliclona viscosa (compounds 168–173).
A new sesterterpene, caminatal (174), and two novel sesterterpenes, oxaspirosuberitenone (175) A new sesterterpene, caminatal (174), and two novel sesterterpenes, oxaspirosuberitenone (175) and
and 19‐episuberitenone (176) (Scheme 8) were obtained from the Antarctic sponge Suberites 19-episuberitenone (176) (Scheme 8) were obtained from the Antarctic sponge Suberites caminatus [99,100].
caminatus [99,100]. Their possible biogenesis were proposed as shown in Scheme 8. Their possible biogenesis were proposed as shown in Scheme 8.
Four new diterpenoids, 177–180 (Figure 18) were isolated from the Antarctic sponge Dendrilla Four new diterpenoids, 177–180 (Figure 18) were isolated from the Antarctic sponge Dendrilla
membranosa. Compound 177 was a nor‐diterpene gracilane skeleton derivative, while 178–180 are membranosa.
Compound 177 was a nor-diterpene gracilane skeleton derivative, while 178–180 are C-20
C‐20 aplysulphurane‐type diterpenes [101]. aplysulphurane-type
diterpenes [101].
Three new sesterterpenes of the suberitane class, suberitenones C (181) and D (182) and Three
new
sesterterpenes
of the suberitane class, suberitenones C (181) and D (182) and
suberiphenol (183) (Figure 18), were isolated from the sponge Suberites sp. collected from Antarctica. suberiphenol
(183)the (Figure
were isolated
thecytotoxic sponge Suberites
sp. human collected
from Antarctica.
Unfortunately, new 18),
compounds were from
neither against the leukemia K562 Unfortunately,
the new compounds were neither cytotoxic against the human leukemia K562 cell-line
cell‐line nor antimicrobial against B. subtilis, C. albicans, E. coli and S. aureus [102]. Five new steroids, norselic acids A–E (184–188) (Figure 18), were isolated from the sponge Crella nor antimicrobial
against B. subtilis, C. albicans, E. coli and S. aureus [102].
sp. collected in Antarctica. Norselic acid A displayed antibiotic activity against methicillin‐resistant Five new steroids, norselic acids A–E (184–188) (Figure 18), were isolated from the sponge Crella sp.
Staphylococcus aureus, S. aureus, antibiotic
vancomycin‐resistant Enterococcus faecium and collected
in Antarctica.methicillin‐sensitive Norselic acid A displayed
activity against
methicillin-resistant
Candida albicans, and reduced consumption of food pellets by sympatric mesograzers. Compounds Staphylococcus aureus, methicillin-sensitive S. aureus, vancomycin-resistant Enterococcus faecium and
184–188 were also active against the Leishmania parasite with low micromolar activity [103]. Mar. Drugs 2017, 15, 28
18 of 30
Mar. Drugs 2017, 15, 28 18 of 30 Candida albicans, and reduced consumption of food pellets by sympatric mesograzers. Compounds
+ activity [103].
184–188Mar. Drugs 2017, 15, 28 were also active againstOHthe Leishmania parasite
with low micromolar
18 of 30 OH
OH
H
OH +
H
OH
+
H
+
H+
+
OH
- H+
- H+
H+
H+
H+
OH
O
+
H
+
- H+
+
-H
O
O
O
[O]
O
O
H
+
[O]
H
H
H
HO
OH
[O]
OAc
O
Caminatal (174)
O
OAc
Caminatal (174)
[O]
+
OH
O
OH
H
H
OAc
OAc
+
OH
O
OH
OH
O
+
O
+
HO
OH
H
H
OH
[O]
HO
[O]
OAc
OAc
19-Episuberitenone
(176)
19-Episuberitenone (176)
OAc
H+
H
+ H+, -H+
+ H+, -H+
H
O
H
O
O
H
OAc
H+
H
O H
HH
H
OH
H
OH
OAc
OAc
Oxaspirosuberitenone
(175)
Oxaspirosuberitenone (175) Scheme 8. 8. Possible (174), oxaspirosuberitenone oxaspirosuberitenone (175) (175) Scheme Possible biogenesis biogenesis of of caminatal caminatal (174), and and Scheme
8. Possible biogenesis of caminatal (174), oxaspirosuberitenone (175) and 19-episuberitenone (176).
19‐episuberitenone (176). 19‐episuberitenone (176). Figure 18. Secondary metabolites derived from the Antarctic sponges (compounds 177–189) and the Arctic sponge (compounds 190–193). Figure 18. Secondary metabolites derived from the Antarctic sponges (compounds 177–189) and the Figure
18. Secondary metabolites derived from the Antarctic sponges (compounds 177–189) and the
Arctic sponge (compounds 190–193). Arctic sponge (compounds 190–193).
Mar. Drugs 2017, 15, 28
19 of 30
Darwinolide (189), a novel spongian diterpene, was characterized from the Antarctic sponge
Dendrilla membranosa. Darwinolide displayed antibiofilm activity against MRSA with no mammalian
cytotoxicity, and may present a suitable scaffold for the development of novel antibiofilm agents to
treat drug resistant bacterial infections [104].
Barettin (190), 8,9-dihydrobarettin (191), bromoconicamin (192) and a novel brominated marine
indole (193) (Figure 18) were isolated from the sponge Geodia barretti collected off the Norwegian coast.
The compounds were evaluated as inhibitors of electric eel acetylcholinesterase. Compounds 190 and
191 displayed significant inhibition of the enzyme, 192 was less potent against acetylcholinesterase,
and 193 was inactive. Based on the inhibitory activity, a library of 22 simplified synthetic analogs was
designed and prepared to probe the role of the brominated indole. From the structure–activity
investigation, it was shown that the brominated indole motif is not sufficient to generate a
high acetylcholinesterase inhibitory activity, even when combined with natural cationic ligands
for the acetylcholinesterase active site. The four natural compounds were also analysed for
butyrylcholinesterase inhibitory activity and shown to display comparable activities [105].
10. Tunicates
Tunicates comprise >2800 species and have yielded a diverse array of bioactive metabolites [10,106],
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 [107,108].
Bioassay-guided fractionation of CH2Cl2/MeOH extracts of the tunicate Aplidium cyaneum
collected in Antarctica led to the isolation of aplicyanins A–F (194–199) (Figure 19), a group of alkaloids
containing a bromoindole nucleus and a 6-tetra-hydropyrimidine substituent at C-3. Cytotoxic activity
in the submicromolar range as well as antimitotic properties were found for compounds 195, 197, and
199, whereas compounds 194 and 196 proved to be inactive at the highest concentrations tested and
compound 198 displayed only mild cytotoxic properties. The results clearly suggested a key role for
the presence of the acetyl group at N-16 in the biological activity of this family of compounds [109].
Five new ecdysteroids, hyousterones A–D (200–203) and abeohyousterone (204) (Figure 19), were
isolated from the Antarctic tunicate Synoicum adareanum by Baker and co-workers. Abeohyousterone
(204) has moderate cytotoxicity toward several cancer cell lines. Hyousterones bearing the 14β-hydroxy
group (200 and 202) were weakly cytotoxic, while the 14α-hydroxy hyousterones (201 and 203) were
devoid of cytotoxicity [110]. Further chemical investigation of the same Antarctic tunicate S. adareanum
yielded five new bioactive macrolides, palmerolide A (205) and D–G (206–209) (Figure 19). Most
of these palmerolides were potent V-ATPase inhibitors and had sub-micromolar activity against
melanoma [111,112]. Especially, palmerolide A remained the most potent of this series of natural
products against melanoma cells. In the National Cancer Institute (NCI) sixty-cell panel, palmerolide
A did not display cytotoxicity below 1 µM against any non-melanoma cell lines. In vivo activity
of palmerolide A in mice has been confirmed in the NCI’s hollow fiber assay [113]. Structural
features of palmerolide A such as the carbamate and the vinyl amide moieties led the Baker group
to hypothesize a bacterial origin for this polyketide. One finding that supported the possibility was
the identification of polyketide synthase (PKS) genes, similar to bryostatin biosynthetic genes [114].
Due to promising biological activity and limited access to natural supplies, as well as their challenging
structures, palmerolide A and congeneric structures are important targets for chemical synthesis.
Recent advances in the synthesis of the palmerolides have been reviewed by Lisboa and Dudley [115].
To date, three total syntheses [116–120] of palmerolide A have been reported. Four groups disclosed
formal syntheses [121–126], and various synthetic approaches have also been described [127–135]. The
synthesis of the reported structure of palmerolide C has also been achieved, and a structural revision
has been proposed [136].
Mar. Drugs 2017, 15, 28
20 of 30
Mar. Drugs 2017, 15, 28 20 of 30 Mar. Drugs 2017, 15, 28 20 of 30 Figure 19. Secondary metabolites derived from the Antarctic tunicates (compounds 194–209). Figure 19. Secondary metabolites derived from the Antarctic tunicates (compounds 194–209).
Figure 19. Secondary metabolites derived from the Antarctic tunicates (compounds 194–209). In 2009, bioassay‐guided fractionation
fractionation of
of the
the Antarctic species, led led
to the In 2009,
bioassay-guided
Antarctic ascidian ascidianAplidium Aplidium
species,
to the
In 2009, bioassay‐guided fractionation of the Antarctic ascidian Aplidium species, led to the characterization of two new biologically active meroterpene derivatives, rossinones A (210) and B characterization of two new biologically active meroterpene derivatives, rossinones A (210) and B (211)
characterization of two new biologically active meroterpene derivatives, rossinones A (210) and B (211) (Figure 20). The rossinones exhibited antiinflammatory, antiviral and antiproliferative (Figure 20). The rossinones exhibited antiinflammatory, antiviral and antiproliferative activities [137].
(211) (Figure 20). The rossinones exhibited antiinflammatory, antiviral and antiproliferative activities [137]. In additon, rossinone B (211) was proven to take part in the whole‐colony chemical In additon, rossinone B (211) was proven to take part in the whole-colony
chemical defense of
The following year, a activities [137]. In additon, rossinone B (211) was proven to take part in the whole‐colony chemical defense of Aplidium falklandicum, repelling both sea stars and amphipods [138].
Aplidium
falklandicum, repelling both sea stars and amphipods [138]. The following
year, a biomimetic
The following year, a defense of Aplidium falklandicum, repelling both sea stars and amphipods [138].
biomimetic total synthesis of (±)‐rossinone B was achieved through a highly efficient strategy as totalshown synthesis
of
(
±
)-rossinone
B
was
achieved
through
a
highly
efficient
strategy
as
shown
biomimetic total synthesis of (±)‐rossinone was novel achieved through a highly efficient strategy as in
in Scheme 9 [139]. Two years later, B three rossinone‐related meroterpenes (212–214) Scheme
9
[139].
Two
years
later,
three
novel
rossinone-related
meroterpenes
(212–214)
(Figure
shown in Scheme 9 [139]. Two years later, three novel rossinone‐related meroterpenes (212–214) 20)
(Figure 20) were obtained from the Antarctic ascidian Aplidium fuegiense. The new compounds were were
obtained from the Antarctic ascidian Aplidium fuegiense. The new
compounds were found to be
(Figure 20) were obtained from the Antarctic ascidian Aplidium fuegiense. The new compounds were found to be selectively localized in the viscera of the ascidian [140].
found to be selectively localized in the viscera of the ascidian [140].
selectively
localized in the viscera of the ascidian [140].
OHC
OHC
h
h
O
O
OTMS
O
O
NC
a
TBDPSO
TBDPSO
211
211
NC
a
OTMS
b
TBDPSO
TBDPSO
TBDPSO
TBDPSO
OH
O
OH
O
O
O
H
O
O
H
O
O
H
H
g
g
OH
OH
O
O
O
O
c
OTMS
b
OTMS
OH
OH
O
f
O
f
OMe
OMe
OH
OH
c
OMe
OMe OMe
OMe
OAc
OAc
d
d
O
O
OMe
OMe OMe
OMe
MOMO
MOMO
OH
OH
OH
OH
O
O
e
e
OMOM
OMOM
OMe
OMe OMe
OMe
MOMO
MOMO
OH
OH
OAc
OAc
O
O
Scheme 9. Synthesis of rossinone B (211). Reagents and conditions: (a) Trimethylsilyl cyanide Scheme 9. Synthesis of rossinone B (211). Reagents and conditions: (a) Trimethylsilyl cyanide (TMSCN), NEt
3, CH3of
CN, 99%; (b) LiHMDS, THF, −78 °C, then 3‐methyl‐2‐butenal, TMS migration, Scheme
9. Synthesis
rossinone B (211). Reagents and conditions: (a) Trimethylsilyl cyanide
(TMSCN), NEt
3, CH3CN, 99%; (b) LiHMDS, THF, −78 °C, then 3‐methyl‐2‐butenal, TMS migration, 75%; (c) 1 N HCl, THF, then 2O/py, then HF, CH
3CN, then 2,2‐Dimethoxypropane (DMP), (TMSCN), NEt3 , CH3 CN, 99%;
(b)Ac
LiHMDS,
THF, −78 ◦ C,
then 3-methyl-2-butenal, TMS migration,
75%; (c) 1 N HCl, THF, then Ac2O/py, then HF, CH3CN, then 2,2‐Dimethoxypropane (DMP), 4‐(Dicyanomethylene)‐2‐methyl‐6‐(4‐dimethylaminostyryl)‐4H‐pyran (DCM), 51%; (d) nBuLi, −78 °C, 75%; (c) 1 N HCl, THF, then Ac2 O/py, then HF, CH3 CN, then 2,2-Dimethoxypropane (DMP),
4‐(Dicyanomethylene)‐2‐methyl‐6‐(4‐dimethylaminostyryl)‐4H‐pyran (DCM), 51%; (d) nBuLi, −78 °C, 88%; (e) K2CO3/MeOH, 79%; (f) 6 N HNO3, then AgO, 90%; (g) toluene, sealed 150 °C; 4-(Dicyanomethylene)-2-methyl-6-(4-dimethylaminostyryl)-4H-pyran
(DCM),
51%;tube, (d) nBuLi,
−(h) 78 ◦ C,
88%; (e) K
2CO3/MeOH, 79%; (f) 6 N HNO3, then AgO, 90%; (g) toluene, sealed tube, 150 °C; (h) CH3OH/H2O, TsOH, 80 °C, 31%. ◦
88%;CH
(e)
K2 CO
3 /MeOH, 79%; (f) 6 N HNO3 , then AgO, 90%; (g) toluene, sealed tube, 150 C;
3OH/H
2O, TsOH, 80 °C, 31%. (h) CH3 OH/H2 O, TsOH, 80 ◦ C, 31%.
Mar. Drugs 2017, 15, 28
21 of 30
From
the sub-Arctic ascidian Synoicum pulmonaria collected off the Norwegian coast,21 of 30 three new
Mar. Drugs 2017, 15, 28 brominated guanidinium oxazolidinones were isolated, named synoxazolidinones A–C (215–217)
From the sub‐Arctic ascidian Synoicum pulmonaria collected off the Norwegian coast, three new (Figure 20)
[141–143]. The backbone of the compounds contains a 4-oxazolidinone ring rarely
brominated oxazolidinones were isolated, (215–217) and
seen in natural guanidinium products. Synoxazolidinones
A (215)named and Bsynoxazolidinones (216) exhibitedA–C antibacterial
(Figure 20) [141–143]. The backbone of the compounds contains a 4‐oxazolidinone ring rarely seen antifungal activities, and 215 displayed higher activity than 216 because of the chlorine atom in its
in natural products. Synoxazolidinones A (215) and B (216) exhibited antibacterial and antifungal structure
[141]. Synoxazolidinone C could inhibit the growth of Gram-positive bacteria Staphylococcus
activities, and 215 displayed higher activity than 216 because of the chlorine atom in its structure aureus[141]. Synoxazolidinone C could inhibit the growth of Gram‐positive bacteria Staphylococcus aureus and methicillin-resistant S. aureus at a concentration of 10 µg/mL [142]. In addition, 215
and 217
a broadS. and
high
toward
adhesion
and
growth
16217 known
and displayed
methicillin‐resistant aureus at a activity
concentration of 10 the
μg/mL [142]. In addition, 215 of
and displayed a broad and high activity microalgae,
toward the adhesion and growth of 16 known biofouling
species
of marine
bacteria,
and crustaceans.
Compound
217biofouling was the most
of marine bacteria, microalgae, crustaceans. Compound was the most active [144].
activespecies compound
and was
comparable
to and the commercial
antifouling217 product
Sea-Nine-211
compound and was comparable to the commercial antifouling product Sea‐Nine‐211 [144]. Pulmonarins A (218) and B (219) (Figure 20) were two new dibrominated marine acetylcholinesterase
Pulmonarins A (218) and B (219) (Figure 20) were two new dibrominated marine inhibitors that were also isolated from this sub-Arctic ascidian. Both 218 and 219 displayed
acetylcholinesterase inhibitors that were also isolated from this sub‐Arctic ascidian. Both 218 and reversible, noncompetitive acetylcholinesterase inhibition comparable to several known natural
219 displayed reversible, noncompetitive acetylcholinesterase inhibition comparable to several acetylcholinesterase
inhibitiors [145]. inhibitiors In addition,
the
were generally
against
known natural acetylcholinesterase [145]. In pulmonarins
addition, the pulmonarins were active
generally the adhesion
and
growth
of
several
bacteria
[144].
active against the adhesion and growth of several bacteria [144]. FigureFigure 20. Secondary metabolites derived from the Antarctic tunicates (compounds 210–214) and the 20. Secondary metabolites derived from the Antarctic tunicates (compounds 210–214) and the
Arctic tunicate (compounds 215–219). Arctic tunicate (compounds 215–219).
11. Conclusions 11. Conclusions
As demonstrated by this review, polar organisms have yielded an impressive array of novel As
demonstrated
polar
organisms
have yielded
anactivities impressive
array the of novel
compounds (Table by
1) this
with review,
complex structures and potent biological including compounds
(Table 1) with complex structures and potent biological activities including the cytotoxic
cytotoxic cyclic acylpeptides, mixirins A–C (1–3), from the Arctic marine bacterium Bacillus sp. [15];
unusual mixirins
antibacterial lindgomycin (46) bacterium
from the Bacillus
culture sp.broth of unusual
a cyclic the acylpeptides,
A–C polyketide, (1–3), from the
Arctic marine
[15]; the
Lindgomycetaceae strain [36]; the antioxidant (104) from the Antarctic lichen antibacterial
polyketide,
lindgomycin
(46) fromcompound the cultureramalin broth of
a Lindgomycetaceae
strain [36];
the new antiparasitic tricyclic sesquiterpenoids, shagenes A (130) and B (131) Ramalina terebrata [61];
the antioxidant compound ramalin (104) from the Antarctic lichen Ramalina terebrata [61]; the new
from an undescribed Antarctic soft coral [76]; and the new macrolides, palmerolide A (205) and D–G antiparasitic tricyclic sesquiterpenoids, shagenes A (130) and B (131) from an undescribed Antarctic
(206–209) with potent V‐ATPase inhibitory and sub‐micromolar activity against melanoma from the soft coral
[76]; and the new macrolides, palmerolide A (205) and D–G (206–209) with potent V-ATPase
Antarctic tunicate Synoicum adareanum [111,112]. inhibitoryThe andnatural sub-micromolar
activity
against
melanoma
from
the a Antarctic
tunicate
Synoicum
products derived from polar regions appear to have high hit rate regarding adareanum
[111,112].
biological activity, varying from cytotoxic, enzyme inhibitory, antioxidant, antiparasitic, antiviral to antibacterial and so on. Secondary metabolism polar habitats largely by ecological The
natural products
derived
from polar
regionsin appear
to have ais high
hit driven rate regarding
biological
requirements of the producing organism. Successful organisms antiparasitic,
will often have specific to
metabolic activity,
varying from
cytotoxic,
enzyme
inhibitory,
antioxidant,
antiviral
antibacterial
that produce unique natural products that bestow ecological advantage, of the
and sopathways on. Secondary
metabolism
infunctional polar habitats
is largely
driven
by ecological
requirements
increasing the possibility of finding pharmaceutical lead molecules. producing organism. Successful organisms will often have specific metabolic pathways that produce
unique functional natural products that bestow ecological advantage, increasing the possibility of
finding pharmaceutical lead molecules.
Mar. Drugs 2017, 15, 28
22 of 30
Table 1. Novel natural products isolated from polar organisms.
PHYLUM/Class
Species
Compounds
Bioactivity
Region
References
Bacillus sp.
1–3
Cytotoxic
Arctic
[15]
MICROORGANISMS
Bacteria
Salegentibacter sp.
Pseudoalteromonas
haloplanktis
Nostoc sp.
Janthinobacterium sp.
Pseudomonas sp.
Actinomyces
Antimicrobial and cytotoxic
Arctic
[16,17]
Rradical scavenging
Antarctic
[18]
18
19, 20
21, 22
Antibacterial
Antimycobacterial
Antibacterial
Antarctic
Antarctic
Antarctic
[19]
[20]
[21]
Streptomyces sp.
23–25
Nocardiopsis sp.
Nocardia dassonvillei
Streptomyces nitrosporeus
Streptomyces griseus
Streptomyces griseus
Microbispora aerata
Nocardiopsis sp.
26
27
28, 29
30
31
32
33
34
35, 36
Anti-angiogenesis
Antifungal and cytotoxic
Antiviral
Enzyme inhibitory
Enzyme inhibitory and cytotoxic
Antibacterial
Neuroprotective
Antiproliferative and cytotoxic
Penicillium algidum
37
Anticancer
38–40
41
42
43–45
46, 47
48
49, 50
51–53
54–59
60–62
63–66
67, 68
69
70–78
79
80, 81
82–85
86–90
91
Cytotoxicity
Antibacterial
Cytotoxicity
Immunosuppression
Antibacterial
Antifungal
Streptomyces sp.
Fungi
4–14
15 16, 17
Eutypella sp.
Lindgomycetaceae
Trichoderma polysporum
Geomyces sp.
Trichoderma asperellum
Oidiodendron truncatum
Penicillium crustosu m
Penicillium sp.
Penicillium funiculosum
Pseudogymnoascus sp.
Aspergillus
ochraceopetaliformis
Antifungal and antibacterial
Antifungal
Arctic
[22]
Arctic
Arctic
Arctic
[23]
[24]
[25]
Arctic
[27]
Antarctic
Antarctic
Antarctic
Antarctic
[28]
[29]
[30]
[31]
Arctic
[32]
Arctic
[33–35]
Arctic
Arctic
[36,37]
[38]
Antarctic
[39]
Antarctic
[40]
Cytotoxic
Antarctic
[42]
NF-κB inhibitory
Moderate cytotoxic
Antarctic
[43]
Antarctic
[45,46]
Antarctic
Antarctic
[47]
[48]
Antiviral
Antarctic
[49]
Cytotoxic
Stereocaulon alpinum
92
93–98
99
Cytotoxic and enzyme inhibitory
Enzyme inhibitory
Antioxidant and antibacterial
Antarctic
[55–59]
Huea sp.
Ramalina terebrata
100–103
104
Enzyme inhibitory
Antioxidant
Antarctic
Antarctic
[60]
[61]
Polytrichastrum alpinum
105, 106
Enzyme inhibitory
Antarctic
[62]
BRYOZOANS
Tegella cf. spitzbergensis
107–110
Antibacterial
Arctic
[64]
CNIDARIANS
Ainigmaptilon antarcticus
111, 112
Predation inhibitory
Antarctic
[66]
Dasystenella acanthina
Anthomastus
bathyproctus
Alcyonium grandis
Undescribed octocoral
Thuiria breitfussi
113
Ichthyotoxic
Antarctic
[67]
114–120
Weak cytotoxic
Antarctic
[68]
Antiparasitic
Antarctic
Antarctic
Arctic
[69]
[76]
[77]
Arctic
[80]
Antarctic
[81]
LICHEN
MOSS
121–129
130, 131
132, 133
134–136
137
Antibacterial
Staurocucumis liouvillei
138, 139
Antiviral
Staurocucumis turqueti
Achlionice violaecuspidata
140
141–143
Antarctic
Antarctic
[82]
[83]
Austrodoris
kerguelenensis
144–147
Antarctic
[84,85]
Gersemia fruticosa
ECHINODERMS
MOLLUSCS
Mar. Drugs 2017, 15, 28
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Table 1. Cont.
PHYLUM/Class
Species
Austrodoris
kerguelenensis
Charcotia granulosa
SPONGES
Bioactivity
Region
References
148–166
Erythroleukemia inhibitory
Antarctic
[89]
167
Antarctic
[91]
Haliclona viscosa
168–173
Arctic
[93–96]
Suberites caminatus
Dendrilla membranosa
Suberites sp.
Crella sp.
Dendrilla membranosa
174–176
177–180
181–183
184–188
189
190
191–193
Antibacterial and antifungal
Antibacterial
Antarctic
Antarctic
Antarctic
Antarctic
Antarctic
[99,100]
[101]
[102]
[103]
104]
Enzyme inhibitory
Arctic
[105]
Antarctic
[109]
Antarctic
[110–112]
Antarctic
[137]
Antarctic
[140]
Arctic
[141–145]
Geodia barretti
TUNICATES
Compounds
Aplidium cyaneum
194–199
Antimitotic
Moderate cytotoxic
Synoicum adareanum
200–203
204
205–209
Aplidium sp.
210, 211
Aplidium fuegiense
212–214
215–217
Synoicum pulmonaria
218, 219
Cytotoxic and enzyme inhibitory
Antiinflammatory, antiviral and
antiproliferative
Antibacterial and antifungal
Enzyme inhibitory and
antibacterial
However, when compared to the large number of polar microorganisms which have been reported,
very few have been screened for the production of interesting secondary metabolites. This situation
may be attributed to the difficulties in cultivating polar microorganisms, some of which cannot survive
under normal laboratory conditions and therefore cannot be cultured using traditional techniques.
As yet, the potential of this area remains virtually untapped. Nowadays, advances in laboratory
techniques have led to cultivation of some previously inaccessible extremophiles. Moreover, new tools
developed recently in the fields of bioinformatics [146], analytics [147], and molecular biology [148], in
combination with rapid improvement in sequencing technology, might herald a new era of research
into this specific source.
Acknowledgments: The authors express thanks to the people who helped with this work. This work was
financed by NSFC grant (21602152, 81403036), Shandong Provincial Natural Science Foundation (ZR2016BB01,
ZR2014HM048), Shandong Provincial Key Research and Development Program (2016GSF202002), Shandong
Provincial Medical Science and Technology Development Project (2013WS0321), Taian Science and Technology
Development Project (2016NS1214), Shandong Provincial Education Department Project (J15LM56), National
Undergraduate Training Program for Innovation and Entrepreneurship (201610439263) and Taishan Medical
University High-level Development Project (2015GCC15).
Author Contributions: Yuan Tian and Yan-Ling Li contributed equally in the writing of this manuscript.
Feng-Chun Zhao collected all the references.
Conflicts of Interest: The authors declare no conflict of interest.
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