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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,

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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.

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  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].

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  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].

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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

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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)

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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 

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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 

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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]. 

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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).

 

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  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

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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.

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  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]. 

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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 

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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].

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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%.

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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].

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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).

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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]. 

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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).

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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].

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    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%.

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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.

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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

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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.

References 1.

2. 3.

Santiago, I.F.; Soares, M.A.; Rosa, C.A.; Rosa, L.H. Lichensphere: A protected natural microhabitat of the non-lichenised fungal communities living in extreme environments of Antarctica. Extremophiles 2015, 19, 1087–1097. [CrossRef] [PubMed] Li, J.; Tian, X.P.; Zhu, T.J.; Yang, L.L.; Li, W.J. Streptomyces fildesensis sp. nov., a novel streptomycete isolated from Antarctic soil. Antonie Van Leeuwenhoek 2011, 100, 537–543. [CrossRef] [PubMed] Kim, E.H.; Jeong, H.J.; Lee, Y.K.; Moon, E.Y.; Cho, J.C.; Lee, H.K.; Hong, S.G. Actimicrobium antarcticum gen. nov., sp. nov., of the family Oxalobacteraceae, isolated from Antarctic coastal seawater. Curr. Microbiol. 2011, 63, 213–217. [CrossRef] [PubMed]

Mar. Drugs 2017, 15, 28

4.

5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

17. 18. 19.

20. 21.

22.

23.

24. 25.

24 of 30

Snauwaert, I.; Peeters, K.; Willems, A.; Vandamme, P.; Vuyst, L.D.; Hoste, B.; Bruyne, K.D. Carnobacterium iners sp. nov., a psychrophilic, lactic acid-producing bacterium from the littoral zone of an Antarctic pond. Int. J. Syst. Evol. Microbiol. 2013, 63, 1370–1375. [CrossRef] [PubMed] Zhang, L.; Ruan, C.; Peng, F.; Deng, Z.; Hong, K. Streptomyces arcticus sp. nov., isolated from the Arctic. Int. J. Syst. Evol. Microbiol. 2016, in press. [CrossRef] Lebar, M.D.; Heimbegner, J.L.; Baker, B. Cold-water marine natural products. J. Nat. Prod. Rep. 2007, 24, 774–797. [CrossRef] [PubMed] Wilson, Z.E.; Brimble, M.A. Molecules derived from the extremes of life. Nat. Prod. Rep. 2009, 26, 44–71. [CrossRef] [PubMed] Abbas, S.; Kelly, M.; Bowling, J.; Sims, J.; Waters, A.; Hamann, M. Advancement into the Arctic region for bioactive sponge secondary metabolites. Mar. Drugs 2011, 9, 2423–2437. [CrossRef] [PubMed] Liu, J.T.; Lu, X.L.; Liu, X.Y.; Gao, Y.; Hu, B.; Jiao, B.H.; Zheng, H. Bioactive natural products from the antarctic and arctic organisms. Mini Rev. Med. Chem. 2013, 13, 617–626. [CrossRef] [PubMed] Skropeta, D.; Wei, L. Recent advances in deep-sea natural products. Nat. Prod. Rep. 2013, 31, 999–1025. [CrossRef] [PubMed] Blunt, J.W.; Copp, B.R.; Keyzers, R.A.; Munro, M.H.G.; Prinsep, M.R. Marine natural products. Nat. Prod. Rep. 2014, 31, 160–258. [CrossRef] [PubMed] Blunt, J.W.; Copp, B.R.; Keyzers, R.A.; Munro, M.H.G.; Prinsep, M.R. Marine natural products. Nat. Prod. Rep. 2015, 32, 116–211. [CrossRef] [PubMed] Blunt, J.W.; Copp, B.R.; Keyzers, R.A.; Munro, M.H.G.; Prinsep, M.R. Marine natural products. Nat. Prod. Rep. 2016, 33, 382–431. [CrossRef] [PubMed] De Pascale, D.; De Santi, C.; Fu, J.; Landfald, B. The microbial diversity of Polar environments is a fertile ground for bioprospecting. Mar. Genom. 2012, 8, 15–22. [CrossRef] [PubMed] Zhang, H.L.; Hua, H.M.; Pei, Y.H.; Yao, X.S. Three new cytotoxic cyclic acylpeptides from marine Bacillus sp. Chem. Pharm. Bull. 2004, 52, 1029–1030. [CrossRef] [PubMed] Al-Zereini, W.; Schuhmann, I.; Laatsch, H.; Helmke, E.; Anke, H. New aromatic nitro compounds from Salegentibacter sp. T436, an Arctic Sea ice bacterium: Taxonomy, fermentation, isolation and biological activities. J. Antibiot. 2007, 60, 301–308. [CrossRef] [PubMed] Schuhmann, I.; Yao, C.B.F.; Al-Zereini, W.; Anke, H.; Helmke, E.; Laatsch, H. Nitro derivatives from the Arctic ice bacterium Salegentibacter sp. isolate T436. J. Antibiot. 2009, 62, 453–460. [CrossRef] [PubMed] Mitova, M.; Tutino, M.L.; Infusini, G.; Marino, G.; De Rosa, S. Exocellular peptides from Antarctic psychrophile Pseudoalteromonas haloplanktis. Mar. Biotechnol. 2005, 7, 523–531. [CrossRef] [PubMed] Asthana, R.K.; Deepali; Tripathi, M.K.; Srivastava, A.; Singh, A.P.; Singh, S.P.; Nath, G.; Srivastava, R.; Srivastava, B.S. Isolation and identification of a new antibacterial entity from the Antarctic cyanobacterium Nostoc CCC 537. J. Appl. Phycol. 2009, 21, 81–88. [CrossRef] Mojib, N.; Philpott, R.; Huang, J.P.; Niederweis, M.; Bej, A.K. Antimycobacterial activity in vitro of pigments isolated from Antarctic bacteria. Antonie Van Leeuwenhoek 2010, 98, 531–540. [CrossRef] [PubMed] Tedesco, P.; Maida, I.; Esposito, F.P.; Tortorella, E.; Subko, K.; Ezeofor, C.C.; Zhang, Y.; Tabudravu, J.; Jaspars, M.; Fani, R.; et al. Antimicrobial activity of monoramnholipids produced by bacterial strains isolated from the Ross Sea (Antarctica). Mar. Drugs 2016, 14, 83. [CrossRef] [PubMed] Macherla, V.R.; Liu, J.; Bellows, C.; Teisan, S.; Nicholson, B.; Lam, K.S.; Potts, B.C.M. Glaciapyrroles A, B, and C, pyrrolosesquiterpenes from a Streptomyces sp. isolated from an Alaskan marine sediment. J. Nat. Prod. 2005, 68, 780–783. [CrossRef] [PubMed] Shin, H.J.; Mondol, M.A.M.; Yu, T.K.; Lee, H.S.; Lee, Y.J.; Jung, H.J.; Kim, J.H.; Kwon, H.J. An angiogenesis inhibitor isolated from a marine-derived actinomycete, Nocardiopsis sp. 03N67. Phytochem. Lett. 2010, 3, 194–197. [CrossRef] Gao, X.; Lu, Y.; Xing, Y.; Ma, Y.; Lu, J.; Bao, W.; Wang, Y.; Xi, T. A novel anticancer and antifungus phenazine derivative from a marine actinomycete BM-17. Microbiol. Res. 2012, 167, 616–622. [CrossRef] [PubMed] Yang, A.; Si, L.; Shi, Z.; Tian, L.; Liu, D.; Zhou, D.; Prokch, P.; Lin, W. Nitrosporeusines A and B, unprecedented thioester-bearing alkaloids from the Arctic Streptomyces nitrosporeus. Org. Lett. 2013, 15, 5366–5369. [CrossRef] [PubMed]

Mar. Drugs 2017, 15, 28

26.

27.

28.

29.

30.

31.

32. 33. 34. 35.

36.

37.

38.

39. 40. 41.

42. 43. 44. 45.

25 of 30

Philkhana, S.C.; Jachak, G.R.; Gunjal, V.B.; Dhage, N.M.; Bansode, A.H.; Reddy, D.S. First synthesis of nitrosporeusines, alkaloids with multiple biological activities. Tetrahedron Lett. 2015, 56, 1252–1254. [CrossRef] Moon, K.; Ahn, C.H.; Shin, Y.; Won, T.H.; Ko, K.; Lee, S.K.; Oh, K.B.; Shin, J.; Nam, S.I.; Oh, D.C. New benzoxazine secondary metabolites from an Arctic Actinomycete. Mar. Drugs 2014, 12, 2526–2538. [CrossRef] [PubMed] Bruntner, C.; Binder, T.; Pathom-aree, W.; Goodfellow, M.; Bull, A.T.; Potterat, O.; Puder, C.; Hörer, S.; Schmid, A.; Bolek, W.; et al. Frigocyclinone, a novel angucyclinone antibiotic produced by a Streptomyces griseus strain from Antarctica. J. Antibiot. 2005, 58, 346–349. [CrossRef] [PubMed] Bringmann, G.; Lang, G.; Maksimenka, K.; Hamm, A.; Gulder, T.A.M.; Dieter, A.; Bull, A.T.; Stach, J.E.M.; Kocher, N.; Müller, W.E.G.; Fiedler, H.P. Gephyromycin, the first bridged angucyclinone, from Streptomyces griseus strain NTK 14. Phytochemistry 2005, 66, 1366–1373. [CrossRef] [PubMed] Ivanova, V.; Kolarova, M.; Aleksieva, K.; Gräfe, U.; Dahse, H.M.; Laatsch, H. Microbiaeratin, a new natural indole alkaloid from a Microbispora aerata strain, isolated from Livingston Island, Antarctica. Prep. Biochem. Biotechnol. 2007, 37, 161–168. [CrossRef] [PubMed] Zhang, H.; Saurav, K.; Yu, Z.; Mándi, A.; Kurtán, T.; Li, J.; Tian, X.; Zhang, Q.; Zhang, W.; Zhang, C. α-Pyrones with diverse hydroxy substitutions from three marine-derived Nocardiopsis Strains. J. Nat. Prod. 2016, 79, 1610–1618. [CrossRef] [PubMed] Dalsgaard, P.W.; Larsen, T.O.; Christophersen, C. Bioactive cyclic peptides from the psychrotolerant fungus Penicillium algidum. J. Antibiot. 2005, 58, 141–144. [CrossRef] [PubMed] Liu, J.T.; Hu, B.; Gao, Y.; Zhang, J.P.; Jiao, B.H.; Lu, X.L.; Liu, X.Y. Bioactive tyrosine-derived cytochalasins from fungus Eutypella sp. D-1. Chem. Biodivers. 2014, 11, 800–806. [CrossRef] [PubMed] Lu, X.L.; Liu, J.T.; Liu, X.Y.; Gao, Y.; Zhang, J.; Jiao, B.H.; Zheng, H. Pimarane diterpenes from the Arctic fungus Eutypella sp. D-1. J. Antibiot. 2014, 67, 171–174. [CrossRef] [PubMed] Zhang, L.Q.; Chen, X.C.; Chen, Z.Q.; Wang, G.M.; Zhu, S.G.; Yan, Y.F.; Chen, K.X.; Liu, X.Y.; Li, Y.M. Eutypenoids A–C: Novel pimarane diterpenoids from the Arctic fungus Eutypella sp. D-1. Mar. Drugs 2016, 14, 44. [CrossRef] [PubMed] Wu, B.; Wiese, J.; Labes, A.; Kramer, A.; Schmaljohann, R.; Imhoff, J.F. Lindgomycin, an unusual antibiotic polyketide from a marine fungus of the Lindgomycetaceae. Mar. Drugs 2015, 13, 4617–4632. [CrossRef] [PubMed] Ondeyka, J.G.; Smith, S.K.; Zink, D.L.; Vicente, F.; Basilio, A.; Bills, G.F.; Polishook, J.D.; Garlisi, C.; Mcguinness, D.; Smith, E.; et al. Isolation, structure elucidation and antibacterial activity of a new tetramic acid, ascosetin. J. Antibiot. 2014, 67, 527–531. [CrossRef] [PubMed] Kamo, M.; Tojo, M.; Yamazaki, Y.; Itabashi, T.; Takeda, H.; Wakana, D.; Hosoe, T. Isolation of growth inhibitors of the snow rot pathogen Pythium iwayamai from an arctic strain of Trichoderma polysporum. J. Antibiot. 2016, 69, 451–455. [CrossRef] [PubMed] Li, Y.; Sun, B.; Liu, S.; Jiang, L.; Liu, X.; Zhang, H.; Che, Y. Bioactive asterric acid derivatives from the Antarctic ascomycete fungus Geomyces sp. J. Nat. Prod. 2008, 71, 1643–1646. [CrossRef] [PubMed] Ren, J.; Xue, C.; Tian, L.; Xu, M.; Chen, J.; Deng, Z.; Proksch, P.; Lin, W. Asperelines A–F, peptaibols from the marine-derived fungus Trichoderma asperellum. J. Nat. Prod. 2009, 72, 1036–1044. [CrossRef] [PubMed] Ren, J.; Yang, Y.; Liu, D.; Chen, W.; Proksch, P.; Shao, B.; Lin, W. Sequential determination of new peptaibols asperelines G-Z12 produced by marine-derived fungus Trichoderma asperellum using ultrahigh pressure liquid chromatography combined with electrospray-ionization tandem mass spectrometry. J. Chromatogr. A 2013, 1309, 90–95. [CrossRef] [PubMed] Li, L.; Li, D.; Luan, Y.; Gu, Q.; Zhu, T. Cytotoxic metabolites from the antarctic psychrophilic fungus Oidiodendron truncatum. J. Nat. Prod. 2012, 75, 920–927. [CrossRef] [PubMed] Wu, G.; Ma, H.; Zhu, T.; Li, J.; Gu, Q.; Li, D. Penilactones A and B, two novel polyketides from Antarctic deep-sea derived fungus Penicillium crustosum PRB-2. Tetrahedron 2012, 68, 9745–9749. [CrossRef] Spence, J.T.J.; George, J.H. Total synthesis of ent-penilactone A and penilactone B. Org. Lett. 2013, 15, 3891–3893. [CrossRef] [PubMed] Wu, G.; Lin, A.; Gu, Q.; Zhu, T.; Li, D. Four new chloro-eremophilane sesquiterpenes from an Antarctic deep-sea derived fungus, Penicillium sp. PR19N-1. Mar. Drugs 2013, 11, 1399–1408. [CrossRef] [PubMed]

Mar. Drugs 2017, 15, 28

46. 47.

48.

49.

50. 51. 52.

53. 54. 55. 56. 57.

58.

59. 60. 61.

62.

63. 64.

65.

66. 67.

26 of 30

Lin, A.; Wu, G.; Gu, Q.; Zhu, T.; Li, D. New eremophilane-type sesquiterpenes from an Antarctic deepsea derived fungus, Penicillium sp. PR19N-1. Arch. Pharm. Res. 2014, 37, 839–844. [CrossRef] [PubMed] Zhou, H.; Li, L.; Wang, W.; Che, Q.; Li, D.; Gu, Q.; Zhu, T. Chrodrimanins I and J from the Antarctic moss-derived fungus Penicillium funiculosum GWT2-24. J. Nat. Prod. 2015, 78, 1442–1445. [CrossRef] [PubMed] Figueroa, L.; Jiménez, C.; Rodríguez, J.; Areche, C.; Chávez, R.; Henríquez, M.; de la Cruz, M.; Díaz, C.; Segade, Y.; Vaca, I. 3-Nitroasterric acid derivatives from an Antarctic sponge-derived Pseudogymnoascus sp. fungus. J. Nat. Prod. 2015, 78, 919–923. [CrossRef] [PubMed] Wang, J.; Wei, X.; Qin, X.; Tian, X.; Liao, L.; Li, K.; Zhou, X.; Yang, X.; Wang, F.; Zhang, T.; et al. Antiviral merosesquiterpenoids produced by the Antarctic fungus Aspergillus ochraceopetaliformis SCSIO 05702. J. Nat. Prod. 2016, 79, 59–65. [CrossRef] [PubMed] Ingólfsdóttir, K. Usnic acid. Phytochemistry 2002, 61, 729–736. [CrossRef] Kumar, K.C.S.; Müller, K. Lichen metabolites. 1. Inhibitory action against leukotriene B4 biosynthesis by a non-redox mechanism. J. Nat. Prod. 1999, 62, 817–820. [CrossRef] [PubMed] Paudel, B.; Bhattarai, H.D.; Lee, J.S.; Hong, S.G.; Shin, H.W.; Yim, J.H. Antibacterial potential of Antarctic lichens against human pathogenic Gram-positive bacteria. Phytother. Res. 2008, 22, 1269–1271. [CrossRef] [PubMed] Paudel, B.; Bhattarai, H.D.; Lee, J.S.; Hong, S.G.; Shin, H.W.; Yim, J.H. Antioxidant activity of polar lichens from King George Island (Antarctica). Polar Biol. 2008, 31, 605–608. [CrossRef] Ivanova, V.; Kolarova, M.; Aleksieva, K. Diphenylether and macrotriolides occurring in a fungal isolate from the antarctic lichen Neuropogon. Prep. Biochem. Biotechnol. 2007, 37, 39–45. [CrossRef] [PubMed] Seo, C.; Yim, J.H.; Lee, H.K.; Park, S.M.; Sohn, J.H.; Oh, H. Stereocalpin A, a bioactive cyclic depsipeptide from the Antarctic lichen Stereocaulon alpinum. Tetrahedron Lett. 2008, 49, 29–31. [CrossRef] Seo, C.; Sohn, J.H.; Park, S.M.; Yim, J.H.; Lee, H.K.; Oh, H. Usimines A-C, bioactive usnic acid derivatives from the Antarctic lichen Stereocaulon alpinum. J. Nat. Prod. 2008, 71, 710–712. [CrossRef] [PubMed] Koren, S.; Fantus, I.G. Inhibition of the protein tyrosine phosphatase PTP1B: Potential therapy for obesity, insulin resistance and type-2 diabetes mellitus. Best Pract. Res. Clin. Endocrinol. Metab. 2007, 21, 621–640. [CrossRef] [PubMed] Seo, C.; Sohn, J.H.; Ahn, J.S.; Yim, J.H.; Lee, H.K.; Oh, H. Protein tyrosine phosphatase 1B inhibitory effects of depsidone and pseudodepsidone metabolites from the Antarctic lichen Stereocaulon alpinum. Bioorg. Med. Chem. Lett. 2009, 19, 2801–2803. [CrossRef] [PubMed] Bhattarai, H.D.; Kim, T.; Oh, H.; Yim, J.H. A new pseudodepsidone from the Antarctic lichen Stereocaulon alpinum and its antioxidant, antibacterial activity. J. Antibiot. 2013, 66, 559–561. [CrossRef] [PubMed] Cui, Y.; Yim, J.H.; Lee, D.S.; Kim, Y.C.; Oh, H. New diterpene furanoids from the Antarctic lichen Huea sp. Bioorg. Med. Chem. Lett. 2012, 22, 7393–7396. [CrossRef] [PubMed] Paudel, B.; Bhattarai, H.D.; Koh, H.Y.; Lee, S.G.; Han, S.J.; Lee, H.K.; Oh, H.; Shin, H.W.; Yim, J.H. Ramalin, a novel nontoxic antioxidant compound from the Antarctic lichen Ramalina terebrata. Phytomedicine 2011, 18, 1285–1290. [CrossRef] [PubMed] Seo, C.; Choi, Y.H.; Sohn, J.H.; Ahn, J.S.; Yim, J.H.; Lee, H.K.; Oh, H. Ohioensins F and G: Protein tyrosine phosphatase 1B inhibitory benzonaphthoxanthenones from the Antarctic moss Polytrichastrum alpinum. Bioorg. Med. Chem. Lett. 2008, 18, 772–775. [CrossRef] [PubMed] Sharp, J.H.; Winson, M.K.; Porter, J.S. Bryozoan metabolites: An ecological perspective. Nat. Prod. Rep. 2007, 24, 659–673. [CrossRef] [PubMed] Tadesse, M.; Tabudravu, J.N.; Jaspars, M.; Strøm, M.B.; Hansen, E.; Andersen, J.H.; Kristiansen, P.E.; Haug, T. The antibacterial ent-eusynstyelamide B and eusynstyelamides D, E, and F from the Arctic bryozoan Tegella cf. spitzbergensis. J. Nat. Prod. 2011, 74, 837–841. [CrossRef] [PubMed] Tapiolas, D.M.; Bowden, B.F.; Abou-Mansour, E.; Willis, R.H.; Doyle, J.R.; Muirhead, A.N.; Liptrot, C.; Llewellyn, L.E.; Wolff, C.W.W.; Wright, A.D.; et al. Eusynstyelamides A, B, and C, nNOS inhibitors, from the ascidian Eusynstyela latericius. J. Nat. Prod. 2009, 72, 1115–1120. [CrossRef] [PubMed] Iken, K.B.; Baker, B.J. Ainigmaptilones, sesquiterpenes from the Antarctic gorgonian coral Ainigmaptilon antarcticus. J. Nat. Prod. 2003, 66, 888–890. [CrossRef] [PubMed] Gavagnin, M.; Mollo, E.; Castelluccio, F.; Crispino, A.; Cimino, G. Sesquiterpene metabolites of the antarctic gorgonian Dasystenella acanthina. J. Nat. Prod. 2003, 66, 1517–1519. [CrossRef] [PubMed]

Mar. Drugs 2017, 15, 28

68. 69.

70.

71.

72.

73.

74. 75. 76.

77.

78. 79. 80.

81.

82.

83.

84.

85.

27 of 30

Mellado, G.G.; Zubía, E.; Ortega, M.J.; López-González, P.J. Steroids from the Antarctic octocoral Anthomastus bathyproctus. J. Nat. Prod. 2005, 68, 1111–1115. [CrossRef] [PubMed] Carbone, M.; Nunez-Pons, L.; Castelluccio, F.; Avila, C.; Gavagnin, M. Illudalane sesquiterpenoids of the alcyopterosin series from the Antarctic marine soft coral Alcyonium grandis. J. Nat. Prod. 2009, 72, 1357–1360. [CrossRef] [PubMed] Palermo, J.A.; Rodriguez Brasco, M.F.; Spagnuolo, C.; Seldes, A.M. Illudalane sesquiterpenoids from the soft coral Alcyonium paessleri: The first natural nitrate esters. J. Org. Chem. 2000, 65, 4482–4486. [CrossRef] [PubMed] Finkielsztein, L.M.; Bruno, A.M.; Renou, S.G.; Moltrasio de Iglesias, G.Y. Design, synthesis, and biological evaluation of alcyopterosin A and illudalane derivatives as anticancer agents. Bioorg. Med. Chem. 2006, 14, 1863–1870. [CrossRef] [PubMed] Tanaka, R.; Nakano, Y.; Suzuki, D.; Urabe, H.; Sato, F.J. Selective preparation of benzyltitanium compounds by the metalative Reppe reaction. Its Application to the first synthesis of alcyopterosin A. J. Am. Chem. Soc. 2002, 124, 9682–9683. [CrossRef] [PubMed] Nakao, Y.; Hirata, Y.; Ishihara, S.; Oda, S.; Yukawa, T.; Shirakawa, E.; Hiyama, T. Stannylative cycloaddition of enynes catalyzed by palladium-iminophosphine. J. Am. Chem. Soc. 2004, 126, 15650–15651. [CrossRef] [PubMed] Jones, A.L.; Snyder, J.K. Intramolecular rhodium-catalyzed [2+2+2] cyclizations of diynes with enones. J. Org. Chem. 2009, 74, 2907–2910. [CrossRef] [PubMed] Welsch, T.; Tran, H.A.; Witulski, B. Total syntheses of the marine illudalanes alcyopterosin I, L, M, N, and C. Org. Lett. 2010, 12, 5644–5647. [CrossRef] [PubMed] Von Salm, J.L.; Wilson, N.G.; Vesely, B.A.; Kyle, D.E.; Cuce, J.; Baker, B.J. Shagenes A and B, new tricyclic sesquiterpenes produced by an undescribed Antarctic octocoral. Org. Lett. 2014, 16, 2630–2633. [CrossRef] [PubMed] Hanssen, K.Ø.; Schuler, B.; Williams, A.J.; Demissie, T.B.; Hansen, E.; Andersen, J.H.; Svenson, J.; Blinov, K.; Repisky, M.; Mohn, F.; et al. A combined atomic force microscopy and computational approach for the structural elucidation of breitfussin A and B: Highly modified halogenated dipeptides from Thuiaria breitfussi. Angew. Chem. Int. Ed. 2012, 51, 12238–12241. [CrossRef] [PubMed] Pandey, S.K.; Guttormsen, Y.; Haug, B.E.; Hedberg, C.; Bayer, A. A concise total synthesis of breitfussin A and B. Org. Lett. 2015, 17, 122–125. [CrossRef] [PubMed] Khan, A.H.; Chen, J.S. Synthesis of breitfussin B by late-stage bromination. Org. Lett. 2015, 17, 3718–3721. [CrossRef] [PubMed] Angulo-Preckler, C.; Genta-Jouve, G.; Mahajan, N.; de la Cruz, M.; de Pedro, N.; Reyes, F.; Iken, K.; Avila, C.; Thomas, O.P. Gersemiols A-C and eunicellol A, diterpenoids from the Arctic soft coral Gersemia fruticosa. J. Nat. Prod. 2016, 79, 1132–1136. [CrossRef] [PubMed] Maier, M.S.; Roccatagliata, A.J.; Kuriss, A.; Chludil, H.; Seldes, A.M.; Pujol, C.A.; Damonte, E.B. Two new cytotoxic and virucidal trisulfated triterpene glycosides from the Antarctic sea cucumber Staurocucumis liouvillei. J. Nat. Prod. 2001, 64, 732–736. [CrossRef] [PubMed] Silchenko, A.S.; Kalinovsky, A.I.; Avilov, S.A.; Andryjashchenko, P.V.; Dmitrenok, P.S.; Kalinin, V.I.; Taboada, S.; Avila, C. Triterpene glycosides from Antarctic sea cucumbers IV. Turquetoside A, a 3-O-methylquinovose containing disulfated tetraoside from the sea cucumber Staurocucumis turqueti (Vaney, 1906) (=Cucumaria spatha). Biochem. Syst. Ecol. 2013, 51, 45–49. [CrossRef] Antonov, A.S.; Avilov, S.A.; Kalinovsky, A.I.; Anastyuk, S.D.; Dmitrenok, P.S.; Kalinin, V.I.; Taboada, S.; Bosh, A.; Avila, C.; Stonik, V.A. Triterpene glycosides from Antarctic sea cucumbers. 2. Structure of Achlioniceosides A(1), A(2), and A(3) from the sea cucumber Achlionice violaecuspidata (=Rhipidothuria racowitzai). J. Nat. Prod. 2009, 72, 33–38. [CrossRef] [PubMed] Gavagnin, M.; Carbone, M.; Mollo, E.; Cimino, G. Austrodoral and austrodoric acid: Nor-sesquiterpenes with a new carbon skeleton from the Antarctic nudibranch Austrodoris kerguelenensis. Tetrahedron Lett. 2003, 44, 1495–1498. [CrossRef] Alvarez-Manzaneda, E.J.; Chahboun, R.; Barranco, I.; Torres, E.C.; Alvarez, E.; Alvarez-Manzaneda, R. First enantiospecific synthesis of marine nor-sesquiterpene (+)-austrodoral from (–)-sclareol. Tetrahedron Lett. 2005, 46, 5321–5324. [CrossRef]

Mar. Drugs 2017, 15, 28

86.

87.

88. 89. 90.

91. 92. 93. 94. 95. 96. 97. 98. 99. 100.

101. 102. 103.

104.

105.

106. 107. 108.

28 of 30

Gavagnin, M.; Carbone, M.; Mollo, E.; Cimino, G. Further chemical studies on the Antarctic nudibranch Austrodoris kerguelenensis: New terpenoid acylglycerols and revision of the previous stereochemistry. Tetrahedron 2003, 59, 5579–5583. [CrossRef] Alvarez-Manzaneda, E.J.; Chahboun, R.; Barranco, I.; Torres, E.C.; Alvarez, E.; Alvarez-Manzaneda, R. First enantiospecific synthesis of the antitumor marine sponge metabolite (–)-15-oxopuupehenol from (–)-sclareol. Org. Lett. 2005, 7, 1477–1480. [CrossRef] [PubMed] Barrero, A.F.; Alvarez-Manzaneda, E.J.; Chahboun, R.; González Díaz, C. New routes toward drimanes and nor-drimanes from (–)-Sclareol. Synlett 2000, 11, 1561–1564. Diyabalanage, T.; Iken, K.B.; McClintock, J.B.; Amsler, C.D.; Baker, B.J. Palmadorins A–C, diterpene glycerides from the antarctic nudibranch Austrodoris kerguelenensis. J. Nat. Prod. 2010, 73, 416–421. [CrossRef] [PubMed] Maschek, J.A.; Mevers, E.; Diyabalanage, T.; Chen, L.; Ren, Y.; McClintock, J.B.; Amsler, C.D.; Wu, J.; Baker, B.J. Palmadorin chemodiversity from the Antarctic nudibranch Austrodoris kerguelenensis and inhibition of Jak2/STAT5-dependent HEL leukemia cells. Tetrahedron 2012, 68, 9095–9104. [CrossRef] Cutignano, A.; Moles, J.; Avila, C.; Fontana, A. Granuloside, a unique linear homosesterterpene from the Antarctic nudibranch Charcotia granulosa. J. Nat. Prod. 2015, 78, 1761–1764. [CrossRef] [PubMed] Skropeta, D.; Pastro, N.; Zivanovic, A. Kinase inhibitors from marine sponges. Mar. Drugs 2011, 9, 2131–2154. [CrossRef] [PubMed] Volk, C.A.; Köck, M. Viscosamine: The first naturally occurring trimeric 3-alkyl pyridinium alkaloid. Org. Lett. 2003, 5, 3567–3569. [CrossRef] [PubMed] Volk, C.A.; Köck, M. Viscosaline: New 3-alkyl pyridinium alkaloid from the Arctic sponge Haliclona viscosa. Org. Biomol. Chem. 2004, 2, 1827–1830. [CrossRef] [PubMed] Volk, C.A.; Lippert, H.; Lichte, E.; Köck, M. Two new haliclamines from the Arctic sponge Haliclona viscosa. Eur. J. Org. Chem. 2004, 3154–3158. [CrossRef] Schmidt, G.; Timm, C.; Köck, M. New haliclamines E and F from the Arctic sponge Haliclona viscosa. Org. Biomol. Chem. 2009, 7, 3061–3064. [CrossRef] Timm, C.; Mordhorst, T.; Köck, M. Synthesis of 3-alkyl pyridinium alkaloids from the arctic sponge Haliclona viscosa. Mar. Drugs 2010, 8, 483–497. [CrossRef] [PubMed] Shorey, B.J.; Lee, V.; Baldwin, J.E. Synthesis of the Arctic sponge alkaloid viscosaline and the marine sponge alkaloid theonelladin C. Tetrahedron 2007, 63, 5587–5592. [CrossRef] Díaz-Marrero, A.R.; Brito, I.; Dorta, E.; Cueto, M.; San-Martín, A.; Darias, J. Synthesis of the Arctic sponge alkaloid viscosaline and the marine sponge alkaloid theonelladin C. Tetrahedron Lett. 2003, 44, 5939–5942. Díaz-Marrero, A.R.; Brito, I.; Cueto, M.; San-Martín, A.; Darias, J. Suberitane network, a taxonomical marker for Antarctic sponges of the genus Suberites? Novel sesterterpenes from Suberites caminatus. Tetrahedron Lett. 2004, 45, 4707–4710. [CrossRef] Díaz-Marrero, A.R.; Dorta, E.; Cueto, M.; San-Martín, A.; Darias, J. Conformational analysis and absolute stereochemistry of ‘spongian’-related metabolites. Tetrahedron 2004, 60, 1073–1078. [CrossRef] Lee, H.S.; Ahn, J.W.; Lee, Y.H.; Rho, J.R.; Shin, J. New sesterterpenes from the Antarctic sponge Suberites sp. J. Nat. Prod. 2004, 67, 672–674. [CrossRef] [PubMed] Ma, W.S.; Mutka, T.; Vesley, B.; Amsler, M.O.; McClintock, J.B.; Amsler, C.D.; Perman, J.A.; Singh, M.P.; Maiese, W.M.; Zaworotko, M.J.; et al. Norselic acids A–E, highly oxidized anti-infective steroids that deter mesograzer predation, from the Antarctic sponge Crella sp. J. Nat. Prod. 2009, 72, 1842–1846. [CrossRef] [PubMed] von Salm, J.L.; Witowski, C.G.; Fleeman, R.M.; McClintock, J.B.; Amsler, C.D.; Shaw, L.N.; Baker, B.J. Darwinolide, a new diterpene scaffold that inhibits methicillin-resistant Staphylococcus aureus biofilm from the Antarctic sponge Dendrilla membranosa. Org. Lett. 2016, 18, 2596–2599. [CrossRef] [PubMed] Olsen, E.K.; Hansen, E.; Moodie, L.W.K.; Isaksson, J.; Sepˇci´c, K.; Cergolj, M.; Svenson, J.; Andersen, J.H. Marine AChE inhibitors isolated from Geodia barretti: Natural compounds and their synthetic analogs. Org. Biomol. Chem. 2016, 14, 1629–1640. [CrossRef] [PubMed] Wang, W.F.; Namikoshi, M. Bioactive nitrogenous metabolites from ascidians. Heterocycles 2007, 74, 53–88. Newman, D.J.; Cragg, G.M. Marine natural products and related compounds in clinical and advanced preclinical trials. J. Nat. Prod. 2004, 67, 1216–1238. [CrossRef] [PubMed] Davidson, B.S. Ascidians: Producers of amino acid derived metabolites. Chem. Rev. 1993, 93, 1771–1791. [CrossRef]

Mar. Drugs 2017, 15, 28

29 of 30

109. Reyes, F.; Fernández, R.; Rodríguez, A.; Francesch, A.; Taboada, S.; Ávila, C.; Cuevas, C. Aplicyanins A–F, new cytotoxic bromoindole derivatives from the marine tunicate Aplidium cyaneum. Tetrahedron 2008, 64, 5119–5123. [CrossRef] 110. Miyata, Y.; Diyabalanage, T.; Amsler, C.D.; McClintock, J.B.; Valeriote, F.A.; Baker, B.J. Ecdysteroids from the Antarctic tunicate Synoicum adareanum. J. Nat. Prod. 2007, 70, 1859–1864. [CrossRef] [PubMed] 111. Diyabalanage, T.; Amsler, C.D.; McClintock, J.B.; Baker, B.J. Palmerolide A, a cytotoxic macrolide from the Antarctic tunicate Synoicum adareanum. J. Am. Chem. Soc. 2006, 128, 5630–5631. [CrossRef] [PubMed] 112. Noguez, J.H.; Diyabalanage, T.K.K.; Miyata, Y.; Xie, X.S.; Valeriote, F.A.; Amsler, C.D.; McClintock, J.B.; Baker, B.J. Palmerolide macrolides from the Antarctic tunicate Synoicum adareanum. Bioorg. Med. Chem. 2011, 19, 6608–6614. [CrossRef] [PubMed] 113. Mi, Q.; Pezzuto, J.M.; Farnsworth, N.R.; Wani, M.C.; Kinghorn, A.D.; Swanson, S.M. Use of the in vivo hollow fiber assay in natural products anticancer drug discovery. J. Nat. Prod. 2009, 72, 573–580. [CrossRef] [PubMed] 114. Riesenfeld, C.S.; Murray, A.E.; Baker, B.J. Characterization of the microbial community and polyketide biosynthetic potential in the palmerolide-producing tunicate Synoicum adareanum. J. Nat. Prod. 2008, 71, 1812–1818. [CrossRef] [PubMed] 115. Lisboa, M.P.; Dudley, G.B. Synthesis of cytotoxic palmerolides. Chem. Eur. J. 2013, 19, 16146–16168. [CrossRef] [PubMed] 116. Jiang, X.; Liu, B.; Lebreton, S.; De Brabander, J.K. Total synthesis and structure revision of the marine metabolite palmerolide A. J. Am. Chem. Soc. 2007, 129, 6386–6387. [CrossRef] [PubMed] 117. Nicolaou, K.C.; Guduru, R.; Sun, Y.P.; Banerji, B.; Chen, D.Y.K. Total synthesis of the originally proposed and revised structures of palmerolide A. Angew. Chem. Int. Ed. 2007, 46, 5896–5900. [CrossRef] [PubMed] 118. Nicolaou, K.C.; Sun, Y.P.; Guduru, R.; Banerji, B.; Chen, D.Y.K. Total synthesis of the originally proposed and revised structures of palmerolide A and isomers thereof. J. Am. Chem. Soc. 2008, 130, 3633–3644. [CrossRef] [PubMed] 119. Ravu, V.R.; Leung, G.Y.C.; Lim, C.S.; Ng, S.Y.; Sum, R.J.; Chen, D.Y.K. Chemical synthesis and biological evaluation of second-generation palmerolide A analogues. Eur. J. Org. Chem. 2011, 2011, 463–468. [CrossRef] 120. Penner, M.; Rauniyar, V.; Kaspar, L.T.; Hall, D.G. Catalytic asymmetric synthesis of palmerolide A via organoboron methodology. J. Am. Chem. Soc. 2009, 131, 14216–14217. [CrossRef] [PubMed] 121. Jägel, J.; Maier, M.E. Formal total synthesis of palmerolide A. Synthesis 2009, 17, 2881–2892. 122. Gowrisankar, P.; Pujari, S.A.; Kaliappan, K.P. A formal total synthesis of palmerolide A. Chem. Eur. J. 2010, 16, 5858–5862. [CrossRef] [PubMed] 123. Pujari, S.A.; Gowrisankar, P.; Kaliappan, K.P. A Shimizu non-aldol approach to the formal total synthesis of palmerolide A. Chem. Asian J. 2011, 6, 3137–3151. [CrossRef] [PubMed] 124. Prasad, K.R.; Pawar, A.B. Enantioselective formal synthesis of palmerolide A. Org. Lett. 2011, 13, 4252–4255. [CrossRef] [PubMed] 125. Pawar, A.B.; Prasad, K.R. Formal total synthesis of palmerolide A. Chem. Eur. J. 2012, 18, 15202–15206. [CrossRef] [PubMed] 126. Lisboa, M.P.; Jones, D.M.; Dudley, G.B. Formal synthesis of palmerolide A, featuring alkynogenic fragmentation and syn-selective vinylogous aldol chemistry. Org. Lett. 2013, 15, 886–889. [CrossRef] [PubMed] 127. Kaliappan, K.P.; Gowrisankar, P. Synthetic studies on a marine natural product, palmerolide A: Synthesis of C1-C9 and C15-C21 fragments. Synlett 2007, 1537–1540. [CrossRef] 128. Jägel, J.; Schmauder, A.; Binanzer, M.; Maier, M.E. A concise route to the C3–C23 fragment of the macrolide palmerolide A. Tetrahedron 2007, 63, 13006–13017. [CrossRef] 129. Cantagrel, G.; Meyer, C.; Cossy, J. Synthetic studies towards the marine natural product palmerolide A: Synthesis of the C3-C15 and C16-C23 fragments. Synlett 2007, 19, 2983–2986. 130. Lebar, M.D.; Baker, B.J. Synthesis of the C3–14 fragment of palmerolide A using a chiral pool based strategy. Tetrahedron 2010, 66, 1557–1562. [CrossRef] 131. Prasad, K.R.; Pawar, A.B. Stereoselective synthesis of C1–C18 region of palmerolide A from tartaric acid. Synlett 2010, 7, 1093–1095. [CrossRef]

Mar. Drugs 2017, 15, 28

30 of 30

132. Wen, Z.K.; Xu, Y.H.; Loh, T.P. Palladium-catalyzed cross-coupling of unactivated alkenes with acrylates: Application to the synthesis of the C13–C21 fragment of palmerolide A. Chem. Eur. J. 2012, 18, 13284–13287. [CrossRef] [PubMed] 133. Jones, D.M.; Dudley, G.B. Synthesis of the C1–C15 region of palmerolide A using refined Claisen-type addition-bond cleavage methodology. Synlett 2010, 2, 223–226. 134. Lisboa, M.P.; Jeong-Im, J.H.; Jones, D.M.; Dudley, G.B. Toward a new palmerolide assembly strategy: Synthesis of C16–C24. Synlett 2012, 23, 1493–1496. 135. Jena, B.K.; Mohapatra, D.K. Synthesis of the C1–C15 fragment of palmerolide A via protecting group dependent RCM reaction. Tetrahedron Lett. 2013, 54, 3415–3418. [CrossRef] 136. Florence, G.J.; Wlochal, J. Synthesis of the originally proposed structure of palmerolide C. Chem. Eur. J. 2012, 18, 14250–14254. [CrossRef] [PubMed] 137. Appleton, D.R.; Chuen, C.S.; Berridge, M.V.; Webb, V.L.; Copp, B.R. Rossinones A and B, biologically active meroterpenoids from the Antarctic ascidian, Aplidium species. J. Org. Chem. 2009, 74, 9195–9198. [CrossRef] [PubMed] 138. Núñez-Pons, L.; Carbone, M.; Vázquez, J.; Rodríguez, J.; Nieto, R.M.; Varela, M.M.; Gavagnin, M.; Avila, C. Natural products from Antarctic colonial Ascidians of the genera Aplidium and Synoicum: Variability and defensive role. Mar. Drugs 2012, 10, 1741–1764. [CrossRef] [PubMed] 139. Zhang, Z.; Chen, J.; Yang, Z.; Tang, Y. Rapid biomimetic total synthesis of (±)-rossinone B. Org. Lett. 2010, 12, 5554–5557. [CrossRef] [PubMed] 140. Carbone, M.; Núñez-Pons, L.; Paone, M.; Castelluccio, F.; Avila, C.; Gavagnin, M. Rossinone-related meroterpenes from the Antarctic ascidian Aplidium fuegiense. Tetrahedron 2012, 68, 3541–3544. [CrossRef] 141. Tadesse, M.; Strøm, M.B.; Svenson, J.; Jaspars, M.; Milne, B.F.; Tørfoss, V.; Andersen, J.H.; Hansen, E.; Stensvåg, K.; Haug, T. Synoxazolidinones A and B: Novel bioactive alkaloids from the ascidian Synoicum pulmonaria. Org. Lett. 2010, 21, 4752–4755. [CrossRef] [PubMed] 142. Tadesse, M.; Svenson, J.; Jaspars, M.; Strøm, M.B.; Abdelrahman, M.H.; Andersen, J.H.; Hansen, E.; Kristiansen, P.E.; Stensvåg, K.; Haug, T. Synoxazolidinone C; a bicyclic member of the synoxazolidinone family with antibacterial and anticancer activities. Tetrahedron Lett. 2011, 52, 1804–1806. [CrossRef] 143. Hopmann, K.H.; Šebestík, J.; Novotná, J.; Stensen, W.; Urbanov˝a, M.; Svenson, J.; Svendsen, J.S.; Bouˇr, P.; Ruud, K. Determining the absolute configuration of two marine compounds using vibrational chiroptical spectroscopy. J. Org. Chem. 2012, 77, 858–886. [CrossRef] [PubMed] 144. Trepos, R.; Cervin, G.; Hellio, C.; Pavia, H.; Stensen, W.; Stensvåg, K.; Svendsen, J.S.; Haug, T.; Svenson, J. Antifouling compounds from the sub-Arctic ascidian Synoicum pulmonaria: Synoxazolidinones A and C, pulmonarins A and B, and synthetic analogues. J. Nat. Prod. 2014, 77, 2105–2113. [CrossRef] [PubMed] 145. Tadesse, M.; Svenson, J.; Sepˇci´c, K.; Trembleau, L.; Engqvist, M.; Andersen, J.H.; Jaspars, M.; Stensvåg, K.; Haug, T. Isolation and synthesis of pulmonarins A and B, acetylcholinesterase inhibitors from the colonial ascidian Synoicum pulmonaria. J. Nat. Prod. 2014, 77, 364–369. [CrossRef] [PubMed] 146. Harvey, A.L.; Edrada-Ebel, R.; Quinn, R.J. The re-emergence of natural products for drug discovery in the genomics era. Nat. Rev. Drug Discov. 2015, 14, 111–129. [CrossRef] [PubMed] 147. Bouslimani, A.; Sanchez, L.M.; Garg, N.; Dorrestein, P.C. Mass spectrometry of natural products: Current, emerging and future technologies. Nat. Prod. Rep. 2014, 31, 718–729. [CrossRef] [PubMed] 148. Weissman, K.J. The structural biology of biosynthetic megaenzymes. Nat. Chem. Biol. 2015, 11, 660–670. [CrossRef] [PubMed] © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

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