Secondary Metabolites from Polar Organisms

marine drugs

Review Secondary Metabolites from Polar Organisms

Yuan Tian 1,*, Yan-Ling Li 1 and Feng-Chun Zhao 2

1 College of Life Science, Taishan Medical University, Taian 271016, Shandong, China; [email protected] 2 College of Life Science, Shandong Agricultural University, Taian 271018, Shandong, China; [email protected] * Correspondence: [email protected]; Tel.: +86-358-623-5778

Academic Editor: Orazio Taglialatela-Scafati Received: 7 January 2017; Accepted: 29 January 2017; Published: 23 February 2017

Abstract: Polar organisms have been found to develop unique defences against the extreme environment environment, leading to the biosynthesis of novel molecules with diverse bioactivities. This review covers the 219 novel natural products described since 2001, from the Arctic and the Antarctic microoganisms, lichen, moss and marine faunas. The structures of the new compounds and details of the source organism, along with any relevant biological activities are presented. Where reported, synthetic and biosynthetic studies on the polar metabolites have also been included.

Keywords: natural products; secondary metabolism; structure elucidation; biological activity; biosynthesis; chemical synthesis

1. Introduction Organisms from special ecosystems such as the polar regions are a rich source of various chemical scaffolds and novel natural products with promising bioactivities. Polar regions, which refer to the Arctic, the Antarctic and their subregions, are remote and challenging areas on the earth. To survive under the constant influence of low temperatures, strong winds, low nutrient and high UV radiation or combinations of these factors [1], polar organisms require a diverse array of biochemical and physiological adaptations that are essential for survival. These adaptations are often accompanied by modifications to both gene regulation and metabolic pathways, increasing the possibility of finding unique functional metabolites of pharmaceutical importance. Polar regions are complex ecosystems that harbor diverse groups of fauna and microorganisms including bacteria, actinomycetes and fungi. Physiological adaptations have enabled psychrophilic organisms to thrive in the polar regions, especially microorganisms which are high in number and usually uncharacterized [2–5]. However, when compared to the large number of polar microorganisms which have been reported, very few have been screened for the production of interesting secondary metabolites. The advent of modern techniques provides the opportunity to find novel metabolites. From 2001 to 2016, a vast amount of new biological natural compounds with various activities, such as anti-bacteria, anti-tumor, anti-virus and so on, have been isolated from polar organisms including microorganisms, lichen, moss, bryozoans, cnidarians, echinoderms, molluscs, sponges and tunicates. Natural products from the Arctic or the Antarctic organisms have been the subject of several review articles. In 2007, Lebar et al. reviewed the studies on structure and bioactivity of cold-water marine natural products, including many polar examples [6]. In 2009, Wilson and Brimble reviewed molecules derived from the extremes of life, including some polar examples [7]. In 2011, advances in the chemistry and bioactivity of arctic sponge were reviewed by Hamann and his co-workers [8]. In 2013, Liu et al. reviewed a number of new secondary metabolites with various activities derived from both Antarcitc and Arctic organisms [9], while in 2014, Skropeta and Wei published a review on natural products isolated from deep-sea sources, which included some polar organisms [10]. Moreover,

Mar. Drugs 2017, 15, 28; doi:10.3390/md15030028 www.mdpi.com/journal/marinedrugs Mar. Drugs 2017, 15, 28 2 of 30

published a review on natural products isolated from deep‐sea sources, which included some polar organisms [10]. Moreover, Blunt and his co‐workers published periodical reviews on the Mar.characteristics Drugs 2017, 15, 28of various marine natural products with some polar examples [11–13]. 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 Bluntpolar and organisms. his co-workers We also published summarize periodical the chemical reviews synthesis on the characteristics and the biosynthetic of various relationship marine natural of productsmetabolites. with someThe Metabolites polar examples Name [11 Index–13]. in combination with the Source Index, the Biological ActivityHowever, Index comprehensive and the References reviews on isolation of natural in products the accompanying from polar tables, regions will were help rare;understand therefore, the we describefascinating here thechemistry source, and chemistry, biology of and natural biology products of the derived newly discovered from polar biomoleculesorganisms. 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 ReferencesThe microbial on isolation diversity in the of polar accompanying environments tables, is a will fertile help ground understand for new the bioactive fascinating compounds, chemistry andgenes, biology proteins, of natural microorganisms products derived and other from products polar organisms. with potential for commercial use [14].

2. Microorganisms2.1. Unicellular Bacteria TheThe microbial culture broth diversity of the of marine polar environmentsbacterium Bacillus is a sp., fertile isolated ground from for the new sea bioactivemud near compounds,the Arctic genes,pole, proteins, was found microorganisms to yield three andnew other cyclic products acylpeptides with named potential as formixirins commercial A (1), B use (2) [ 14and]. C (3) (Figure 1) [15]. All of the three compounds were found to display significant cytotoxicity against 2.1.human Unicellular colon Bacteria tumor cells (HCT‐116) with half maximal inhibitory concentration (IC50) values of 0.68, 1.6, 1.3 μg/mL, respectively. The culture broth of the marine bacterium Bacillus sp., isolated from the sea mud near the Arctic Four new aromatic nitro compounds (4–7) (Figure 1) along with fifteen known ones were pole,reported was found from the to Salegentibacter yield three new strain cyclic T436, acylpeptides isolated from nameda bottom as section mixirins of a Asea ( 1ice), Bfloe (2 collected) and C (3) (Figurefrom1 )[the15 Arctic]. All Ocean. of the threeThe new compounds natural wereproducts found showed to display weak signiﬁcant antimicrobial cytotoxicity and cytotoxic against humanactivities colon [16]. tumor Further cells study (HCT-116) of the same with bacterium half maximal isolate inhibitory yielded another concentration seven new (IC50 aromatic) values nitro of 0.68, 1.6,compounds 1.3 µg/mL, (8 respectively.–14) (Figure 1) [17].

FigureFigure 1. 1.Secondary Secondary metabolites metabolites derivedderived from the the Arctic Arctic bacteria bacteria (compounds (compounds 1–114–14). ).

A novel diketopiperazine, named cyclo‐(D‐pipecolinyl‐L‐isoleucine) (15) (Figure 2), and two newFour linear new peptides aromatic ( nitro16, 17 compounds) (Figure 2), (along4–7) (Figure with seven1) along known with diketopiperazines ﬁfteen known ones were were isolated reported fromfrom the theSalegentibacter cell‐free culturestrain supernatant T436, isolated of the from Antarctic a bottom psychrophilic section of bacterium a sea ice Pseudoalteromonas ﬂoe collected from thehaloplanktis Arctic Ocean. TAC125 The new[18]. Peptide natural products17 and a known showed phenyl weak‐containing antimicrobial diketopiperazine and cytotoxic showed activities free [16 ]. Furtherradical study scavenging of the sameproperties, bacterium with the isolate phenyl yielded group anotheressential seven for activity. new aromatic nitro compounds (8–14) (Figure1)[17]. A novel diketopiperazine, named cyclo-(D-pipecolinyl-L-isoleucine) (15) (Figure2), and two new linear peptides (16, 17) (Figure2), along with seven known diketopiperazines were isolated from the cell-free culture supernatant of the Antarctic psychrophilic bacterium Pseudoalteromonas haloplanktis TAC125 [18]. Peptide 17 and a known phenyl-containing diketopiperazine showed free radical scavenging properties, with the phenyl group essential for activity. Mar. Drugs 2017, 15, 28 3 of 30 Mar. Drugs 2017, 15, 28 3 of 30

Figure 2. Secondary metabolites derived from the Antarctic bacteria (compounds 15–22). Figure 2. Secondary metabolites derived from the Antarctic bacteria (compounds 15–22). From the Antarctic cyanobacterium Nostoc CCC 537, an antibacterial lead molecule (18) (Figure 2) wasFrom obtained. the Antarctic Compound cyanobacterium 18 exhibited NostocantibacterialCCC 537,activity an antibacterial against two leadGram molecule positive (pathogenic18) (Figure 2) wasstrains obtained. and seven Compound Gram negative18 exhibited strains antibacterial including three activity multi against‐drug resistant two Gram strains positive of Escherichia pathogenic strainscoli, with and sevenminimal Gram inhibition negative concentration strains including (MIC) values three multi-drug in the range resistant of 0.5–16.0 strains μg/mL of [19].Escherichia coli, with minimalTwo pigments inhibition named concentration violacein (MIC)(19) and values flexirubin in the range(20) (Figure of 0.5–16.0 2) wereµg/mL isolated [19]. from two AntarcticTwo pigments bacterial named strains. violacein The two (19 )compounds and ﬂexirubin displayed (20) (Figure antibacterial2) were isolated activities from against two Antarctic some bacterialmycobacteria strains. with The low two MIC compounds values (ranging displayed from antibacterial 2.6 to 34.4 μg/mL), activities and againstmight be some valuable mycobacteria natural withlead low compounds MIC values for (ranging new antimycobacterial from 2.6 to 34.4 drugsµg/mL), used and for mighttuberculosis be valuable chemotherapy natural lead [20]. compounds for newBioassay antimycobacterial‐guided purification drugs used of forAntarctic tuberculosis strain chemotherapyPseudomonas BNT1 [20]. extracts produced three rhamnolipidsBioassay-guided including puriﬁcation two new ones of Antarctic (21, 22). Compound strain Pseudomonas 21 was effectiveBNT1 against extracts the producedtested human 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 moderate2.2. Actinomycetes antimicrobial effect against S. aureus with an MBC value of 100 µg/mL [21]. 2.2. ActinomycetesIn this century, actinomyces derived from polar regions have yielded an array of interesting new metabolites. Three new pyrrolosesquiterpenes, glyciapyrroles A (23), B (24), and C (25) (Figure 3),In along this century,with three actinomyces known ones, derived iketopiperazines from polar cyclo(leucyl regions have‐prolyl), yielded cyclo(isoleucyl an array of interesting‐prolyl), and new metabolites.cyclo(phenylalanyl Three new‐prolyl), pyrrolosesquiterpenes, were isolated from the glyciapyrroles Streptomyces Asp. (23 NPS008187), B (24), and originating C (25) (Figure from a 3), alongmarine with sediment three known collected ones, in Alaska iketopiperazines near the Arctic cyclo(leucyl-prolyl), [22]. cyclo(isoleucyl-prolyl), and 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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FigureFigure 3. 3.Secondary Secondary metabolites metabolites derived derived fromfrom the Arctic actinomyces actinomyces (compounds (compounds 2323–27–27, 30, ,30 31,).31 ).

The Arctic seaweed‐associated actinomycete Nocardiopsis sp. 03N67 was found to produce a rareThe bioactive Arctic seaweed-associated diketopiperazine, cyclo actinomycete‐(L‐Pro‐L‐Met)Nocardiopsis (26) (Figuresp. 03N67 3). It wasinhibited found tumor to produce necrosis a rare bioactivefactor‐α diketopiperazine,(TNF‐α)‐induced cyclo-(tube formationL-Pro-L-Met) and (invasion26) (Figure at 310). μ ItM, inhibited a concentration tumor necrosis at which factor- no α (TNF-cytotoxicityα)-induced was tube observed. formation Anti‐ andangiogenesis invasion activity at 10 µM, against a concentration human umbilical at which vein no endothelial cytotoxicity cells was observed.(HUVECs) Anti-angiogenesis of compound 26 is activity an encouraging against humanbioprobe umbilical to develop vein new endothelial anticancer therapeutics cells (HUVECs) from of compoundsuch type26 ofis small an encouraging molecules in bioprobenear future to [23]. develop new anticancer therapeutics from such type of small moleculesThe marine in nearactinomycete future [23 ].Nocardia dassonvillei BM‐17, obtained from a sediment sample collectedThe marine in the actinomycete Arctic Ocean,Nocardia has furnished dassonvillei a newBM-17, secondary obtained metabolite, from a sediment N‐(2‐hydroxyphenyl) sample collected‐ in the2‐phenazinamine Arctic Ocean, has(27) furnished (Figure 3), a new and secondary six known metabolite, antibiotics.N The-(2-hydroxyphenyl)-2-phenazinamine new compound showed weak (27)antifungal (Figure3), activity and six knownagainst antibiotics.Candida albicans The, new with compound a MIC value showed of 64 weak μg/mL antifungal and low activity cancer against cell Candidacytotoxicity albicans against, with aHepG2, MIC value A549, of HCT 64 µg/mL‐116 and and COC1 low cancercells, with cell cytotoxicityIC50 values of against 40.33, 38.53, HepG2, 27.82 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) (Scheme1), 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 the viral progeny which was produced by the the infected MDCK cells with influenza A/WSN/33 virus. The half effective concentration (EC50) infectedvalue of MDCK 29 for the cells inhibition with influenza of viral plaque A/WSN/33 formation virus. was quite The halfcomparable effective to concentrationthat of the positive (EC 50) valuecontrol of 29oseltamivirfor the inhibitionphosphate of(Osv viral‐P) [25]. plaque Their formation biological was activities quite have comparable attracted to interest that of to the positivesynthesize control these oseltamivir compounds. phosphate Efficient (Osv-P) stereoselective [25]. Their synthesis biological of activities the natural have enantiomer attracted interest of to synthesizenitrosporeusines these A compounds. and B was performed Efficient by stereoselective Reddy’s groups. synthesis An overall of thefive‐ naturalstep process enantiomer starting of nitrosporeusinesfrom 5,6‐dihydrocyclopenta[ A and B wasc]pyrrole performed‐1,3(2 byH,4 Reddy’sH)‐dione groups. and p‐hydroxybenzoic An overall five-step acid is process summarized starting fromin 5,6-dihydrocyclopenta[Scheme 1 [26]. c]pyrrole-1,3(2H,4H)-dione and p-hydroxybenzoic acid is summarized in SchemeTwo1[26 ].new secondary metabolites, arcticoside (30) and C‐1027 chromophore‐V (31) (Figure 3), wereTwo isolated new secondary along with metabolites, three kown compounds, arcticoside C (30‐1027) and chromophore C-1027 chromophore-V‐III, fijiolides A ( 31and) (Figure B from3 ), werethe isolated culture alongof an Arctic with threemarine kown actinomycete compounds, Streptomyces C-1027 chromophore-III,strain. Compounds fijiolides 30 and 31 A andinhibited B from theCandida culture albicans of an Arctic isocitrate marine lyase, actinomycete an enzyme thatStreptomyces plays an importantstrain. Compounds role in the pathogenicity30 and 31 inhibited of C. Candidaalbicans. albicans Furthermore,isocitrate 31 lyase,exhibited an enzymesignificant that cytotoxicity plays an against important breast role carcinoma in the pathogenicity MDA‐MB231 of cells and colorectal carcinoma HCT‐116 cells, with IC50 values of 0.9 and 2.7 μM, respectively [27]. C. albicans. Furthermore, 31 exhibited significant cytotoxicity against breast carcinoma MDA-MB231 cells and colorectal carcinoma HCT-116 cells, with IC50 values of 0.9 and 2.7 µM, respectively [27].

Mar. Drugs 2017, 15, 28 5 of 30 Mar. Drugs 2017, 15, 28 5 of 30

O O AcO O HO O H Mar. Drugs 2017, 15, 28 N 5 of 30 HO O O a b NH NH c NH NH O O S H AcO O HO O H HO N O O O O O OH a b c O O NH NH NH NH e NitrosporeusineS A (28) H O SH O OH + H O O N OH O O HO O O O e Nitrosporeusine A (28) d O SH S H O OH + H N HO O OOH O OH d OH NitrosporeusineS B (29) H OH SchemeScheme 1. Synthesis1. Synthesis of of natural natural products products nitrosporeusines nitrosporeusines A A ( (2828)) and and B B (29 (29). ).Reagents Reagents and andO conditions: conditions: OH 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, (c) AmanoScheme PS1. Synthesis lipase, phosphate of natural products buffer, 92%; nitrosporeusines (d) Lawesson A's ( reagent,28) and B acetonitrile, (29). Reagents microwave, and conditions: 100 ◦ C, 53%; (e) H2O, room temperature (rt), 65%. (a) SeO2, 1,4‐dioxane, microwave, 110 °C, 61%; (b) Amano PS lipase, THF, CH2=CHOAc, 38%; (c) 53%; (e)H2O, room temperature (rt), 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) H2O, room temperature (rt), 65%. newA Streptomycesangucyclinone griseus antibioticstrain frigocyclinone NTK 97, recovered (32) (Figure from 4), an consisting Antarctic of terrestrial a tetrangomycin sample, moiety yielded a newattached angucyclinoneA Streptomyces through antibiotica griseus C‐glycosidic strain frigocyclinone NTK linkage 97, recovered with (32 )the (Figure fromaminodeoxysugar 4an), consistingAntarctic terrestrial ofossamine. a tetrangomycin sample, Frigocyclinone yielded moiety a attachednewrevealed angucyclinone through good ainhibitory C-glycosidic antibiotic activities linkagefrigocyclinone against with theBacillus (32 aminodeoxysugar) (Figure subtilis 4), and consisting Staphylococcus ossamine. of a tetrangomycin Frigocyclinone aureus [28]. Another moiety revealed goodattachedAntarctic inhibitory throughStreptomyces activities a C ‐griseusglycosidic against strainBacillus linkage NTK14 subtilis with was andtheshown aminodeoxysugarStaphylococcus to contain the aureus novelossamine.[28‐type]. Another Frigocyclinoneangucyclinone Antarctic Streptomycesrevealedgephyromycin good griseus (inhibitory33strain) (Figure NTK14 activities 4), and was two against shown known Bacillus to compounds, contain subtilis the novel-type andfridamycin Staphylococcus angucyclinoneE and dehydrorabelomycin.aureus [28]. gephyromycin Another (33)AntarcticGephyromycin, (Figure4 ),Streptomyces and twowith known angriseus unprecedented compounds, strain NTK14 fridamycinintramolecular was shown E andto ether contain dehydrorabelomycin. bridge, the noveldisplayed‐type angucyclinoneglutaminergic Gephyromycin, withgephyromycinactivity an unprecedented (agonist) (33 towards) (Figure intramolecular neuronal 4), and two cells. ether known In bridge, addition, compounds, displayed 33 exhibited fridamycin glutaminergic no acute E and cytostatic activity dehydrorabelomycin. (agonist) activities, towards and neuronalGephyromycin,the lack cells. of cytotoxicity In addition, with anmade33 unprecedentedexhibited its neuroprotective no acute intramolecular cytostatic properties activities, ethereven morebridge, and valuable thedisplayed lack [29]. of cytotoxicity glutaminergic made A new sulphur‐containing natural alkaloid named microbiaeratin (34) (Figure 4) was its neuroprotectiveactivity (agonist) propertiestowards neuronal even more cells. valuable In addition, [29]. 33 exhibited no acute cytostatic activities, and characterized, together with the known bacillamide from the culture of Microbispora aerata strain theA lack new of cytotoxicity sulphur-containing made its neuroprotective natural alkaloid properties named even microbiaeratin more valuable [29]. (34) (Figure4) was IMBAS‐11A, isolated from the Antarctic Livingston Island. A low antiproliferative and cytotoxic characterized,A new togethersulphur‐containing with the known natural bacillamide alkaloid named from themicrobiaeratin culture of Microbispora (34) (Figure aerata 4) wasstrain characterized,effects of 34 was together determined with the with known L‐929 bacillamide mouse fibroblast from thecells, culture K‐562 ofhuman Microbispora leukemia aerata cells strain and IMBAS-11A, isolated from the Antarctic Livingston Island. A low antiproliferative and cytotoxic effects IMBASHeLa human‐11A, isolatedcervix carcinoma from the cellsAntarctic [30]. 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 effectsThe of Nocardiopsis34 was determined sp. SCSIO with KS107 L‐929 was mouse isolated fibroblast from Antarctic cells, K seashore‐562 human sediment. leukemia Fermentation cells and cervix carcinoma cells [30]. HeLaand isolation human ofcervix this carcinomastrain provided cells [30].two new α‐pyrones germicidin H (35), 4‐hydroxymucidone (36), The Nocardiopsis sp. SCSIO KS107 was isolated from Antarctic seashore sediment. Fermentation and Thea known Nocardiopsis compound sp. SCSIO 7‐hydroxymucidone. KS107 was isolated Only from the Antarctic known seashorecompound sediment. showed Fermentation antibacterial α andandactivity isolation isolation against of of this Micrococcusthis strain strain provided provided luteus with two two an new new MIC α‐-pyrones valuepyrones of 16 germicidin μg/mL [31]. H H ( 35 (35),), 4‐ 4-hydroxymucidonehydroxymucidone (36 (),36 ), andand a known a known compound compound 7-hydroxymucidone. 7‐hydroxymucidone. Only the the known known compound compound showed showed antibacterial antibacterial activityactivity against againstMicrococcus Micrococcus luteus luteuswith with an an MIC MIC valuevalue of 16 μµg/mLg/mL [31]. [31 ].

Figure 4. Secondary metabolites derived from the Antarctic actinomyces (compounds 32–36).

2.3. Fungi FigureFigure 4. 4.Secondary Secondary metabolites metabolites derived derived fromfrom the Antarctic actinomyces actinomyces (compounds (compounds 32–3236–).36 ). The rapid growth and ability to metabolize a wide variety of substrates have enabled fungi to 2.3. Fungi 2.3.become Fungi the predominant components of the microorganisms in polar regions. The psychrotolerant fungusThe Penicillium rapid growth algidum and ,ability collected to metabolize from soil aunder wide varietya Ribes ofsp. substrates in Greenland have enablednear the fungi Arctic, to becomeyieldedThe rapid thethe newpredominant growth cyclic and nitropeptide, components ability to psychrophilin metabolize of the microorganisms a wideD (37) variety (Figure in polar of5), substratestogether regions. with haveThe two psychrotolerant enabled known cyclic fungi to become the predominant components of the microorganisms in polar regions. The psychrotolerant fungus Penicillium algidum, collected from soil under a Ribes sp. in Greenland near the Arctic, yielded the new cyclic nitropeptide, psychrophilin D (37) (Figure 5), together with two known cyclic

Mar. Drugs 2017, 15, 28 6 of 30 fungusMar. DrugsPenicillium 2017, 15, 28 algidum , collected from soil under a Ribes sp. in Greenland near the Arctic,6 yielded of 30 the new cyclic nitropeptide, psychrophilin D (37) (Figure5), 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 assays. Psychrophilin D exhibited a moderate activity with half infective half infective dose (ID50) value of 10.1 μg/mL in the P388 murine leukaemia cell assay. dose (ID ) value of 10.1 µg/mL in the P388 murine leukaemia cell assay. Cycloaspeptide A and D Cycloaspeptide50 A and D exhibited moderate activity (IC50 = 3.5 and 4.7 μg/mL, respectively) against exhibitedPlasmodium moderate falciparum activity [32]. (IC 50 = 3.5 and 4.7 µg/mL, respectively) against Plasmodium falciparum [32].

HN H H O NO2 N HN HN O HN O O HO O HO OH O O O O Cytochalasins Z (39) Psychrophilin D (37) Cytochalasins Z24 (38) 25

O H

O O HN O O O OH HO O HO O OH O O O Cytochalasins Z26 (40) Libertellenone G (41) Libertellenone H (42)

OH O N

O O OH OH O O O O O OH O O OH Eutypenoid A (43) Eutypenoid A (44) Eutypenoid A (45)

OH OH O O

O O O HN HN O H H H H O O O (48) O O H H

Lindgomycin (46) 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, wereThree isolated new cytochalasins from the Arctic Z24,Z fungus25,Z26 Eutypella(38–40) (Figuresp. D‐1.5) andThese one compounds known compound, were evaluated scoparasin for B, werecytotoxic isolated activities from the against Arctic fungusseveral Eutypellahuman tumorsp. D-1. cell These lines. compounds Among them, were compound evaluated 38 for showed cytotoxic activitiesmoderate against cytotoxicity several toward human human tumor breast cell lines.cancer AmongMCF‐7 cell them, line compoundwith IC50 value38 showedof 9.33 m moderateΜ [33]. cytotoxicityFurther investigation toward human of Eutypella breast sp. cancer D‐1 led MCF-7 to the cell discovery line with of ICtwo50 newvalue diterpenes, of 9.33 mM libertellenone [33]. Further investigationG (41) and of libertellenoneEutypella sp. H D-1 (42 led) (Figure to the discovery5), together of twowith new two diterpenes,known pimarane libertellenone diterpenes. G ( 41) andCompound libertellenone 41 Hexhibited (42) (Figure antibacterial5), together activity with twoagainst known Escherichia pimarane coli, diterpenes. Bacillus subtilis Compound and 41 exhibitedStaphylococcus antibacterial aureus. Compound activity against 42 showedEscherichia slight coli cytotoxicity, Bacillus subtilis towardand mostStaphylococcus cell lines, with aureus . Compoundhalf‐maximal42 showedinhibitory slight concentration cytotoxicity values toward ranging most from cell 3.31 lines, to with 44.1 μ half-maximalM. In addition, inhibitory the concentrationcytotoxicity valuesof 42 is rangingmost likely from dependent 3.31 to 44.1on theµM. presence In addition, of its cyclopropane the cytotoxicity ring ofas 42deducedis most from 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 compoundrecently 44described exhibited ascosetin potent ( immunosuppressive47) (Figure 5) [37] were activities extracted [35 ].from different Lindgomycetaceae strains, which were isolated from an Arctic sponge. Both the compounds exhibited strong antibiotic

Mar. Drugs 2017, 15, 28 7 of 30

An unusual polyketide with a new carbon skeleton, lindgomycin (46) (Figure5)[ 36], and the recently described ascosetin (47) (Figure5)[ 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

StaphylococcusMar. Drugs aureus2017, 15, )28 and human pathogenic yeast Candida albicans. 7 of 30 Trichoderma polysporum strain OPU1571, recovered from a moss, Sanionia uncinata, growing in theactivities high arctic against wetlands the clinically on Spitsbergen relevant Gram Island,‐positive Svalbard, bacteria Norway, (including yielded methicillin eleven‐resistant compounds, includingStaphylococcus a new one aureus (48)) (Figureand human5). Thepathogenicin vitro yeastinvestigation Candida albicans 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 [ 38new]. one (48) (Figure 5). The in vitro investigation suggested that compound 48 showed a Fermentationconcentration‐dependent of the Antarctic growth‐inhibitory ascomycete effect funguson snow Geomycesrot pathogensp. Pythium yielded iwayamai five at new 5 days asterric [38]. acid derivatives,Fermentation ethyl asterrate of the ( 49Antarctic), n-butyl ascomycete asterrate fungus (50), Geomyces and geomycins sp. yielded A–C five (51 new–53 asterric) (Figure acid6). The new metabolitesderivatives, wereethyl testedasterrate for (49 their), n‐butyl antibacterial asterrate and(50), antifungaland geomycins activities. A–C (51 Geomycin–53) (Figure B 6). (52 The) showed significantnew metabolites antifungal were activity tested against for theirAspergillus antibacterial fumigatus and antifungalATCC 10894, activities. with Geomycin IC50/MIC B ( values52) of showed significant antifungal activity against Aspergillus fumigatus ATCC 10894, with IC50/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 Streptococcus pneumoniae (StaphylococcusATCC 6538 aureus and ATCC 6538 and StreptococcusCGMCC pneumoniae 1.1692) CGMCC and 1.1692) Gram-negative and Gram‐negative bacterium (Escherichiabacterium coli CGMCC(Escherichia 1.2340) coli CGMCC [39]. 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 Chemicalsediment of investigation the Antarctic ofPenguin the marine-derived Island, resulted in fungus the isolationTrichoderma of six new asperellum peptaibols, collected named from the sedimentasperelines of A–F the ( Antarctic54–59) (Figure Penguin 6), which Island, are characterized resulted in by the an isolationacetylated ofN‐terminus six new and peptaibols a namedC‐ asperelinesterminus containing A–F (54 an– 59uncommon) (Figure 6prolinol), which residue. are characterized The compounds by were an acetylatedtested against N-terminus fungi and aand C-terminus bacteria, but containing they showed an only uncommon weak inhibitory prolinol activity residue. toward The the early compounds blight pathogen were tested againstAlternaria fungi and solani bacteria,, the rice blast but theyPyricularia showed oryzae only, and weak the bacteria inhibitory Staphylococcus activity aureus toward and theEscherichia early blight coli [40]. Further study on the same fungus strain determined thirty‐eight short peptaibols, including pathogen Alternaria solani, the rice blast Pyricularia oryzae, and the bacteria Staphylococcus aureus and thirty‐two new compounds namely asperelines G–Z13 [41].

Mar. Drugs 2017, 15, 28 8 of 30

Escherichia coli [40]. Further study on the same fungus strain determined thirty-eight short peptaibols, including thirty-two new compounds namely asperelines G–Z13 [41]. TwoMar. new Drugs 2017 epipolythiodioxopiperazines,, 15, 28 named chetracins B (60) and C (61), and8 of five30 new diketopiperazines,Two new named epipolythiodioxopiperazines, chetracin D (62) and named oidioperazines chetracins A–D B (60 ()63 and–66 C) (Figure (61), and7), five were new obtained from thediketopiperazines, Antarctic fungus namedOidiodendron chetracin truncatumD (62) andGW3-13. oidioperazines An in vitroA–D 3-(4,(63–66 5-dimethylthiazol-2-yl)) (Figure 7), were 2, Mar. Drugs 2017, 15, 28 8 of 30 5-diphenylobtained tetrazolium from the bromide Antarctic (MTT) fungus cytotoxicity Oidiodendron assay truncatum revealed GW3 potent‐13. biological An in vitro activity 3‐(4, for 60 in the nanomolar5‐dimethylthiazolTwo range new against epipolythiodioxopiperazines,‐2‐yl) 2, a 5 panel‐diphenyl of five tetrazolium human named cancerbromide chetracins lines, (MTT) HCT-8,B cytotoxicity (60) and BEL-7402, C assay (61), revealedand BGC-823, five potentnew A-549 and A-2780.biological Newdiketopiperazines, metabolites activity for named 6160 inand the chetracin62 nanomolardisplayed D (range62) significant and against oidioperazines a cytotoxicitypanel of A–Dfive human at(63 a–66 micromolar )cancer (Figure lines, 7), concentration, HCTwere‐8, BEL‐7402, BGC‐823, A‐549 and A‐2780. New metabolites 61 and 62 displayed significant cytotoxicity at whereas obtained63–66 showed from the no Antarctic significant fungus cytotoxicity Oidiodendron at 10truncatumµM. Comparison GW3‐13. An of in the vitro bioactivity 3‐(4, data a micromolar concentration, whereas 63–66 showed no significant cytotoxicity at 10 μM. Comparison suggested5‐dimethylthiazol that the sulfide‐2‐yl) bridge 2, 5‐diphenyl was a determinant tetrazolium bromide factor (MTT) for their cytotoxicity cytotoxicity, assay revealed while thepotent number of ofbiological the bioactivity activity data for suggested 60 in the nanomolarthat the sulfide range bridge against was a panela determinant of five human factor cancerfor their lines, cytotoxicity, HCT‐8, sulfur atomswhileBEL ‐the7402, in number the BGC bridge‐823, of sulfurA did‐549 notandatoms A seem‐ 2780.in the to New bridge influence metabolites did not activity seem61 and to [ 6242 influence displayed]. activity significant [42]. 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 Inrelated 2012, two structure highlyFigure but 7. oxygenated Secondaryopposite metabolitesabsolute polyketides, stereochemistry, derived penilactonesfrom the Antarctic were Aisolated fungi and (compounds B from (67 andthe Antarctic6068–68) (Figure). deep7)‐sea of related structurederived but opposite fungus Penicillium absolute crustosum stereochemistry, PRB‐2. The nuclear were isolated factor‐κB from (NF‐κ theB) inhibitory Antarctic activities deep-sea of 67 derived In 2012, two highly oxygenated polyketides, penilactones A and B (67 and 68) (Figure 7) of andPenicillium 68 were tested crustosum by means of transient transfection andκ reporterκ gene expression assay, and only67 68 fungus related structure but oppositePRB-2. absolute The nuclear stereochemistry, factor- wereB (NF- isolatedB) inhibitoryfrom the Antarctic activities deep of‐sea and 67 showed weak activity with an inhibitory rate of 40% at a concentration of 10 μM. A plausible were testedderived by means fungus ofPenicillium transient crustosum transfection PRB‐2. andThe nuclear reporter factor gene‐κB expression (NF‐κB) inhibitory assay, activities and only of 67 showed weak activitybiosyntheticand 68 with were pathway tested an inhibitory by for means 67 and of rate transient 68 of was 40% transfectionproposed at a concentration as and shown reporter in Scheme ofgene 10 expressionµ M.2 [43]. A plausibleThe assay, penilactones and biosyntheticonly contain a new carbon skeleton formed from two 3,5‐dimethyl‐2,4‐diol‐acetophenone units and a pathway67 for showed67 and weak68 wasactivity proposed with an inhibitory as shown rate in of Scheme 40% at a2 [concentration43]. The penilactones of 10 μM. A plausible contain a new γ‐butyrolactone moiety, and have been prepared by a biomimetic synthesis reported the following carbon skeletonbiosynthetic formed pathway from for two67 and 3,5-dimethyl-2,4-diol-acetophenone 68 was proposed as shown in Scheme 2 units [43]. The and penilactones a γ-butyrolactone yearcontain as shown a new in carbonScheme skeleton 3 [44]. formed from two 3,5‐dimethyl‐2,4‐diol‐acetophenone units and a moiety, andγ‐butyrolactone have been moiety, prepared and byhave a been biomimetic prepared synthesis by a biomimetic reported synthesis the reported following the yearfollowing as shown in Scheme3year[44]. as shown in Scheme 3 [44].

Scheme 2. Proposed biosynthesis of penilactones A (67) and B (68).

Scheme 2. Proposed biosynthesis of penilactones A (67) and B (68). Scheme 2. Proposed biosynthesis of penilactones A (67) and B (68).

Mar. Drugs 2017, 15, 28 9 of 30 Mar. Drugs 2017, 15, 28 9 of 30

Mar. Drugs 2017, 15, 28 9 of 30

SchemeScheme 3. 3.Synthesis Synthesis of ofent ent-penilactone‐penilactone A A ( (entent-‐6767) )and and penilactone penilactone B ( B68 ().68 Reagents). Reagents and conditions: and conditions: (a) AcOH, BF3.Et2O, 90 °C,◦ 71%; (b) HCHO, NaOAc, AcOH, 80 °C,◦ 75%; (c) HCHO, NaOAc, AcOH, (a)Scheme AcOH, BF3. Synthesis3.Et2O, 90 of C,ent 71%;‐penilactone (b) HCHO, A (ent NaOAc,‐67) and penilactone AcOH, 80 BC, (68 75%;). Reagents (c) HCHO, and conditions: NaOAc, AcOH, (a) ◦90 °C, then 110◦ °C, 46%; (d) toluene, 110◦ °C, 93%; (e) Ph3P=C=C=O, toluene, 110 °C,◦ 52%; (f) H2, PD/C, 90 AcOH,C, then BF 1103.Et2C,O, 46%; 90 °C, (d )71%; toluene, (b) HCHO, 110 C, 93%;NaOAc, (e) PhAcOH,3P=C=C=O, 80 °C, 75%; toluene, (c) HCHO, 110 C, 52%;NaOAc, (f)H AcOH,2, PD/C, MeOH, rt, 99%; (g) dioxane, 110◦ °C, 86%. MeOH,90 °C, rt, then 99%; 110 (g °C,) dioxane, 46%; (d) 110 toluene,C, 86%. 110 °C, 93%; (e) Ph3P=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 eremophilaneA new chloro-trinoreremophilane sesquiterpenes (70–72) (Figure sesquiterpene 8), together with (69) a (Figure known8 compound,), three new eremofortine chlorinated C A new chloro‐trinoreremophilane sesquiterpene (69) (Figure 8), three new chlorinated eremophilane(73) (Scheme sesquiterpenes 4), were isolated (70 from–72 )the (Figure Antarctic8), together deep‐sea with derived a known fungus, compound, Penicillium sp. eremofortine PR19N‐1 eremophilane sesquiterpenes (70–72) (Figure 8), together with a known compound, eremofortine C C(73in )2013. (Scheme Compound4), were 69 isolated showed from moderate the Antarctic cytotoxic deep-sea activity against derived HL fungus,‐60 and A549Penicillium cancersp. cell PR19N-1 lines. (73) (Scheme 4), were isolated from the Antarctic deep‐sea derived fungus, Penicillium sp. PR19N‐1 in 2013.In addition, Compound the 69plausibleshowed metabolic moderate network cytotoxic of activity these againstisolated HL-60 products and A549was cancerproposed cell lines.as in 2013. Compound 69 showed moderate cytotoxic activity against HL‐60 and A549 cancer cell lines. In addition,demonstrated the plausible in Scheme metabolic 4 [45]. network Further of these investigation isolated products of this was strain proposed yielded as demonstratedfive new 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 Schemedemonstrated4[ 45]. Furtherin Scheme investigation 4 [45]. of Further this strain investigation yielded ﬁve newof this eremophilane-type strain yielded sesquiterpenes five new Their cytotoxities against HL‐60 and A‐549 human cancer cell lines were valuated, and 78 was the (74–eremophilane78) and a new‐type rare sesquiterpenes lactam-type eremophilane (74–78) and a new (79) (Figurerare lactam8). Their‐type cytotoxitieseremophilane against (79) (Figure HL-60 8). and most active one with IC50 value of 5.2 μM against the A‐549 cells [46]. A-549Their human cytotoxities cancer against cell lines HL were‐60 and valuated, A‐549 andhuman78 wascancer the cell most lines active were one valuated, with IC 50andvalue 78 was of 5.2 theµ M against the A-549 cells [46]. most active one with IC50 value of 5.2 μM againstOH the A‐549 cells [46].OH OH O O farnesyl H2O PPO diphosphate hydroxylation OH isomerization OH OH [O] O O farnesyl H2O PPO diphosphate hydroxylation isomerization H [O] hydroxylation epoxidation O O H O O OH hydroxylation O O O O epoxidation HCl O O acetylation H [O] O O OH [H] O O O O OH O O HO O O HO O HCl O O O acetylation O H [O] O 73a 73b [H] Cl O OH O O HO O HO O O O O HCl O HO O degradation 73a H2O 73b 72 HCl epoxidation O acetylation Cl 70 69 methylation 71 O deacetylation [O] HCl O HOO O OH degradation H2O 72 HCl epoxidation O O acetylation 70 69 methylation 71 deacetylation [O] O OH O Scheme 4. Proposed biogenetic network for compounds 69–73. Scheme 4. Proposed biogenetic network for compounds 69–73. Two new meroterpenoids,Scheme 4. Proposed named chrodrimanins biogenetic network I and for J compounds (80 and 81)69 (Figure–73. 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 the reported fiveTwo known new biosynthetically meroterpenoids, related named chrodrimanins, chrodrimanins were I and isolated J (80 fromand the81) culture (Figure of8), the together Antarctic with chrodrimanins, compounds 80 and 81 possess a unique cyclohexanone (E ring) instead of a δ‐lactone ﬁvemoss known‐derived biosynthetically fungus Penicillium related funiculosum chrodrimanins, GWT2 were‐24. Distinguished isolated from thefrom culture all of ofthe the reported Antarctic moss-derivedchrodrimanins, fungus compoundsPenicillium 80 and funiculosum 81 possess aGWT2-24. unique cyclohexanone Distinguished (E ring) from instead all ofof a the δ‐lactone reported chrodrimanins, compounds 80 and 81 possess a unique cyclohexanone (E ring) instead of a δ-lactone

Mar. Drugs 2017, 15, 28 10 of 30 Mar. Drugs 2017, 15, 28 10 of 30 ring.Mar.ring. However, Drugs However, 2017, 15 only ,only 28 the the known known compounds exhibited exhibited inhibitory inhibitory activities activities against against influenza inﬂuenza virus10 of virus 30A A (H1N1)(H1N1) [[47].47]. ring. However, only the known compounds exhibited inhibitory activities against influenza virus A (H1N1) [47].Cl Cl Cl Cl O O O HO O HO O O O Cl Cl Cl Cl O O OOH HO O OH HO O HOO O O O O

O 69 OH HO 70OH 71 O 72 O O OH O O O HO 69 OH 70O 71 O 72 OH HO OH HO O O HOO O O

77 74 HO 75 76 HO OH 74 75 76 O 77 O O H OH O O N O O O O O O O H O O O N O O O OH O O 78 79 Chrodrimanin I 80 O O O O OH

CO2Me 78 OH 79 OR Pseudogymnoascins AChrodrimanin (82)R= I 80 O O OH O CO2Me OH OR CO2H Pseudogymnoascins AB (8283)R= O O O O OH O CO2H O Pseudogymnoascins BC (8384)R=)R= CO2H O OH O O HO Chrodrimanin J 81 NO2 O CO H O Pseudogymnoascins3-Nitroasterric acid C (8584)R=)R= H 2 O OH HO

FigureChrodrimanin 8. Secondary J 81 metabolites derivedNO from2 O the Antarctic fungi (compounds 69–72, 74–85). Figure 8. Secondary metabolites derived from the Antarctic fungi3-Nitroasterric (compounds acid (85)R=69–72, 74 H–85). FermentationFigure 8. Secondary of a Pseudogymnoascus metabolites derived sp. from fungus the Antarctic isolated fungi from (compounds an Antarctic 69–72 marine, 74–85). sponge, yieldedFermentation four new of nitroasterric a Pseudogymnoascus acid derivatives,sp. fungus pseudogymnoascins isolated from an AntarcticA–C (82–84 marine) and 3 sponge,‐nitroasterric yielded fouracid new Fermentation(85 nitroasterric) (Figure of8), acid a alongPseudogymnoascus derivatives, with two pseudogymnoascins knownsp. fungus compounds isolated A–C fromquestin (82 –an84 )andAntarctic and pyriculamide. 3-nitroasterric marine sponge, These acid ( 85) (Figureyieldedcompounds8), alongfour arenew with the nitroasterric first two nitro known derivatives acid compounds derivatives, of the questin pseudogymnoascinsknown and fungal pyriculamide. metabolite A–C asterric(82 These–84) acidand compounds 3[48].‐nitroasterric are the firstacid nitro Five(85 derivatives) new(Figure highly of8), theoxygenatedalong known with fungal α‐ twopyrone metaboliteknown merosesquiterpenoids, compounds asterric acid questin [48 ].ochraceopones and pyriculamide. A–E (86These–90) compounds(SchemeFive new 5), aretogether highly the first with oxygenated nitro one derivatives newα double-pyrone of thebond merosesquiterpenoids, known isomer fungal of asteltoxin, metabolite isoasteltoxin ochraceopones asterric acid ( 91[48].) (Figure A–E (86 9),– 90) Five new highly oxygenated α‐pyrone merosesquiterpenoids, ochraceopones A–E (86–90) (Schemeand two5), known together asteltoxin with one derivatives, new double asteltoxin bond isomerand asteltoxin of asteltoxin, B, were isoasteltoxinisolated from (the91 )Antarctic (Figure 9), (Scheme 5), together with one new double bond isomer of asteltoxin, isoasteltoxin (91) (Figure 9), andsoil two‐derived known fungus asteltoxin Aspergillus derivatives, ochraceopetaliformis asteltoxin and SCSIO asteltoxin 05702. Ochraceopones B, were isolated A–D from (86 the–89 Antarctic) were and two known asteltoxin derivatives, asteltoxin and asteltoxin B, were isolated from the Antarctic soil-derivedthe first examples fungus ofAspergillus α‐pyrone ochraceopetaliformismerosesquiterpenoidsSCSIO possessing 05702. a Ochraceoponeslinear tetracyclic carbon A–D (86 skeleton.–89) were soil‐derived fungus Aspergillus ochraceopetaliformis SCSIO 05702. Ochraceopones A–D (86–89) were theAll first the examples isolated of αcompounds-pyrone merosesquiterpenoids were tested for their possessing antiviral, a linear cytotoxic, tetracyclic antibacterial, carbon skeleton. and the first examples of α‐pyrone merosesquiterpenoids possessing a linear tetracyclic carbon skeleton. Allantitubercular the isolated compounds activities. Among were tested the new for their compounds, antiviral, 86 cytotoxic, and 91 antibacterial,exhibited promising and antitubercular antiviral Allactivities the isolatedagainst thecompounds H1N1 and were H3N2 tested influenza for theirviruses. antiviral, In addition, cytotoxic, a possible antibacterial, biosynthetic and activities. Among the new compounds, 86 and 91 exhibited promising antiviral activities against the antitubercularpathway for ochraceopones activities. Among A–E was the proposed new compounds, in Scheme 86 5 [49].and 91 exhibited promising antiviral H1N1activities and H3N2 against influenza the H1N1 viruses. and H3N2 In addition, influenza a possible viruses. biosynthetic In addition, pathway a possible for ochraceoponesbiosynthetic A–Epathway was proposed for ochraceopones in Scheme 5A–E[49 ].was proposed in Scheme 5 [49].

Figure 9. The structure of isoasteltoxin (91) derived from the Antarctic fungus Aspergillus ochraceopetaliformis SCSIO 05702. FigureFigure 9. 9. TheThe structurestructure ofof isoasteltoxinisoasteltoxin ( (9191)) derived derived from from the the Antarctic Antarctic fungus fungus AspergillusAspergillus ochraceopetaliformis SCSIO 05702. ochraceopetaliformis SCSIO 05702.

Mar. Drugs 2017, 15, 28 11 of 30 Mar. Drugs 2017, 15, 28 11 of 30

Scheme 5. Postulated biogenetic pathway for ochraceopones A–E (86–90). Scheme 5. Postulated biogenetic pathway for ochraceopones A–E (86–90).

3. Lichen 3. Lichen Lichens are symbiotic associations of fungi and algae and/or cyanobacteria that produce unique characteristicLichens are secondary symbiotic associationsmetabolites by of fungicomparison and algae to those and/or of higher cyanobacteria plants. thatSeveral produce species unique of characteristiclichens have secondary been used metabolitesfor various remedies by comparison in folk medicine to those ofsince higher ancient plants. time and Several variety species of of lichensbiologically have active been usedlichen formetabolites, various remedies including in antimycobacterial, folk medicine since antiviral, ancient antioxidant time and varietyand of biologicallyantiherbivore active properties, lichen have metabolites, been described including [50,51]. antimycobacterial, Antarctic lichens may antiviral, have evolved antioxidant unique and antiherbivoresecondary metabolites properties, to have help beenin surviving described the extreme [50,51]. environment Antarctic lichens in which may they have live evolved [52–54]. unique secondaryProfessor metabolites Oh’s group to help has in made surviving great efforts the extreme in discovery environment of new metabolites in which they from live the [52 Antarctic–54]. lichens.Professor From Oh’s the group MeOH has extract made greatof the efforts Antarctic in discovery lichen ofStereocaulon new metabolites alpinum from, a new the Antarcticcyclic lichens.depsipeptide From the stereocalpin MeOH extract A (92 of) the (Figure Antarctic 10) [55], lichen togetherStereocaulon with three alpinum new, a usnic new cyclicacid derivatives depsipeptide stereocalpinusimines AA–C (92 )( (Figure93–95) 10(Figure)[55], together10) [56], with were three isolated new usnicby various acid derivatives chromatographic usimines A–Cmethods. (93– 95) (FigureCompound 10)[56 ],92 were incorporated isolated byan variousunprecedented chromatographic 5‐hydroxy‐ methods.2,4‐dimethyl Compound‐3‐oxo‐octanoic92 incorporated acid in the an unprecedentedstructure, and 5-hydroxy-2,4-dimethyl-3-oxo-octanoic showed marginal levels of cytotoxicity against acid in three the human structure, tumor and cell showed lines, HT marginal‐29, 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 targetdepsidone type 2‐ diabetestype compound, and obesity lobaric [57]. Furheracid ( investigation96) (Figure 10) of thisand Antarctic two pseudodepsidone lichen recovered‐type seven phenoliccompounds, lichen 97 metabolites. and 98 (Figure Among 10), exhibited the compounds, potent inhibitory the depsidone-type activity against compound, PTP1B with lobariclow IC50 acid (96)values (Figure in 10a non) and‐competitive two pseudodepsidone-type manner [58]. In 2013, compounds, a new pseudodepsidone97 and 98 (Figure‐type metabolite, 10), exhibited lobastin potent inhibitory(99) (Figure activity 10), with against antioxidant PTP1B with and antibacterial low IC50 values activity in awas non-competitive also reported from manner this strain [58]. In[59]. 2013, a new pseudodepsidone-typeFour new diterpene furanoids, metabolite, hueafuranoids lobastin (99 )A–D (Figure (100 10–103), with) (Figure antioxidant 10) have and been antibacterial isolated activityfrom wasthe MeOH also reported extract of from the this Antarctic strain lichen [59]. Huea sp. Compound 100 showed inhibitory activity againstFour newtherapeutically diterpene furanoids,targeted protein, hueafuranoids PTP1B with A–D an (IC50100– 103value) (Figure of 13.9 μ10M) have[60]. been isolated from the MeOHFrom extract the Antarctic of the Antarctic lichen Ramalina lichen Hueaterebratasp., the Compound novel compound100 showed ramalin inhibitory (104) (Figure activity 10) against was therapeuticallyisolated. The targetedexperimental protein, data PTP1B showed with that an ramalin IC50 value displayed of 13.9 potentµM[ antioxidant60]. activity and can be a strong therapeutic candidate for controlling oxidative stress in cells [61].

Mar. Drugs 2017, 15, 28 12 of 30

From the Antarctic lichen Ramalina terebrata, the novel compound ramalin (104) (Figure 10) was isolated. The experimental data showed that ramalin displayed potent antioxidant activity and can be a strongMar. therapeuticDrugs 2017, 15, 28 candidate for controlling oxidative stress in cells [61]. 12 of 30

OH O O O H NH O N Mar. Drugs 2017, 15, 28 O N COOH 12 of 30 O O OH OR O OH OH N OH H COOH O O O O H OH O O NH HO O N HO O N COOH O O O OH OR O 93 OOH N Usimine A ( )R=CHOH 3 H StereocalpinO A (92) Usimine C (95) COOH Usimine B (94)R=H OH HO O HO O O O O OH O Usimine A (93)R=CH O Stereocalpin A (92) O 3 Usimine C (95) OH UsimineO B (94)R=H O O O O O R O H3CO O O O OH H3CO O OH O HO OH O HO OH OH O OCH 3 O OCH O O O R 3 Lobaric acid (96) O (97)R=H O H3CO (99) (98) R =COOH OH H3CO HO OH OH HO OH OCH3 OCH3 Lobaric acid (96) (97)R=H 14 (99) (98) R =COOH O O OH 14 O H OH HO O N O HO N H HO O HO NH 14 14 2 Hueafuranoids A (100) 14 Hueafuranoids B (101) O O OH 14 O Ramalin (H104) Hueafuranoids C (102) HueafuranoidsHO D (103O ) N O HO N HO HO H O NH2 Figure 10. Secondary metabolites14 derivedHueafuranoids from the B (101 Antarctic) 14 lichen (compounds 92–104). Figure 10. SecondaryHueafuranoids A metabolites (100) derived from the Antarctic lichen (compoundsRamalin (104) 92–104). Hueafuranoids C (102) Hueafuranoids D (103) 4. Mosses 4. Mosses Figure 10. Secondary metabolites derived from the Antarctic lichen (compounds 92–104). Mosses represent a relatively untapped natural source to be explored for new bioactive 4. Mosses Mossesmetabolites. represent Chemical a studies relatively of Antarctic untapped moss natural Polytrichastrum source alpinum to be exploredled to the isolation for new of bioactive two metabolites.new benzonaphthoxanthenones,Mosses Chemical represent studies a relatively of ohioensins Antarctic untapped mossF naturaland PolytrichastrumG (source105 and to 106be )explored alpinum(Figure for11),led newalong to thebioactive with isolation two of two newknownmetabolites. benzonaphthoxanthenones, compounds Chemical ohioensins studies ofA Antarctic and ohioensins C. Allmoss of Polytrichastrum F the and four G ( 105compounds alpinumand 106 led )showed (Figure to the isolationpotent 11), along inhibitoryof two with two knownactivity compoundsnew benzonaphthoxanthenones,against therapeutically ohioensins A targeted and ohioensins C. All protein of theF tyrosineand four G compounds(105 phosphatase and 106) showed (Figure1B (PTP1B). 11), potent alongKinetic inhibitory with analysis two activity of againstPTP1Bknown therapeutically inhibition compounds by targeted ohioensin ohioensins protein F A(105 and) tyrosine suggested C. All of phosphatase thatthe fourbenzonaphthoxanthenones compounds 1B (PTP1B). showed Kinetic potent inhibited analysis inhibitory PTP1B of PTP1B activity against therapeutically targeted protein tyrosine phosphatase 1B (PTP1B). Kinetic analysis of inhibitionactivity by in ohioensin a non‐competitive F (105) suggested manner [62]. that benzonaphthoxanthenones inhibited PTP1B activity in a PTP1B inhibition by ohioensin F (105) suggested that benzonaphthoxanthenones inhibited PTP1B non-competitiveactivity in a manner non‐competitive [62]. 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 5. BryozoansBryozoans (moss animals and lace corals) have yielded a significant number of bioactive metabolitesBryozoans and have(moss been animals reviewed and lace elsewhere corals) have[63]. yieldedHowever, a significantthere is only number a single of bioactive report on Bryozoanssecondarymetabolites metabolites (moss and have animals from been areviewed andpolar lace bryozoan. elsewhere corals) In have[63]. 2011, However, yieldedan investigation there a signiﬁcant is onlyinto athe single number chemistry report of ofon bioactive the metabolitesArcticsecondary bryozoan and have metabolites Tegella been reviewed cf.from spitzbergensis a polar elsewhere bryozoan. resulted [63 In]. However,in2011, the an isolation investigation there and is only structuralinto a singlethe chemistry determination report onof the secondary of Arctic bryozoan Tegella cf. spitzbergensis resulted in the isolation and structural determination of metabolitesent‐eusynstyelamide from a polar B bryozoan. (107) and three In 2011, new an derivatives, investigation eusynstyelamides into the chemistry D–F (108 of– the110 Arctic) (Figure bryozoan 12) ent‐eusynstyelamide B (107) and three new derivatives, eusynstyelamides D–F (108–110) (Figure 12) Tegella[64]. spitzbergensisEnt‐eusynstyelamide B (107) is the enantiomer of the known brominatedent tryptophan cf.[64]. Ent‐eusynstyelamideresulted inB the(107 isolation) is the enantiomer and structural of the determination known brominated of -eusynstyelamide tryptophan B metabolite eusynstyelamide B [65]. Antimicrobial activities were reported for 107–110, with MIC (107) andmetabolite three new eusynstyelamide derivatives, eusynstyelamides B [65]. Antimicrobial D–F activities (108– 110were) (Figure reported 12 for)[ 64107].–Ent110,-eusynstyelamide with MIC

Mar. Drugs 2017, 15, 28 13 of 30

B(107) is the enantiomer of the known brominated tryptophan metabolite eusynstyelamide B [65]. AntimicrobialMar. Drugs activities 2017, 15, 28 were reported for 107–110, with MIC values as low as 6.25 µg/mL13 for of 30107 and 110 againstvaluesStaphylococcus as low as 6.25 μ aureusg/mL. for Eusynstyelamides 107 and 110 against were Staphylococcus generally aureus more. activeEusynstyelamides against Gram-positive were bacteriagenerally than Gram-negative more active against bacteria Gram [‐64positive]. bacteria 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 Cnidariansreported each are year, the second with a predominance largest source of (after terpenoids sponges) [11–13] of and new are marine also well natural represented products in the reported each year,polar with regions. a predominance In 2003, fractionation of terpenoids of the bioactive [11–13] andextract are from also the well chemically represented defended in the Antarctic polar regions. In 2003,gorgonian fractionation coral Ainigmaptilon of the bioactive antarcticus extract yielded from two the sesquiterpenes, chemically defended ainigmaptilones Antarctic A (111 gorgonian) and B coral Ainigmaptilon(112) (Figure antarcticus 13). Ainigmaptiloneyielded two A sesquiterpenes, has broad spectrum ainigmaptilones bioactivity toward A sympatric (111) and predatory B (112) (Figure and 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 includingthree antibiotic main nonpolar activity and [ 66relatively]. transient sesquiterpene metabolites, including a new compound, Thefuranoeudesmane ethereal extract (113 of) another (Figure Antarctic13). Compound gorgonian 113 wasDasystenella toxic at 46 acanthina μM in a wasGambusia found affinis to contain three mainichthyotoxicity nonpolar test. and According relatively to transient this result, sesquiterpene an involvement metabolites, of these molecules including in the a newdefensive compound, furanoeudesmanemechanisms of ( 113the )animal (Figure could 13 be). suggested Compound [67]. 113 was toxic at 46 µM in a Gambusia afﬁnis ichthyotoxicitySeven test. new steroids, According compounds to this 114 result,–120 (Figure an involvement 13), were isolated of these from molecules the Antarctic in octocoral 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 Sevenadenocarcinoma). new steroids, Compounds compounds 115–114118 –displayed120 (Figure weak 13 activity), were as isolated inhibitors from of cell the growth Antarctic [68]. octocoral AnthomastusChemical bathyproctus investigation. The in of vitro the lipophiliccytotoxicity extract has of been the Antarctic tested against soft coral three Alcyonium human grandis tumor led cell lines MDA-MB-231to the finding (breast of adenocarcinoma), nine unreported sesquiterpenoids, A-549 (lung carcinoma), compounds and121–129 HT-29 (Figure (colon 13) adenocarcinoma).[69]. These Compoundsmolecules115 –are118 membersdisplayed of weak the illudalane activity as class inhibitors and in of particular cell growth belong [68]. to the group of Chemicalalcyopterosins. investigation Similar illudalanes of the lipophilic have been extract isolated of from the the Antarctic sub‐Antartic soft coraldeep seaAlcyonium soft coral grandis Alcyonium paessleri [70]. Repellency experiments conducted using the omnivorous Antarctic sea star 121 129 led to theOdontaster ﬁnding validus of nine revealed unreported a strong sesquiterpenoids, activity in the lipophilic compounds extract of A. grandi– s (Figureagainst predation 13)[69]. These molecules[69]. are The members total synthesis of the of illudalanesome members class of andthe alcyopterosin in particular family belong has to been the reported group of already alcyopterosins. by Similarmany illudalanes research have groups been [71–75]. isolated from the sub-Antartic deep sea soft coral Alcyonium paessleri [70]. Repellency experimentsMore recently, conducted the isolation using and the characterization omnivorous Antarcticof two new sea startricyclicOdontaster sesquiterpenoids, validus revealed a strongshagenes activity A in(130 the) and lipophilic B (131) (Figure extract 13) of wereA. presented. grandis against The two predation compounds [ 69were]. The isolated total from synthesis an of some membersundescribed of the soft alcyopterosin coral collected family from the has Scotia been reportedArc in the already Southern by Ocean. many Exploration research groups of the [ 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) andIn B (2012,131) two (Figure halogenated 13) were natural presented. products The breitfussin two compounds A (132) and were breitfussin isolated B (133 from) (Figure an undescribed 13) soft coralwere collected isolated from the the Arctic Scotia hydrozoan Arc in the Thuiria Southern breitfussi Ocean. collected Exploration at Bjørnøya of (Bear the Island) bioactivity [77]. found that shagenesRecently, A Hedberg was active and co against‐workers the synthesized visceral leishmaniasis breitfussins A and causing B firstly parasite, using SuzukiLeishmania coupling donovani

(IC50 value = 5 µM), with no cytotoxicity against the mammalian host [76]. In 2012, two halogenated natural products breitfussin A (132) and breitfussin B (133) (Figure 13) were isolated from the Arctic hydrozoan Thuiria breitfussi collected at Bjørnøya (Bear Island) [77]. Mar. Drugs 2017, 15, 28 14 of 30

Recently,Mar. Drugs Hedberg 2017, 15, and 28 co-workers synthesized breitfussins A and B ﬁrstly using Suzuki14 coupling of 30 reactionsMar. Drugs to join 2017, the 15, 28 heteroaromatic rings, thus conﬁrming the assigned structure of these14 of natural 30 reactions to join the heteroaromatic rings, thus confirming the assigned structure of these natural products (Scheme6)[ 78]. Soon after, a conceptually distinct synthesis of breitfussin B through late-stage productsreactions to(Scheme join the 6) heteroaromatic [78]. Soon after, rings, a conceptually thus confirming distinct the assignedsynthesis structureof breitfussin of these B throughnatural brominationlateproducts‐stage of (Schemebromination the breitfussin 6) [78]. of the Soon core breitfussin wasafter, reported a core conceptually was by reported Khan distinct and by Khan Chen synthesis and [79 Chen]. of breitfussin [79]. B through late‐stage bromination of the breitfussin core was reported by Khan and Chen [79]. H H O O O R CO Me H H 2 O O O R CO Me H 2 OH OH H Ainigmaptilones A (111) Ainigmaptilones B (112) Furanoeudesmane (113) H H H OH OH O Ainigmaptilones A (111) Ainigmaptilones B (112) Furanoeudesmane (113) H H H H H O CO Me (114) 2 O H H 118 CO Me ( ) R O Cl (114) 2 O 2 (118) O R2 R2O Cl (115) R1O O CO2Me O R2 (121)R1 =COCH2CH2CH3;R2 =COCH2CH2CH3 (115) R1O O(124) CO2Me R1 (122)R =COCH ;R =COCH (121)R1 =COCH3CH2 CH ;R =COCH3 CH CH H 1 2 2 3 2 2 2 3 (124) R1 ((123122)R)R1 =COCH3;R2 =COCH2CH2CH3 116 OAc 1 3 2 3 ( ) H OAc CO2Me H H (123)R1 =COCH3;R2 =COCH2CH2CH3 (116) O R2O CO2Me H H O (119)R1 =OH,R2 =H ClR2O Cl OH (120)R1 =H,R2 =OH (117) (119)R1 =OH,R2 =H Cl R O Cl RO OH (120)R =H,R =OH 1 (117) 1 2 (125)R1 =COCH3,R2 =COCH3 (128)R=COCH R O RO 3 126 1 (125)R1 =COCH3,R2 =COCH2CH2CH3 (129)R=COCH2CH2CH3 ( )R1 =COCH3,R2 =COCH3 (128)R=COCH3 (127126)R1 =H,R2 =H ( )R1 =COCH3,R2 =COCH2CH2CH3 (129)R=COCH2CH2CH3 (127)R1 =H,R2 =H O O H H NH NH O O O O O H H N NH Br N NH O O N O Br H O O O HN N N O O Br H O O HN N O Br O Br O Br Shagenes A (130) Shagenes B (131) Breitfussin A (132) Breitfussin B (133) Shagenes A (130) Shagenes B (131) Breitfussin A (132) Breitfussin B (133)

H H H H H H H H H H H H H H H H HO OH OH H OH OH HO OH OH H OH Gersemiol A (134) Gersemiol B (135) Gersemiol COH (136) Eunicellol A (137) Gersemiol A (134) Gersemiol B (135) Gersemiol C (136) Eunicellol A (137) Figure 13. Secondary metabolites derived from the polar cnidarians (compounds 111–137). FigureFigure 13. Secondary13. Secondary metabolites metabolites derived derived fromfrom the the polar polar cnidarians cnidarians (compounds (compounds 111–111137).–137 ). O N B O N N TIPS OB O TIPS N TIPS O O TIPS OH OMe OMe OMe I OMe O OH Me OMe Me OMe OMe OMe O a b c I d Me Me a b c d Br NO Br N Br N Br N 2 Br NO2 H TIPS TIPS Br NO Br N Br N Br N 2 Br NO2 H TIPS TIPS

132 e N B(OH)2 132 Boc e h N B(OH)2 Br Boc N I N h N I I N N I N N I N Br Boc I j N Boc N N g OMe O OMe O 133 OMeI O N i OMeI O f j Boc Boc g OMe O OMe O 133 OMe O i OMe O f

Br N Br N Br N Br N TIPS TIPS TIPS TIPS Br N Br N Br N Br N TIPS TIPS TIPS 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, SchemeDMF, 6. rt,Synthesis 82%; (b) of Dimethylformamide Breitfussin A (132 dimethyl) and B (133acetal). Reagents(DMFDMA), and Pyrrolidine, conditions: DMF, (a) MeI,then CsZn,2 CO3, DMF, rt, 82%; (b) Dimethylformamide dimethyl acetal (DMFDMA), Pyrrolidine, DMF, then Zn, DMF,AcOH/H2O, rt, 82%; (b 80) Dimethylformamide°C, 61%; (c) Iodine chloride, dimethyl Pyridine acetal (ICl, (DMFDMA), Py), CH2Cl2, then Pyrrolidine, NaH, Three DMF, isopropyl then Zn, AcOH/H2O, 80 °C, 61%; (c) Iodine chloride, Pyridine (ICl, Py), CH2Cl2, then NaH, Three isopropyl silicon alkyl◦ chloridec (TIPSCl), THF, 81%; (d) 1,1′‐Bis(diphenylphosphino)ferrocene] AcOH/H2O,silicon alkyl 80 C, 61%;chloride ( ) Iodine(TIPSCl), chloride, THF, Pyridine 81%; (ICl,(d) Py),1,1′‐ CHBis(diphenylphosphino)ferrocene]2Cl2, then NaH, Three isopropyl dichloropalladium (Pd(dppf)Cl2), K3PO4, Toluene/H0 2O, 80 °C; (e) 10% aq HCl, THF, 0 °C, 89%; (f) silicondichloropalladium alkyl chloride (TIPSCl), (Pd(dppf)Cl THF,2), 81%;K3PO (4d, Toluene/H) 1,1 -Bis(diphenylphosphino)ferrocene]dichloropalladium2O, 80 °C; (e) 10% aq HCl, THF, 0 °C, 89%; (f) Lithium hexamethyldisilazide (LiHMDS), −◦78 °C, then I2, −78 °C, 15%; (g) Pd(dppf)Cl◦ 2, Cs2CO3, (Pd(dppf)ClLithium2 ),hexamethyldisilazide K3PO4, Toluene/H (LiHMDS),2O, 80 −78C; °C, (e) then 10% I2, aq −78 HCl, °C, 15%; THF, (g) 0Pd(dppf)ClC, 89%;2, Cs (f)2CO Lithium3, Dioxane/H2O, rt, 61%; (h) Trimethylsilyl ◦trifluoromethanesulfonate◦ (TMSOTf), Et3N, CH2Cl2, 0 °C to hexamethyldisilazideDioxane/H2O, rt, 61%; (LiHMDS), (h) Trimethylsilyl−78 trifluoromethanesulfonateC, then I , −78 C, (TMSOTf), 15%; (g) Et Pd(dppf)Cl3N, CH2Cl2, 0, °C Cs to CO , rt, then Tetrabutylammonium fluoride (TBAF), THF, 02 °C, 64%; (i) N‐Bromosuccinimide (NBS),2 THF,2 3 Dioxane/Hrt, then TetrabutylammoniumO, rt, 61%; (h) Trimethylsilyl fluoride (TBAF), trifluoromethanesulfonate THF, 0 °C, 64%; (i) N‐Bromosuccinimide (TMSOTf), Et N,(NBS), CH THF,Cl , 0 ◦C −78 °C to2 rt, 57%; (j) Trifluoroacetic acid (TFA), CH2Cl2, 0 °C to rt, then TBAF, THF, 0 °C,3 67%. 2 2 ◦ to rt,− then78 °C Tetrabutylammonium to rt, 57%; (j) Trifluoroacetic fluoride acid (TFA), (TBAF), CH2Cl THF,2, 0 °C 0 toC, rt, 64%; then TBAF, (i) N-Bromosuccinimide THF, 0 °C, 67%. (NBS), − ◦ ◦ ◦ THF, 78 C to rt, 57%; (j) Trifluoroacetic acid (TFA), CH2Cl2, 0 C to rt, then TBAF, THF, 0 C, 67%. Mar. Drugs 2017, 15, 28 15 of 30

Mar. Drugs 2017, 15, 28 15 of 30 From the Arctic soft coral Gersemia fruticosa, three new diterpenes named gersemiols A–C (134–136) togetherFrom with the a new Arctic eunicellane soft coral diterpene, Gersemia fruticosa eunicellol, three A ( 137new), havediterpenes been obtained.named gersemiols All compounds A–C were(134 tested–136) fortogether their antimicrobialwith a new eunicellane activity against diterpene, several eunicellol bacteria A and (137 fungi.), have Only been eunicellol obtained. AAll was foundcompounds to exhibit were moderate tested for anti-bacterial their antimicrobial activity activity against against methicillin several resistant bacteriaStaphylococcus and fungi. Only aureus (MRSA)eunicellol with A MIC was value found of 24–48to exhibitµg/mL moderate [80]. anti‐bacterial activity against methicillin resistant Staphylococcus aureus (MRSA) with MIC value of 24–48 μg/mL [80]. 7. Echinoderms 7. EchinodermsEchinoderms are well known producers of bioactive glycosylated metabolites [11–13], and many new naturalEchinoderms products are have well been known described producers from of thebioactive polar examples.glycosylated In metabolites 2001, two new[11–13], trisulfated and triterpenemany new glycosides, natural liouvillosidesproducts have A been (138 )described and B (139 from) (Figure the polar 14), were examples. isolated In from2001, the two Antarctic new seatrisulfated cucumber triterpeneStaurocucumis glycosides, liouvillei liouvillosides. Liouvillosides A (138 A and) and B areB (139 two) (Figure new examples 14), were of isolated a small numberfrom of trisulfatedthe Antarctic triterpene sea cucumber glycosides Staurocucumis from sea liouvillei cucumbers. Liouvillosides belonging A to and the B family are two Cucumariidae. new examples of Both glycosidesa small number were found of trisulfated to be virucidal triterpene against glycosides herpes simplexfrom sea virus cucumbers type 1 belonging (HSV-1) at to concentrations the family belowCucumariidae. 10 µg/mL Both [81]. glycosides A novel were triterpene found holostaneto be virucidal disulfated against tetrasaccharide herpes simplex olygoglycoside,virus type 1 (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 thetriterpene genus glycosidesStaurocucumis is a taxonomical[81,82]. character of the genus Staurocucumis [81,82]. Subsequently,Subsequently, another another threethree new triterpene triterpene glycosides, glycosides, achlioniceosides achlioniceosides A1 (141 A1), (A2141 (142), A2), and (142 ), andA3 A3 (143 (143) )(Figure (Figure 14), 14 ),were were obtained obtained from from the the Antarctic Antarctic sea sea cucumber cucumber AchlioniceAchlionice violaecuspidata violaecuspidata. . GlycosidesGlycosides141 141–143–143are are the the ﬁrst first triterpene triterpene glycosides glycosides isolated from from a a sea sea cucumber cucumber belonging belonging to the to the orderorder Elasipodida Elasipodida [83 [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 continentalThe nudibranch shelves. AustrodorisIn 2003, two kerguelenensis unprecedentedis distributednor‐sesquiterpenes, widely aroundaustrodoral the ( Antarctic144) and coastits andoxidised continental derivative shelves. austrodoric In 2003, acid two unprecedented(145) (Figure 15), nor-sesquiterpenes, were isolated from austrodoralthe skin of the (144 marine) and its oxidiseddorid A. derivative kerguelenensis austrodoric, collected acid in (the145 Antarctic.) (Figure 15A ),role were of stress isolated‐metabolites from the could skin of be the suggested marine for dorid A. kerguelenensisthese compounds, collected [84]. A in short the Antarctic. and efficient A role synthesis of stress-metabolites of 144 and 145 couldwas reported be suggested as shown for thesein compounds [84]. A short and efﬁcient synthesis of 144 and 145 was reported as shown in Scheme7[ 85].

Mar. Drugs 2017, 15, 28 16 of 30

Mar. Drugs 2017, 15, 28 16 of 30 Mar.Mar. Drugs Drugs 2017 2017, 15, 15, 28, 28 16 16of of30 30 FurtherScheme chemical 7 [85]. study Further of this chemical Antarctic study nudibranch of this yielded Antarctic two novelnudibranch 2-monoacylglycerols yielded two novel (146) and Scheme 7 [85]. Further chemical study of this Antarctic nudibranch yielded two novel (147Scheme)2 (Figure‐monoacylglycerols 7 15[85].), along Further with(146) twoandchemical ( known147) (Figure study 1,2-diacyl 15), of along this glyceryl with Antarctic two esters known nudibranch [86 1,2]. ‐diacyl glycerylyielded esterstwo [86].novel 2‐monoacylglycerols2‐monoacylglycerols ( 146(146) )and and ( (147147)) (Figure(Figure 15), along with twotwo known known 1,2 1,2‐diacyl‐diacyl glyceryl glyceryl esters esters [86]. [86].

Figure 15. Secondary metabolites derived from the Antarctic nudibranch Austrodoris FigureFigure 15. Secondary15. Secondary metabolites metabolites derived derived from thefrom Antarctic the Antarctic nudibranch nudibranchAustrodoris Austrodoris kerguelenensis Figurekerguelenensis 15. Secondary (compounds metabolites 144–147). derived from the Antarctic nudibranch Austrodoris (compoundskerguelenensis144–147 (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) Schemefour 7. steps,Synthesis 59% [87,88]; of austrodoral (b) OsO4, H (1442O,) t and‐BuOH, austrodoric trimethylamine acid (145 N‐oxide,). Reagents pyridine, and reflux, conditions: 24 h, 87%; (a) four Schemefour steps, 7. Synthesis 59% [87,88]; of austrodoral (b) OsO4, H2 O,(144 t‐BuOH,) and austrodorictrimethylamine acid N ‐(oxide,145). Reagentspyridine, reflux,and conditions: 24 h, 87%; ( a) steps,(c) 59% BF3∙OEt [87,288, CH];2 (Clb)2, OsO0 °C 4to,H rt,2 20O, min,t-BuOH, 95%; (d trimethylamine) NaBH4, EtOH, rt,N 15-oxide, min, 97%; pyridine, (e) Pb(OAc) reflux,4, CH 242Cl h,2, 87%; four(c) steps,BF3∙OEt 59%2, CH [87,88];2Cl2, ◦0 °C(b) toOsO rt, 420, H min,2O, t95%;‐BuOH, (d) NaBHtrimethylamine4, EtOH, rt, N 15‐oxide, min, 97%; pyridine, (e) Pb(OAc) reflux,4 ,24 CH h,2Cl 87%;2, (c) BFrt,3· OEt45 min,2, CH 92%;2Cl (2f,) 0NaIOC to4, t rt,‐BuOH–H 20 min,2O, 95%; reflux, (d) 12 NaBH h, 91%.4, EtOH, rt, 15 min, 97%; (e) Pb(OAc)4, CH2Cl2, (c)rt, BF 453∙ OEtmin,2, 92%;CH2 Cl(f)2 ,NaIO 0 °C 4to, t ‐rt,BuOH–H 20 min,2O, 95%; reflux, (d) 12NaBH h, 91%.4, EtOH, rt, 15 min, 97%; (e) Pb(OAc)4, CH2Cl2, rt, 45 min, 92%; (f) NaIO4, t-BuOH–H2O, 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 new diterpenes, palmadorins A–C (148–150) (Figure 16) [89]. InvestigationresultedInvestigation in the of isolation theof the nudibranch ofnudibranch three A.new kerguelenensis A.diterpenes, kerguelenensis palmadorinscollected collected near A–C thenear (148 Antarctic the–150 Antarctic) (Figure Peninsula 16)Peninsula [89]. resulted Detailed investigation of this Antarctic nudibranch led to the discovery of a diverse suite of new in theresultedDetailed isolation in investigation the of isolation three newof ofthis three diterpenes, Antarctic new nudibranchditerpenes, palmadorins ledpalmadorins to A–C the discovery (148 A–C–150 ) (of148 (Figure a– diverse150) 16(Figure )[suite89 ].of16) new Detailed [89]. diterpenoid glyceride esters, palmadorins D–S (151–166) (Figure 16), including one (palmadorin L) investigationditerpenoid of glyceride this Antarctic esters, nudibranch palmadorins led D–S to (151 the– discovery166) (Figure of 16), a diverse including suite one of (palmadorin new diterpenoid L) Detailedthat is theinvestigation first halogenated of this diterpeneAntarctic fromnudibranch this well led‐studied to the nudibranch.discovery of Palmadorin a diverse suiteA (148 of), new B glyceridethat is esters, the first palmadorins halogenated D–Sditerpene (151– from166) (Figurethis well 16‐studied), including nudibranch. one (palmadorin Palmadorin A L) (148 that), B is the diterpenoid(149), D (151 glyceride), M (160 esters,), N (161 palmadorins), and O (162 D–S) inhibit (151– 166human) (Figure erythroleukemia 16), including (HEL) one cells(palmadorin with low L) firstthat halogenated(149 is), theD ( 151first), diterpene halogenatedM (160), N from (161 diterpene), this and well-studied O from(162) thisinhibit well nudibranch. human‐studied erythroleukemia nudibranch. Palmadorin Palmadorin(HEL) A (148 cells), B ( with149A (),148 low D), ( 151B ), micromolar IC50, and palmadorin M inhibits Jak2, STAT5, and Erk1/2 activation in HEL cells and micromolar IC50, and palmadorin M inhibits Jak2, STAT5, and Erk1/2 activation in HEL cells and M((160149causes), ND (apoptosis(161151), andM ( at160 O 5 ), (mM162 N )([90].161 inhibit), and human O (162 erythroleukemia) inhibit human erythroleukemia (HEL) cells with (HEL) low micromolarcells with low IC 50, causes apoptosis at 5 mM [90]. andmicromolar palmadorin IC50 M, and inhibits palmadorin Jak2, STAT5, M inhibits and Erk1/2Jak2, STAT5, activation and Erk1/2 in HEL activation cells and in causesHEL cells apoptosis and

causes apoptosis at 5 20mM [90]. O R3 O R1 at 5 mM [90]. 17 O R 20 O R H20 3 R 1 R 17 O 20 3 1 H 16 R3 O R OR4 OH 9 R OH 1 16 O R3 O 2O R 20 R4 OH 9 R4 R OH1 3 17 5 20 2 H R RR4 R 3 2 O 5 3 1 16R2 H O 19 R4 OH 9 R OH 18 18 19H 2 19 R4 3 18 18 195 Palmadorin R1 RR2 2 R3 R4 Other Palmadorin R1 R2 R3 R4 Other Palmadorin R R R R Other H A(148)H191 HCH2 3OH H4 4,18 PalmadorinM(160)CH R1OHR H2 R =CH3 R4 Other5 18 2 4,18 18 192 2 A(148)H HCH2OH H 4,18 M(160)CH2OH H =CH2 5 B(149)H HCHOAc H N(161)HCH2OH =CH2 5 2 4,18 PalmadorinB(149)H R R HCHR OAcR H Other3,4 PalmadorinN(161)HCH R 2ROH =CHR 2 R 5 Other C(150)H1 OHCH2 32 OH H4 O(162)CH2OAc1 H2 =CH3 2 4 5 2 4,183,4 O(162)CHOAc H =CH 5 A(C(148150)H)H HCHOHCH22OHOH H H 4,18 P(M(163160)HCH)CH2 2OH HOH =CH2CH2 5 5 D(151)H H H CH2OH 2 3 4,184,18 P(163)HCHOH CH 5 B(D(149151)H)H HCH H HOAc CH H2OH 3,4 Q(N(164161)HCH)HCH2OH2OH =CHCH2 3 5 5 E(152)=OOHHCH2 2OH 2 3 3,43,4 Q(164)HCHOH CH 5 C(E(150152)H)=OOHHCH OHCHOH H2OH 3,4 O(162)CH2OAc2 H =CH2 3 5 F(153)HOHHCH2 2OH F(153)HOHHCHOH 4,183,4 P(163)HCHOH CH 5 D(G(151154)H)=OH H H H CH CH22OHOH 3,4 2 O 3 2 3,4 G(154)=OH H CHOH 3,43,4 Q(164)HCHOH O CH 5 E(H(152155)=OOHHCH)H OHCHOAc2 H2OH 2 3 2 3,4 H(155)H OHCHOAc H 3,43,4 O O F(I(153156)HOHHCH)=O=OH2 CH2OHOH OH 2 3,4 O O I(156)=O=OH CH2OH 3,43,4 OH G(J(154157)=OH)=OOHCH H2OH CH2 HOH ORO J(157)=OOHCHOH H 3,4 OR H(K(155158)H)=O=OCH OHCHOAc2OH H H 3,43,4 H 22 3,4 O O K(158)=O=OCH2OH H 3,4 H I(156)=O=OH CH2OH Palmadorin R (165)R=AcOH 3,4 Palmadorin R (165)R=Ac J(157)=OOHCH2OHO H Palmadorin S (166)R=HOR O 3,4 Palmadorin S (166)R=H K(158)=O=OCHH 2OH H H H O O O OH O O OH Palmadorin R (165)R=Ac OH H O 4 O Palmadorin S (166)R=HH 4 OH HO H HO O OH O Cl 18 Palmadorin L (159)OH Granuloside (167) 18 Palmadorin L (159) OOH Cl Granuloside (167) H 4 OH Figure 16. Secondary metabolites derived from the Antarctic nudibranch (compounds 148–167). FigureHO 16. Secondary metabolites derived from the Antarctic nudibranch (compounds 148–167). OH Cl 18 Palmadorin L (159) Granuloside (167)

FigureFigure 16. 16.Secondary Secondary metabolites metabolites derived derived fromfrom the Antarctic nudibranch nudibranch (compounds (compounds 148148–167–167). ).

Mar. Drugs 2017, 15, 28 17 of 30

Mar. Drugs 2017, 15, 28 17 of 30 Recently, a new homosesterterpene named granuloside (167) (Figure 16), was characterized from the AntarcticRecently, nudibranch a new homosesterterpeneCharcotia granulosa named. Granuloside granuloside was (167 the) (Figure ﬁrst linear 16), was homosesterterpene characterized skeletonfrom everthe reportedAntarctic and, nudibranch despite the Charcotia low molecular granulosa complexity,. Granuloside its chemical was structurethe first poses linear many questionshomosesterterpene about its biogenesis skeleton ever and originreported in and, the nudibranch despite the [low91]. molecular complexity, its chemical 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] and haveMarine provided sponges a rich are array the oflargest biologically source of important new marine compounds natural [products92]. There reported are a large annually number of studies[11–13] and on sponges have provided from warm a rich orarray tropical of biologically waters, whereas important little compounds is known [92]. about There the are chemistry a large of spongesnumber from of studies the Arctic on orsponges Antarctic from waters. warm Actually,or tropical polar waters, species whereas of marine little is sponges known canabout also the be a richchemistry source of of biologically sponges from and the structurally Arctic or Antarctic interesting waters. molecules. Actually, polar species of marine sponges 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 169 yieldedyielded one one new new 3-alkyl 3‐alkyl pyridinium pyridinium alkaloid,alkaloid, viscosaline viscosaline (169 ( ) )(Figure (Figure 17) 17 [94],)[94 ],and and two two new new 3-alkyltetrahy-dropyridine3‐alkyltetrahy‐dropyridine alkaloids, alkaloids, haliclamineshaliclamines C C ( (170170) )and and D D (171 (171) (Figure) (Figure 17) 17 [95].)[95 In]. In2009, 2009, new new haliclamineshaliclamines E (E172 (172) and) and F (F173 (173) (Figure) (Figure 17 )17) were were subsequently subsequently obtained obtained from from this this Arctic Arctic sponge sponge [96 ]. Compound[96]. Compound169 showed 169 showed activity activity in the in feeding the feeding deterrence deterrence assay assay against against the amphipod the amphipodAnonyx Anonyx nugax andnugax the starﬁshand the Asteriasstarfish Asterias rubens from rubens the from North the SeaNorth [97 Sea]. Compounds [97]. Compounds169 and 169 170and showed170 showed a strong a inhibitionstrong inhibition against two against bacterial two bacterial strains isolated strains isolated from the from vicinity the vicinity of the sponge of the sponge [95,97]. [95,97]. The synthesis The of thesynthesis Arctic of sponge the Arctic alkaloids sponge were alkaloids also achievedwere also byachieved two groups by two [97 groups,98]. [97,98].

FigureFigure 17. 17. SecondarySecondary metabolites derived from the the Arctic Arctic sponge sponge HaliclonaHaliclona viscosa viscosa (compounds(compounds 168168–173–173).).

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) (Scheme8) 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 Scheme8. Four new diterpenoids, 177–180 (Figure 18) were isolated from the Antarctic sponge Dendrilla 177 180 Dendrilla membranosaFour new. Compound diterpenoids, 177 was– a nor(Figure‐diterpene 18) were gracilane isolated skeleton from derivative, the Antarctic while sponge 178–180 are membranosaC‐20 aplysulphurane. Compound‐type177 diterpeneswas a nor-diterpene [101]. gracilane skeleton derivative, while 178–180 are C-20 aplysulphurane-typeThree new sesterterpenes diterpenes [101of the]. suberitane class, suberitenones C (181) and D (182) and suberiphenolThree new (183 sesterterpenes) (Figure 18), were of the isolated suberitane from the class, sponge suberitenones Suberites sp. collected C (181) from and Antarctica. D (182) and suberiphenolUnfortunately, (183 )the (Figure new 18compounds), were isolated were fromneither the cytotoxic sponge Suberitesagainst thesp. human collected leukemia from Antarctica. K562 Unfortunately,cell‐line nor antimicrobial the new compounds against B. were subtilis neither, C. albicans cytotoxic, E. coli against and S. the aureus human [102]. leukemia K562 cell-line nor antimicrobialFive new steroids, against norselicB. subtilis acids, C. A–E albicans (184,–E.188 coli) (Figureand S. 18), aureus were[102 isolated]. from the sponge Crella sp.Five collected new steroids, in Antarctica. norselic Norselic acids A–E acid (A184 displayed–188) (Figure antibiotic 18), were activity isolated against from methicillin the sponge‐resistantCrella sp. collectedStaphylococcus in Antarctica. aureus, methicillin Norselic‐ acidsensitive A displayed S. aureus, antibioticvancomycin activity‐resistant against Enterococcus methicillin-resistant faecium and StaphylococcusCandida albicans aureus, and, methicillin-sensitive reduced consumptionS. of aureus food ,pellets vancomycin-resistant by sympatric mesograzers.Enterococcus Compounds faecium and 184–188 were also active against the Leishmania parasite with low micromolar activity [103].

Mar. Drugs 2017, 15, 28 18 of 30

Mar. Drugs 2017, 15, 28 18 of 30 Candida albicans, and reduced consumption of food pellets by sympatric mesograzers. Compounds + 184–188Mar.were Drugs also 2017, active 15, 28 againstOH the Leishmania parasiteOH with low micromolarOH activity [10318 of]. 30 H + OH OH OH H+ + -H+ H+ H

H+ + -H+ H+ H+ OH O H+ OH O O + O -H+ [O] O O + H -H+ [O] H H H HO OH OAcO [O] O Caminatal (174) OAc [O] Caminatal (174) O + O H OH O + H+ O H OH OH H OH H+ O OH O HO H H OH O H O HO H H + + HH [O] H +H ,-H OH + H + + H + [O] H +H ,-H OH OAc OAc OAc OAc 19-EpisuberitenoneOAc (176) OAc OAc 19-Episuberitenone (176) OAc Oxaspirosuberitenone (175) Oxaspirosuberitenone (175) SchemeScheme 8. 8.Possible Possible biogenesisbiogenesis ofof caminatalcaminatal ((174174),), oxaspirosuberitenoneoxaspirosuberitenone ( 175(175) and) and Scheme 8. Possible biogenesis of caminatal (174), oxaspirosuberitenone (175) and 19-episuberitenone (176). 19‐episuberitenone19‐episuberitenone (176 (176). ).

Figure 18. Secondary metabolites derived from the Antarctic sponges (compounds 177–189) and the Arctic sponge (compounds 190–193). Figure 18. Secondary metabolites derived from the Antarctic sponges (compounds 177–189) and the Figure 18. Secondary metabolites derived from the Antarctic sponges (compounds 177–189) and the Arctic sponge (compounds 190–193). Arctic sponge (compounds 190–193).

Mar. Drugs 2017, 15, 28 19 of 30

Darwinolide (189), a novel spongian diterpene, was characterized from the Antarctic sponge Dendrilla membranosa. Darwinolide displayed antibiofilm activity against MRSA with no mammalian cytotoxicity, and may present a suitable scaffold for the development of novel antibiofilm agents to treat drug resistant bacterial infections [104]. Barettin (190), 8,9-dihydrobarettin (191), bromoconicamin (192) and a novel brominated marine indole (193) (Figure 18) were isolated from the sponge Geodia barretti collected off the Norwegian coast. The compounds were evaluated as inhibitors of electric eel acetylcholinesterase. Compounds 190 and 191 displayed significant inhibition of the enzyme, 192 was less potent against acetylcholinesterase, and 193 was inactive. Based on the inhibitory activity, a library of 22 simplified synthetic analogs was designed and prepared to probe the role of the brominated indole. From the structure–activity investigation, it was shown that the brominated indole motif is not sufficient to generate a high acetylcholinesterase inhibitory activity, even when combined with natural cationic ligands for the acetylcholinesterase active site. The four natural compounds were also analysed for butyrylcholinesterase inhibitory activity and shown to display comparable activities [105].

10. Tunicates Tunicates comprise >2800 species and have yielded a diverse array of bioactive metabolites [10,106], including anticancer agents such as didemnin B from Trididemnum solidum, diazonamide from Diazona angulata, and the approved anticancer drug Ecteinascidin 743 (Yondelis™) from Ecteinascidia turbinata [107,108]. Bioassay-guided fractionation of CH2Cl2/MeOH extracts of the tunicate Aplidium cyaneum collected in Antarctica led to the isolation of aplicyanins A–F (194–199) (Figure 19), a group of alkaloids containing a bromoindole nucleus and a 6-tetra-hydropyrimidine substituent at C-3. Cytotoxic activity in the submicromolar range as well as antimitotic properties were found for compounds 195, 197, and 199, whereas compounds 194 and 196 proved to be inactive at the highest concentrations tested and compound 198 displayed only mild cytotoxic properties. The results clearly suggested a key role for the presence of the acetyl group at N-16 in the biological activity of this family of compounds [109]. Five new ecdysteroids, hyousterones A–D (200–203) and abeohyousterone (204) (Figure 19), were isolated from the Antarctic tunicate Synoicum adareanum by Baker and co-workers. Abeohyousterone (204) has moderate cytotoxicity toward several cancer cell lines. Hyousterones bearing the 14β-hydroxy group (200 and 202) were weakly cytotoxic, while the 14α-hydroxy hyousterones (201 and 203) were devoid of cytotoxicity [110]. Further chemical investigation of the same Antarctic tunicate S. adareanum yielded five new bioactive macrolides, palmerolide A (205) and D–G (206–209) (Figure 19). Most of these palmerolides were potent V-ATPase inhibitors and had sub-micromolar activity against melanoma [111,112]. Especially, palmerolide A remained the most potent of this series of natural products against melanoma cells. In the National Cancer Institute (NCI) sixty-cell panel, palmerolide A did not display cytotoxicity below 1 µM against any non-melanoma cell lines. In vivo activity of palmerolide A in mice has been confirmed in the NCI’s hollow fiber assay [113]. Structural features of palmerolide A such as the carbamate and the vinyl amide moieties led the Baker group to hypothesize a bacterial origin for this polyketide. One finding that supported the possibility was the identification of polyketide synthase (PKS) genes, similar to bryostatin biosynthetic genes [114]. Due to promising biological activity and limited access to natural supplies, as well as their challenging structures, palmerolide A and congeneric structures are important targets for chemical synthesis. Recent advances in the synthesis of the palmerolides have been reviewed by Lisboa and Dudley [115]. To date, three total syntheses [116–120] of palmerolide A have been reported. Four groups disclosed formal syntheses [121–126], and various synthetic approaches have also been described [127–135]. The synthesis of the reported structure of palmerolide C has also been achieved, and a structural revision has been proposed [136]. Mar. Drugs 2017, 15, 28 20 of 30 Mar. Drugs 2017, 15, 28 20 of 30

Mar. Drugs 2017, 15, 28 20 of 30

FigureFigure 19. 19.Secondary Secondary metabolites metabolites derived derived fromfrom the Antarctic Antarctic tunicates tunicates (compounds (compounds 194194–209–209). ). Figure 19. Secondary metabolites derived from the Antarctic tunicates (compounds 194–209). In 2009,In 2009, bioassay-guided bioassay‐guided fractionation fractionation ofof thethe Antarctic ascidian ascidian AplidiumAplidium species,species, led led to the to the In 2009, bioassay‐guided fractionation of the Antarctic ascidian Aplidium species, led to the characterizationcharacterization of twoof two new new biologically biologically active active meroterpene meroterpene derivatives, derivatives, rossinones rossinones A A (210 (210) and) and B B (211 ) (characterization211) (Figure 20). of twoThe newrossinones biologically exhibited active meroterpeneantiinflammatory, derivatives, antiviral rossinones and antiproliferative A (210) and B (Figure 20). The rossinones exhibited antiinﬂammatory, antiviral and antiproliferative activities [137]. activities(211) (Figure [137]. 20).In additon, The rossinones rossinone exhibitedB (211) was antiinflammatory, proven to take part antiviral in the wholeand ‐antiproliferativecolony chemical In additon, rossinone B (211) was proven to take part in the whole-colony chemical defense of defenseactivities of [137]. Aplidium In additon, falklandicum rossinone, repelling B (211 both) was sea proven stars and to takeamphipods part in the[138]. whole The ‐followingcolony chemical year, a Aplidium falklandicum, repelling both sea stars and amphipods [138]. The following year, a biomimetic biomimeticdefense of Aplidium total synthesis falklandicum of (±), repelling‐rossinone both B was sea starsachieved and amphipodsthrough a highly[138]. The efficient following strategy year, asa ± totalshownbiomimetic synthesis in Scheme total of ( synthesis 9)-rossinone [139]. Twoof (±) Byears‐rossinone was later, achieved Bthree was through novelachieved rossinone a through highly‐related a efﬁcient highly meroterpenes efficient strategy strategy as(212 shown–214 as) in Scheme(Figureshown9[ in20)139 Scheme were]. Two obtained 9 years [139]. later,from Two the threeyears Antarctic novellater, three ascidian rossinone-related novel Aplidium rossinone fuegiense. meroterpenes‐related The meroterpenes new (212 compounds–214 ()212 (Figure– were214) 20) werefound(Figure obtained to 20) be selectively fromwere obtained the Antarctic localized from the ascidianin the Antarctic visceraAplidium ascidian of the fuegiense. ascidian Aplidium [140].The fuegiense. new compounds The new compounds were found were to be selectivelyfound to localized be selectively in the localized viscera in of the the viscera ascidian of the [140 ascidian]. [140]. OTMS O O OMe OHC OTMS O O OMe OMe OHC NC a b c OMe NC OTMS OAc a b c TBDPSO OTMS OAc TBDPSO TBDPSO OMOM TBDPSO TBDPSO TBDPSO O d OMOM O d

OH OH OH OAc O OH OH OH OAc O h O g O O f e OMe O 211 O H OMe O h O g O OMe O f e OMe OMe O 211 O H OMe OMe O OMe OMe OMe H O OH OH H O MOMO OH MOMO OH O OH OH O MOMO OH MOMO OH 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 Scheme(TMSCN), 9. Synthesis NEt3, CH3 ofCN, rossinone 99%; (b) LiHMDS, B (211). THF, Reagents −78 °C, and then conditions: 3‐methyl‐2‐ (butenal,a) Trimethylsilyl TMS migration, cyanide (TMSCN), NEt3, CH3CN, 99%; (b) LiHMDS, THF, −78 °C, then 3‐methyl‐2‐butenal, TMS migration, 75%; (c) 1 N HCl, THF, then Ac2O/py, then HF, CH◦ 3CN, then 2,2‐Dimethoxypropane (DMP), (TMSCN), NEt3, CH3CN, 99%; (b) 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), 75%;4‐(Dicyanomethylene) (c) 1 N HCl, THF,‐2‐ thenmethyl Ac‐6‐(4O/py,‐dimethylaminostyryl) then HF, CH CN,‐4H‐pyran then 2,2-Dimethoxypropane(DCM), 51%; (d) nBuLi, −78 (DMP), °C, 4‐(Dicyanomethylene)‐2‐methyl‐62‐(4‐dimethylaminostyryl)3 ‐4H‐pyran (DCM), 51%; (d) nBuLi, −78 °C, 4-(Dicyanomethylene)-2-methyl-6-(4-dimethylaminostyryl)-488%; (e) K2CO3/MeOH, 79%; (f) 6 N HNO3, then AgO, 90%;H -pyran(g) toluene, (DCM), sealed 51%; tube, (d) n 150BuLi, °C;− (78h) ◦C, 88%; (e) K2CO3/MeOH, 79%; (f) 6 N HNO3, then AgO, 90%; (g) toluene, sealed tube, 150 °C; (h) CH3OH/H2O, TsOH, 80 °C, 31%. 88%; (e)K CO /MeOH, 79%; (f) 6 N HNO , then AgO, 90%; (g) toluene, sealed tube, 150 ◦C; CH3OH/H2 2O,3 TsOH, 80 °C, 31%. 3 ◦ (h) CH3OH/H2O, TsOH, 80 C, 31%. Mar. Drugs 2017, 15, 28 21 of 30

FromMar. Drugs the 2017 sub-Arctic, 15, 28 ascidian Synoicum pulmonaria collected off the Norwegian coast,21 three of 30 new brominated guanidinium oxazolidinones were isolated, named synoxazolidinones A–C (215–217) (Figure 20From)[141 the–143 sub].‐Arctic The ascidian backbone Synoicum of the pulmonaria compounds collected contains off the Norwegian a 4-oxazolidinone coast, three ring new rarely seen inbrominated natural guanidinium products. Synoxazolidinonesoxazolidinones were isolated, A (215 )named and Bsynoxazolidinones (216) exhibited A–C antibacterial (215–217) and (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 structureactivities, [141]. and Synoxazolidinone 215 displayed higher C could activity inhibit than the 216 growth because of of Gram-positive the chlorine atom bacteria in its structureStaphylococcus aureus[141].and Synoxazolidinone methicillin-resistant C couldS. inhibit aureus theat growth a concentration of Gram‐positive of 10 µbacteriag/mL Staphylococcus [142]. In addition, aureus 215 and 217and displayedmethicillin‐resistant a broad S. andaureus high at a activityconcentration toward of 10 the μg/mL adhesion [142]. In and addition, growth 215 of and 16 217 known biofoulingdisplayed species a broad of marine and high bacteria, activity microalgae, toward the adhesion and crustaceans. and growth Compound of 16 known217 biofoulingwas the most activespecies compound of marine and wasbacteria, comparable microalgae, to and the commercialcrustaceans. Compound antifouling 217 product was the Sea-Nine-211 most active [144]. Pulmonarinscompound A (218and) andwas Bcomparable (219) (Figure to 20the) werecommercial two new antifouling dibrominated product marine Sea‐Nine acetylcholinesterase‐211 [144]. inhibitorsPulmonarins that were A also(218) isolatedand B from(219) this(Figure sub-Arctic 20) were ascidian. two new Both dibrominated218 and 219 marinedisplayed 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 acetylcholinesteraseknown natural acetylcholinesterase inhibitiors [145]. inhibitiors In addition, [145]. the In pulmonarinsaddition, the pulmonarins were generally were activegenerally against the adhesionactive against and growth the adhesion of several and growth bacteria of several [144]. bacteria [144].

FigureFigure 20. Secondary 20. Secondary metabolites metabolites derived derived from from thethe Antarctic tunicates tunicates (compounds (compounds 210–210214)– and214 )the 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 Ascompounds demonstrated (Table by1) thiswith review, complex polar structures organisms and potent have yieldedbiological an activities impressive including array the of novel compoundscytotoxic (Table cyclic1 )acylpeptides, with complex mixirins structures A–C (1 and–3), from potent the biological Arctic marine activities bacterium including Bacillus the sp. [15]; cytotoxic cyclicthe acylpeptides, unusual mixirinsantibacterial A–C polyketide, (1–3), from thelindgomycin Arctic marine (46) bacteriumfrom the Bacillusculturesp. broth [15]; theof unusuala antibacterialLindgomycetaceae polyketide, strain lindgomycin [36]; the antioxidant (46) from compound the culture ramalin broth of(104 a) Lindgomycetaceae from the Antarctic lichen strain [36]; the antioxidantRamalina terebrata compound [61]; the ramalin new antiparasitic (104) from tricyclic the Antarctic sesquiterpenoids, lichen Ramalinashagenes A terebrata (130) and[61 B ];(131 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 205 206 209 soft coralAntarctic [76]; andtunicate the Synoicum new macrolides, adareanum palmerolide [111,112]. A ( ) and D–G ( – ) with potent V-ATPase inhibitoryThe and natural sub-micromolar products derived activity from against polar regions melanoma appear from to have the a Antarctic high hit rate tunicate regardingSynoicum adareanumbiological[111 ,activity,112]. varying from cytotoxic, enzyme inhibitory, antioxidant, antiparasitic, antiviral Theto antibacterial natural products and so derived on. Secondary from polar metabolism regions in appear polar habitats to have ais high largely hit driven rate regarding by ecological biological activity,requirements varying from of the cytotoxic, producing enzyme organism. inhibitory, Successful antioxidant, organisms antiparasitic,will often have antiviral specific tometabolic antibacterial and sopathways on. Secondary that produce metabolism unique in functional polar habitats natural is largelyproducts driven that bestow by ecological ecological requirements advantage, of the producingincreasing organism. the possibility Successful of finding organisms pharmaceutical will often lead have molecules. speciﬁc metabolic pathways that produce unique functional natural products that bestow ecological advantage, increasing the possibility of ﬁnding pharmaceutical lead molecules. Mar. Drugs 2017, 15, 28 22 of 30

Table 1. Novel natural products isolated from polar organisms.

PHYLUM/Class Species Compounds Bioactivity Region References MICROORGANISMS Bacteria Bacillus sp. 1–3 Cytotoxic Arctic [15] Salegentibacter sp. 4–14 Antimicrobial and cytotoxic Arctic [16,17] Pseudoalteromonas 15 16, 17 Rradical scavenging Antarctic [18] haloplanktis Nostoc sp. 18 Antibacterial Antarctic [19] Janthinobacterium sp. 19, 20 Antimycobacterial Antarctic [20] Pseudomonas sp. 21, 22 Antibacterial Antarctic [21] Actinomyces Streptomyces sp. 23–25 Arctic [22] Nocardiopsis sp. 26 Anti-angiogenesis Arctic [23] Nocardia dassonvillei 27 Antifungal and cytotoxic Arctic [24] Streptomyces nitrosporeus 28, 29 Antiviral Arctic [25] 30 Enzyme inhibitory Streptomyces sp. Arctic [27] 31 Enzyme inhibitory and cytotoxic Streptomyces griseus 32 Antibacterial Antarctic [28] Streptomyces griseus 33 Neuroprotective Antarctic [29] Microbispora aerata 34 Antiproliferative and cytotoxic Antarctic [30] Nocardiopsis sp. 35, 36 Antarctic [31] Fungi Penicillium algidum 37 Anticancer Arctic [32] 38–40 Cytotoxicity 41 Antibacterial Eutypella sp. Arctic [33–35] 42 Cytotoxicity 43–45 Immunosuppression Lindgomycetaceae 46, 47 Antibacterial Arctic [36,37] Trichoderma polysporum 48 Antifungal Arctic [38] 49, 50 Geomyces sp. Antarctic [39] 51–53 Antifungal and antibacterial Trichoderma asperellum 54–59 Antifungal Antarctic [40] 60–62 Oidiodendron truncatum Cytotoxic Antarctic [42] 63–66 Penicillium crustosu m 67, 68 NF-κB inhibitory Antarctic [43] 69 Moderate cytotoxic Penicillium sp. 70–78 Antarctic [45,46] 79 Cytotoxic Penicillium funiculosum 80, 81 Antarctic [47] Pseudogymnoascus sp. 82–85 Antarctic [48] Aspergillus 86–90 Antarctic [49] ochraceopetaliformis 91 Antiviral 92 Cytotoxic and enzyme inhibitory LICHEN Stereocaulon alpinum 93–98 Enzyme inhibitory Antarctic [55–59] 99 Antioxidant and antibacterial Huea sp. 100–103 Enzyme inhibitory Antarctic [60] Ramalina terebrata 104 Antioxidant Antarctic [61] MOSS 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 113 Ichthyotoxic Antarctic [67] Anthomastus 114–120 Weak cytotoxic Antarctic [68] bathyproctus Alcyonium grandis 121–129 Antarctic [69] Undescribed octocoral 130, 131 Antiparasitic Antarctic [76] Thuiria breitfussi 132, 133 Arctic [77] 134–136 Gersemia fruticosa Arctic [80] 137 Antibacterial ECHINODERMS Staurocucumis liouvillei 138, 139 Antiviral Antarctic [81] Staurocucumis turqueti 140 Antarctic [82] Achlionice violaecuspidata 141–143 Antarctic [83] Austrodoris MOLLUSCS 144–147 Antarctic [84,85] kerguelenensis Mar. Drugs 2017, 15, 28 23 of 30

Table 1. Cont.

PHYLUM/Class Species Compounds Bioactivity Region References Austrodoris 148–166 Erythroleukemia inhibitory Antarctic [89] kerguelenensis Charcotia granulosa 167 Antarctic [91] SPONGES Haliclona viscosa 168–173 Arctic [93–96] Suberites caminatus 174–176 Antarctic [99,100] Dendrilla membranosa 177–180 Antarctic [101] Suberites sp. 181–183 Antarctic [102] Crella sp. 184–188 Antibacterial and antifungal Antarctic [103] Dendrilla membranosa 189 Antibacterial Antarctic 104] 190 Geodia barretti Enzyme inhibitory Arctic [105] 191–193 TUNICATES Aplidium cyaneum 194–199 Antimitotic Antarctic [109] 200–203 Moderate cytotoxic Synoicum adareanum 204 Antarctic [110–112] 205–209 Cytotoxic and enzyme inhibitory Antiinﬂammatory, antiviral and Aplidium sp. 210, 211 Antarctic [137] antiproliferative Aplidium fuegiense 212–214 Antarctic [140] 215–217 Antibacterial and antifungal Synoicum pulmonaria Arctic [141–145] Enzyme inhibitory and 218, 219 antibacterial

However, when compared to the large number of polar microorganisms which have been reported, very few have been screened for the production of interesting secondary metabolites. This situation may be attributed to the difficulties in cultivating polar microorganisms, some of which cannot survive under normal laboratory conditions and therefore cannot be cultured using traditional techniques. As yet, the potential of this area remains virtually untapped. Nowadays, advances in laboratory techniques have led to cultivation of some previously inaccessible extremophiles. Moreover, new tools developed recently in the fields of bioinformatics [146], analytics [147], and molecular biology [148], in combination with rapid improvement in sequencing technology, might herald a new era of research into this specific source.

Acknowledgments: The authors express thanks to the people who helped with this work. This work was financed by NSFC grant (21602152, 81403036), Shandong Provincial Natural Science Foundation (ZR2016BB01, ZR2014HM048), Shandong Provincial Key Research and Development Program (2016GSF202002), Shandong Provincial Medical Science and Technology Development Project (2013WS0321), Taian Science and Technology Development Project (2016NS1214), Shandong Provincial Education Department Project (J15LM56), National Undergraduate Training Program for Innovation and Entrepreneurship (201610439263) and Taishan Medical University High-level Development Project (2015GCC15). Author Contributions: Yuan Tian and Yan-Ling Li contributed equally in the writing of this manuscript. Feng-Chun Zhao collected all the references. Conflicts of Interest: The authors declare no conflict of interest.

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