marine drugs Review
Secondary Metabolites from Polar Organisms Yuan Tian 1, *, Yan-Ling Li 1 and Feng-Chun Zhao 2 1 2
*
College of Life Science, Taishan Medical University, Taian 271016, Shandong, China;
[email protected] College of Life Science, Shandong Agricultural University, Taian 271018, Shandong, China;
[email protected] Correspondence:
[email protected]; Tel.: +86-358-623-5778
Academic Editor: Orazio Taglialatela-Scafati Received: 7 January 2017; Accepted: 29 January 2017; Published: 23 February 2017
Abstract: Polar organisms have been found to develop unique defences against the extreme environment environment, leading to the biosynthesis of novel molecules with diverse bioactivities. This review covers the 219 novel natural products described since 2001, from the Arctic and the Antarctic microoganisms, lichen, moss and marine faunas. The structures of the new compounds and details of the source organism, along with any relevant biological activities are presented. Where reported, synthetic and biosynthetic studies on the polar metabolites have also been included. Keywords: natural products; secondary metabolism; structure elucidation; biological activity; biosynthesis; chemical synthesis
1. Introduction Organisms from special ecosystems such as the polar regions are a rich source of various chemical scaffolds and novel natural products with promising bioactivities. Polar regions, which refer to the Arctic, the Antarctic and their subregions, are remote and challenging areas on the earth. To survive under the constant influence of low temperatures, strong winds, low nutrient and high UV radiation or combinations of these factors [1], polar organisms require a diverse array of biochemical and physiological adaptations that are essential for survival. These adaptations are often accompanied by modifications to both gene regulation and metabolic pathways, increasing the possibility of finding unique functional metabolites of pharmaceutical importance. Polar regions are complex ecosystems that harbor diverse groups of fauna and microorganisms including bacteria, actinomycetes and fungi. Physiological adaptations have enabled psychrophilic organisms to thrive in the polar regions, especially microorganisms which are high in number and usually uncharacterized [2–5]. However, when compared to the large number of polar microorganisms which have been reported, very few have been screened for the production of interesting secondary metabolites. The advent of modern techniques provides the opportunity to find novel metabolites. From 2001 to 2016, a vast amount of new biological natural compounds with various activities, such as anti-bacteria, anti-tumor, anti-virus and so on, have been isolated from polar organisms including microorganisms, lichen, moss, bryozoans, cnidarians, echinoderms, molluscs, sponges and tunicates. Natural products from the Arctic or the Antarctic organisms have been the subject of several review articles. In 2007, Lebar et al. reviewed the studies on structure and bioactivity of cold-water marine natural products, including many polar examples [6]. In 2009, Wilson and Brimble reviewed molecules derived from the extremes of life, including some polar examples [7]. In 2011, advances in the chemistry and bioactivity of arctic sponge were reviewed by Hamann and his co-workers [8]. In 2013, Liu et al. reviewed a number of new secondary metabolites with various activities derived from both Antarcitc and Arctic organisms [9], while in 2014, Skropeta and Wei published a review on natural products isolated from deep-sea sources, which included some polar organisms [10]. Moreover,
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published a review on natural products isolated from deep‐sea sources, which included some polar organisms [10]. Moreover, Blunt and his co‐workers published periodical reviews on the Mar.characteristics of various marine natural products with some polar examples [11–13]. Drugs 2017, 15, 28 2 of 30 However, comprehensive reviews of natural products from polar regions were rare; therefore, we describe here the source, chemistry, and biology of the newly discovered biomolecules from the polar We also summarize the chemical and the biosynthetic relationship of Blunt andorganisms. his co-workers published periodical reviewssynthesis on the characteristics of various marine natural metabolites. The Metabolites Name Index in combination with the Source Index, the Biological products with some polar examples [11–13]. Activity Index and the References on isolation in the accompanying tables, will help understand the However, comprehensive reviews of natural products from polar regions were rare; therefore, we fascinating chemistry and biology of natural products derived from polar organisms. describe here the source, chemistry, and biology of the newly discovered biomolecules from the polar
organisms. We also summarize the chemical synthesis and the biosynthetic relationship of metabolites. 2. Microorganisms The Metabolites Name Index in combination with the Source Index, the Biological Activity Index and The microbial diversity of polar environments is a fertile ground for new bioactive compounds, the References on isolation in the accompanying tables, will help understand the fascinating chemistry genes, proteins, microorganisms and other products with potential for commercial use [14]. and biology of natural products derived from polar organisms. 2.1. Unicellular Bacteria 2. Microorganisms
TheThe culture broth of the marine bacterium Bacillus sp., isolated from the sea mud near the Arctic microbial diversity of polar environments is a fertile ground for new bioactive compounds, pole, was found to yield three and new other cyclic acylpeptides as for mixirins A (1), B (2) [14]. and C (3) genes, proteins, microorganisms products with named potential commercial use (Figure 1) [15]. All of the three compounds were found to display significant cytotoxicity against 50) values of 0.68, 2.1.human colon tumor cells (HCT‐116) with half maximal inhibitory concentration (IC Unicellular Bacteria 1.6, 1.3 μg/mL, respectively. TheFour culture broth of the marine bacterium Bacillus sp., isolated from the sea mud near the Arctic new aromatic nitro compounds (4–7) (Figure 1) along with fifteen known ones were pole, was found to yield three new cyclic acylpeptides named as mixirins A (1), B (2) and C (3) reported from the Salegentibacter strain T436, isolated from a bottom section of a sea ice floe collected (Figure [15]. All Ocean. of the three compounds found to display cytotoxicity against from 1) the Arctic The new natural were products showed weak significant antimicrobial and cytotoxic human colon tumor cells (HCT-116) with half maximal inhibitory concentration (IC ) values of 0.68, 50 activities [16]. Further study of the same bacterium isolate yielded another seven new aromatic nitro 1.6,compounds (8–14) (Figure 1) [17]. 1.3 µg/mL, respectively.
Figure 1. Secondary metabolites derived from the Arctic bacteria (compounds 1–14). Figure 1. Secondary metabolites derived from the Arctic bacteria (compounds 1–14).
A novel diketopiperazine, named cyclo‐(D‐pipecolinyl‐L‐isoleucine) (15) (Figure 2), and two
Four newpeptides aromatic(16, nitro compounds (Figure 1) along withdiketopiperazines fifteen known ones were reported new linear 17) (Figure 2), (4–7) along with seven known were isolated from the Salegentibacter strain T436, isolated from a bottom section of a sea ice floe collected from from the cell‐free culture supernatant of the Antarctic psychrophilic bacterium Pseudoalteromonas thehaloplanktis TAC125 [18]. Peptide 17 and a known phenyl‐containing diketopiperazine showed free Arctic Ocean. The new natural products showed weak antimicrobial and cytotoxic activities [16]. Further study of the same bacterium isolate yielded another seven new aromatic nitro compounds radical scavenging properties, with the phenyl group essential for activity. (8–14) (Figure 1) [17]. A novel diketopiperazine, named cyclo-(D-pipecolinyl-L-isoleucine) (15) (Figure 2), and two new linear peptides (16, 17) (Figure 2), along with seven known diketopiperazines were isolated from the cell-free culture supernatant of the Antarctic psychrophilic bacterium Pseudoalteromonas haloplanktis TAC125 [18]. Peptide 17 and a known phenyl-containing diketopiperazine showed free radical scavenging properties, with the phenyl group essential for activity.
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Figure 2. Secondary metabolites derived from the Antarctic bacteria (compounds 15–22).
Figure 2. Secondary metabolites derived from the Antarctic bacteria (compounds 15–22).
From the Antarctic cyanobacterium Nostoc CCC 537, an antibacterial lead molecule (18) (Figure 2) From the Antarctic cyanobacterium CCC 537, an antibacterial molecule (Figure 2) was obtained. Compound 18 exhibited Nostoc antibacterial activity against two lead Gram positive (18) pathogenic wasstrains obtained. Compound negative strains 18 exhibited antibacterial activity against resistant strains two Gram positive pathogenic and seven Gram including three multi‐drug of Escherichia strains and seven Gram negative strains including three multi-drug resistant strains of Escherichia coli, coli, with minimal inhibition concentration (MIC) values in the range of 0.5–16.0 μg/mL [19]. Two pigments named violacein (MIC) (19) and flexirubin (20) (Figure 2) were isolated with minimal inhibition concentration values in the range of 0.5–16.0 µg/mL [19]. from two Antarctic bacterial strains. The two displayed antibacterial activities against some Two pigments named violacein (19)compounds and flexirubin (20) (Figure 2) were isolated from two Antarctic mycobacteria with low MIC values (ranging from 2.6 to 34.4 μg/mL), and might be valuable natural bacterial strains. The two compounds displayed antibacterial activities against some mycobacteria lead compounds for new antimycobacterial drugs used for tuberculosis chemotherapy [20]. with low MIC values (ranging from 2.6 to 34.4 µg/mL), and might be valuable natural lead compounds purification of for Antarctic strain chemotherapy Pseudomonas BNT1 for newBioassay‐guided antimycobacterial drugs used tuberculosis [20]. extracts produced three rhamnolipids including two new ones (21, 22). Compound 21 was effective against the tested human Bioassay-guided purification of Antarctic strain Pseudomonas BNT1 extracts produced three pathogens strains Burkholderia cepacia, B. metallica, B. seminalis, B. latens and Staphylococcus aureus with rhamnolipids including two new ones (21, 22). Compound 21 was effective against the tested human low MIC and minimun bacteriocidal concentration (MBC) values, while compound 22 only had pathogens strains Burkholderia cepacia, B. metallica, B. seminalis, B. latens and Staphylococcus aureus moderate antimicrobial effect against S. aureus with an MBC value of 100 μg/mL [21].
with low MIC and minimun bacteriocidal concentration (MBC) values, while compound 22 only had moderate antimicrobial effect against S. aureus with an MBC value of 100 µg/mL [21]. 2.2. Actinomycetes In this century, actinomyces derived from polar regions have yielded an array of interesting 2.2. Actinomycetes
new metabolites. Three new pyrrolosesquiterpenes, glyciapyrroles A (23), B (24), and C (25) (Figure In this century, actinomyces derived from polar regions have yielded an array of interesting new 3), along with three known ones, iketopiperazines cyclo(leucyl‐prolyl), cyclo(isoleucyl‐prolyl), and metabolites. Three new pyrrolosesquiterpenes, glyciapyrroles A (23), B (24), and C (25) (Figure cyclo(phenylalanyl‐prolyl), were isolated from the Streptomyces sp. NPS008187 originating from a 3), along with three known ones, iketopiperazines cyclo(leucyl-prolyl), cyclo(isoleucyl-prolyl), and marine sediment collected in Alaska near the Arctic [22].
cyclo(phenylalanyl-prolyl), were isolated from the Streptomyces sp. NPS008187 originating from a marine sediment collected in Alaska near the Arctic [22].
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Figure 3. Secondary metabolites derived from the Arctic actinomyces (compounds 23–27, 30, 31). Figure 3. Secondary metabolites derived from the Arctic actinomyces (compounds 23–27, 30, 31).
The Arctic seaweed‐associated actinomycete Nocardiopsis sp. 03N67 was found to produce a Thebioactive Arctic seaweed-associated actinomycete Nocardiopsis sp. 03N67 foundtumor to produce a rare rare diketopiperazine, cyclo‐( L‐Pro‐L‐Met) (26) (Figure 3). It was inhibited necrosis bioactive diketopiperazine, cyclo-( L -ProL -Met) (26) (Figure 3). It inhibited tumor necrosis factor-α factor‐α (TNF‐α)‐induced tube formation and invasion at 10 μM, a concentration at which no (TNF-α)-induced tube formation and invasion at 10 µM, a concentration at which no cytotoxicity was cytotoxicity was observed. Anti‐angiogenesis activity against human umbilical vein endothelial cells observed. Anti-angiogenesis activity against human umbilical vein endothelial cells (HUVECs) of (HUVECs) of compound 26 is an encouraging bioprobe to develop new anticancer therapeutics from compound 26 is an encouraging bioprobe to develop new anticancer therapeutics from such type of such type of small molecules in near future [23]. The marine actinomycete small molecules in near future [23].Nocardia dassonvillei BM‐17, obtained from a sediment sample collected in the Arctic Ocean, has furnished a new secondary metabolite, N‐(2‐hydroxyphenyl)‐ The marine actinomycete Nocardia dassonvillei BM-17, obtained from a sediment sample collected 2‐phenazinamine (27) (Figure 3), and six known antibiotics. The new compound showed weak in the Arctic Ocean, has furnished a new secondary metabolite, N-(2-hydroxyphenyl)-2-phenazinamine antifungal activity against Candida albicans, with a MIC value of 64 μg/mL and low cancer against cell (27) (Figure 3), and six known antibiotics. The new compound showed weak antifungal activity cytotoxicity against HepG2, A549, HCT‐116 and COC1 cells, with IC 50 values of 40.33, 38.53, 27.82 Candida albicans, with a MIC value of 64 µg/mL and low cancer cell cytotoxicity against HepG2, A549, and 28.11 μg/mL, respectively [24]. HCT-116 and COC1 cells, with IC50 values of 40.33, 38.53, 27.82 and 28.11 µg/mL, respectively [24]. Chemical examination from the Arctic actinomycete Streptomyces nitrosporeus CQT14‐24 Chemical examination from the Arctic actinomycete Streptomyces nitrosporeus CQT14-24 resulted resulted in the isolation of two new alkaloids, named as nitrosporeusines A (28) and B (29) (Scheme in the isolation of two new alkaloids, named as nitrosporeusines A (28) and B (29) (Scheme 1), with 1), with an unprecedented skeleton containing benzenecarbothioc cyclopenta[c]pyrrole‐1,3‐dione. an unprecedented skeleton containing benzenecarbothioc cyclopenta[c]pyrrole-1,3-dione. Both 28 Both 28 and 29 showed inhibitory activity against the influenza WSN virus (H1N1) in Madin–Darby and 29 showed inhibitory activity against the influenza WSN virus (H1N1) in Madin–Darby canine canine kidney (MDCK) cells with the dose of 50 μM. In an in vitro plaque reduction assay, 29 kidney (MDCK) cells with the dose of 50 µM. In an in vitro plaque reduction assay, 29 exhibited exhibited dose‐dependent reduction of the production of the viral progeny which was produced by dose-dependent reduction of the production of thevirus. viral The progeny which was produced(EC by50) the the infected MDCK cells with influenza A/WSN/33 half effective concentration infected MDCK cells with influenza A/WSN/33 virus. The half effective concentration (EC50 ) value of 29 for the inhibition of viral plaque formation was quite comparable to that of the positive value of 29 for the inhibition viral [25]. plaque formation was quite have comparable tointerest that ofto the control oseltamivir phosphate of (Osv‐P) Their biological activities attracted positive control oseltamivir phosphate (Osv-P) [25]. Their biological activities have attracted interest synthesize these compounds. Efficient stereoselective synthesis of the natural enantiomer of to synthesize these compounds. Efficient stereoselective synthesis of the natural enantiomer of nitrosporeusines A and B was performed by Reddy’s groups. An overall five‐step process starting nitrosporeusines A and B was performed by Reddy’s groups. An overall five-step process starting from 5,6‐dihydrocyclopenta[c]pyrrole‐1,3(2H,4H)‐dione and p‐hydroxybenzoic acid is summarized in Scheme 1 [26]. from 5,6-dihydrocyclopenta[c]pyrrole-1,3(2H,4H)-dione and p-hydroxybenzoic acid is summarized in new secondary metabolites, arcticoside (30) and C‐1027 chromophore‐V (31) (Figure 3), SchemeTwo 1 [26]. from 3), were isolated along with three kown compounds, C‐1027 chromophore‐III, fijiolides A and B Two new secondary metabolites, arcticoside (30) and C-1027 chromophore-V (31) (Figure the isolated culture along of an Arctic marine actinomycete Streptomyces strain. Compounds 30 and 31 inhibited were with three kown compounds, C-1027 chromophore-III, fijiolides A and B from Candida albicans isocitrate lyase, an enzyme that plays an important role in the pathogenicity of C. the culture of an Arctic marine actinomycete Streptomyces strain. Compounds 30 and 31 inhibited albicans. Furthermore, 31 exhibited significant cytotoxicity against breast carcinoma MDA‐MB231 Candida albicans isocitrate lyase, an enzyme that plays an important role in the pathogenicity of cells and colorectal carcinoma HCT‐116 cells, with IC50 values of 0.9 and 2.7 μM, respectively [27].
C. albicans. Furthermore, 31 exhibited significant cytotoxicity against breast carcinoma MDA-MB231 cells and colorectal carcinoma HCT-116 cells, with IC50 values of 0.9 and 2.7 µM, respectively [27].
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Mar. Drugs 2017, 15, 28 O
5 of 30 O
AcO
Mar. Drugs 2017, 15, 28 NH O O NH
a
a
NH O O NH
O
b
HO
NH O
AcO
O NH
b O
O
O
O HO
c
NH O
HO
O NH SH
c O
OH O
O
HO e HO
O OH
d
e O
SH HO
OH
d
OH
O
H N
S H N O O Nitrosporeusine S A (28) + H N OO Nitrosporeusine A (28) + S H N O O Nitrosporeusine S B (29)
5 of 30 O H O OH H OH O H O OH H
OH Scheme 1. Synthesis of natural products nitrosporeusines A (28) and B (29). Reagents and conditions: O conditions: Scheme 1. Synthesis of natural products nitrosporeusines AOH(28) and B (29). Reagents and OH Nitrosporeusine B (29) (a) SeO2, 1,4‐dioxane, microwave, 110 °C, 61%; (b) Amano PS lipase, THF, CH2=CHOAc, 38%; (c)
(a) SeO2 , 1,4-dioxane, microwave, 110 ◦ C, 61%; (b) Amano PS lipase, THF, CH2 =CHOAc, 38%; Amano PS lipase, phosphate buffer, 92%; (d) Lawessonʹs reagent, acetonitrile, microwave, 100 °C, ◦ Scheme 1. Synthesis of natural products nitrosporeusines A (28) and B (29). Reagents and conditions: (c) Amano PS lipase, phosphate buffer, 92%; (d) Lawesson's reagent, acetonitrile, microwave, 100 C, 53%; (e) H 2O, room temperature (rt), 65%. (a) (e) SeO 1,4‐dioxane, microwave, °C, 61%; (b) Amano PS lipase, THF, CH2=CHOAc, 38%; (c) 53%; H22, O, room temperature (rt),110 65%.
Amano PS lipase, phosphate buffer, 92%; (d) Lawessonʹs reagent, acetonitrile, microwave, 100 °C, A Streptomyces griseus strain NTK 97, recovered from an Antarctic terrestrial sample, yielded a 53%; (e) H 2O, room temperature (rt), 65%.
A Streptomyces griseus strainfrigocyclinone NTK 97, recovered from 4), consisting an Antarctic of terrestrial sample, moiety yielded a new angucyclinone antibiotic (32) (Figure a tetrangomycin new angucyclinone antibiotic frigocyclinone (32) (Figure 4), consisting of a tetrangomycin moiety attached through a C‐glycosidic linkage with the aminodeoxysugar ossamine. Frigocyclinone A Streptomyces griseus strain NTK 97, recovered from an Antarctic terrestrial sample, yielded a revealed good inhibitory activities against Bacillus subtilis and Staphylococcus aureus [28]. Another attached through a C-glycosidic linkage with the aminodeoxysugar ossamine. Frigocyclinone revealed new angucyclinone antibiotic frigocyclinone (32) (Figure 4), consisting of a tetrangomycin moiety Antarctic Streptomyces griseus strain NTK14 was and shown to contain the novel‐type angucyclinone good inhibitory activities against Bacillus subtilis Staphylococcus aureus [28]. Another Antarctic attached through a C‐glycosidic linkage with the aminodeoxysugar ossamine. Frigocyclinone gephyromycin (33) (Figure 4), and two known compounds, fridamycin E and dehydrorabelomycin. Streptomyces griseus strain NTK14 was shownBacillus to contain the novel-type angucyclinone gephyromycin revealed good inhibitory activities against subtilis and Staphylococcus aureus [28]. Another Gephyromycin, an unprecedented intramolecular ether bridge, displayed angucyclinone glutaminergic Streptomyces griseus strain NTK14 was shown contain the novel‐type (33)Antarctic (Figure 4), and with two known compounds, fridamycin E to and dehydrorabelomycin. Gephyromycin, activity (agonist) towards neuronal cells. In addition, 33 exhibited no acute cytostatic activities, and gephyromycin (33) (Figure 4), and two known compounds, fridamycin E and dehydrorabelomycin. with an unprecedented intramolecular ether bridge, displayed glutaminergic activity (agonist) towards the lack of cytotoxicity made its neuroprotective properties even more valuable [29]. glutaminergic Gephyromycin, with an 33unprecedented intramolecular ether bridge, displayed neuronal cells. In addition, exhibited no acute cytostatic activities, and the lack of cytotoxicity made A new sulphur‐containing natural alkaloid named microbiaeratin (34) (Figure 4) was activity (agonist) towards neuronal cells. In addition, 33 exhibited no acute cytostatic activities, and its neuroprotective properties even more valuable [29]. characterized, together with the known bacillamide from the culture of Microbispora aerata strain the lack of cytotoxicity made its neuroprotective properties even more valuable [29]. A new sulphur-containing natural alkaloid named microbiaeratin (34) (Figure 4) was IMBAS‐11A, isolated from the Antarctic Livingston Island. A low antiproliferative and cytotoxic A new together sulphur‐containing natural alkaloid named microbiaeratin (34) (Figure 4) was characterized, with the known bacillamide from the culture of Microbispora aerata strain effects of 34 was determined with L‐929 bacillamide mouse fibroblast cells, K‐562 of human leukemia cells and characterized, together with the known from the culture Microbispora aerata strain IMBAS-11A, isolated from the Antarctic Livingston Island. A low antiproliferative and cytotoxic effects HeLa human cervix carcinoma cells [30]. IMBAS‐11A, isolated from the Antarctic Livingston Island. A low antiproliferative and cytotoxic of 34 was determined with L-929 mouse fibroblast cells, K-562 human leukemia cells and HeLa human The Nocardiopsis sp. SCSIO KS107 was isolated from Antarctic seashore sediment. Fermentation effects of 34 was determined with L‐929 mouse fibroblast cells, K‐562 human leukemia cells and cervix carcinoma cells [30]. and isolation of this strain provided two new α‐pyrones germicidin H (35), 4‐hydroxymucidone (36), HeLa human cervix carcinoma cells [30]. TheThe Nocardiopsis sp. SCSIO KS107 was isolated from Antarctic seashore sediment. Fermentation sp. SCSIO KS107 was isolated from seashore sediment. Fermentation and a Nocardiopsis known compound 7‐hydroxymucidone. Only the Antarctic known compound showed antibacterial andand isolation of this strain provided two new α‐pyrones germicidin H (35), 4‐hydroxymucidone (36), isolation of this strain provided two new α-pyrones germicidin H (35), 4-hydroxymucidone (36), activity against Micrococcus luteus with an MIC value of 16 μg/mL [31]. andand a known compound 7-hydroxymucidone. Only the the known knowncompound compoundshowed showed antibacterial a known compound 7‐hydroxymucidone. Only antibacterial activity against Micrococcus luteus with an MIC value of 16 µg/mL [31]. activity against Micrococcus luteus with an MIC value of 16 μg/mL [31].
Figure 4. Secondary metabolites derived from the Antarctic actinomyces (compounds 32–36).
2.3. Fungi Figure 4. Secondary metabolites derived from the Antarctic actinomyces (compounds 32–36). Figure 4. Secondary metabolites derived from the Antarctic actinomyces (compounds 32–36). The rapid growth and ability to metabolize a wide variety of substrates have enabled fungi to 2.3. Fungi 2.3.become the predominant components of the microorganisms in polar regions. The psychrotolerant Fungi fungus Penicillium algidum, collected from soil under a Ribes sp. in Greenland near the Arctic, The rapid growth and ability to metabolize a wide variety of substrates have enabled fungi to The rapid growth and ability to metabolize a wide variety of substrates have enabled fungi to yielded the new cyclic nitropeptide, psychrophilin D (37) (Figure 5), together with two known cyclic become the predominant components of the microorganisms in polar regions. The psychrotolerant
become thePenicillium predominant components the soil microorganisms insp. polar regions. The psychrotolerant fungus algidum, collected of from under a Ribes in Greenland near the Arctic, yielded the new cyclic nitropeptide, psychrophilin D (37) (Figure 5), together with two known cyclic
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Mar. Drugs 2017, 15, 28 fungus Penicillium algidum, collected from soil under a Ribes sp. in Greenland near the Arctic, 6 of 30 yielded the new cyclic nitropeptide, psychrophilin D (37) (Figure 5), together with two known cyclic peptides, peptides, cycloaspeptide A and cycloaspeptide D. The compounds were tested in antimicrobial, cycloaspeptide A and cycloaspeptide D. The compounds were tested in antimicrobial, antiviral, antiviral, anticancer and antiplasmodial assays. Psychrophilin D exhibited a moderate activity with anticancer and antiplasmodial Psychrophilin D in exhibited a moderate withcell half assay. infective half infective dose (ID50) assays. value of 10.1 μg/mL the P388 murine activity leukaemia dose (ID ) value of 10.1 µg/mL in the P388 murine leukaemia cell assay. Cycloaspeptide A and D 50 50 = 3.5 and 4.7 μg/mL, respectively) against Cycloaspeptide A and D exhibited moderate activity (IC exhibited moderate activity (IC50 = 3.5 and 4.7 µg/mL, respectively) against Plasmodium falciparum [32]. Plasmodium falciparum [32]. O HN
H O NO2
H
N
HN
HN
HO
O
O O
O
HN
HO
O
OH
O
Cytochalasins Z25 (39)
Cytochalasins Z24 (38)
Psychrophilin D (37)
O O
HO O
H
O HN
HO
O
O O
O
O HO
O
O OH
O
OH
Cytochalasins Z26 (40)
O Libertellenone H (42)
Libertellenone G (41) OH
O
N O
O
OH
OH O
O
O
O
O
OH
Eutypenoid A (43)
OH Eutypenoid A (45)
Eutypenoid A (44) OH
O
O
OH
O
O
O
O
HN
O
HN
O
H O H
Lindgomycin (46)
H O
H O
H
O
O
(48)
H
Ascosetin (47)
Figure 5. Secondary metabolites derived from the Arctic fungi (compounds 37–48).
Figure 5. Secondary metabolites derived from the Arctic fungi (compounds 37–48).
Three new cytochalasins Z24, Z25, Z26 (38–40) (Figure 5) and one known compound, scoparasin B, Three new cytochalasins Z24 , fungus Z25 , Z26Eutypella (38–40) (Figure 5) These and one known compound, scoparasin were isolated from the Arctic sp. D‐1. compounds were evaluated for B, were isolatedactivities from theagainst Arctic fungus sp. D-1. These were evaluated38 forshowed cytotoxic cytotoxic several Eutypella human tumor cell lines. compounds Among them, compound activities against several human tumor cell lines. Among them, compound 38 showed moderate moderate cytotoxicity toward human breast cancer MCF‐7 cell line with IC 50 value of 9.33 mΜ [33]. Further investigation of Eutypella sp. D‐1 led to the discovery of two new diterpenes, libertellenone cytotoxicity toward human breast cancer MCF-7 cell line with IC50 value of 9.33 mM [33]. Further G (41) and oflibertellenone 5), together with new two diterpenes, known pimarane diterpenes. investigation Eutypella sp. H D-1(42) led(Figure to the discovery of two libertellenone G (41) Compound 41 exhibited antibacterial activity against Escherichia coli, Bacillus subtilis and and libertellenone H (42) (Figure 5), together with two known pimarane diterpenes. Compound Staphylococcus aureus. Compound 42 showed slight coli, cytotoxicity toward most cell lines, with 41 exhibited antibacterial activity against Escherichia Bacillus subtilis and Staphylococcus aureus. half‐maximal inhibitory concentration values ranging from 3.31 to 44.1 μM. In addition, the Compound 42 showed slight cytotoxicity toward most cell lines, with half-maximal inhibitory cytotoxicity of 42 is most likely dependent on the presence of its cyclopropane ring as deduced from concentration values ranging from 3.31 to 44.1 µM. In addition, the cytotoxicity of 42 is most likely the inactivity of other similar compounds [34]. Recently, three pimarane diterpenoids, Eutypenoids dependent on the presence of its cyclopropane ring as deduced from the inactivity of other similar A–C (43–45), were also isolated from the culture of Eutypella (E.) sp. D‐1. Using a ConA‐induced compounds [34]. Recently, three pimarane diterpenoids, Eutypenoids A–C (43–45), were also isolated splenocyte proliferation model, compound 44 exhibited potent immunosuppressive activities [35]. from the culture of Eutypella (E.) sp. D-1. Using a ConA-induced splenocyte proliferation model, An unusual polyketide with a new carbon skeleton, lindgomycin (46) (Figure 5) [36], and the compound 44 exhibited potent immunosuppressive activities [35]. recently described ascosetin (47) (Figure 5) [37] were extracted from different Lindgomycetaceae strains, which were isolated from an Arctic sponge. Both the compounds exhibited strong antibiotic
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An unusual polyketide with a new carbon skeleton, lindgomycin (46) (Figure 5) [36], and the recently described ascosetin (47) (Figure 5) [37] were extracted from different Lindgomycetaceae strains, which were isolated from an Arctic sponge. Both the compounds exhibited strong antibiotic activities against the clinically relevant Gram-positive bacteria (including methicillin-resistant Staphylococcus aureus) and human pathogenic yeast Candida albicans. Mar. Drugs 2017, 15, 28 7 of 30 Trichoderma polysporum strain OPU1571, recovered from a moss, Sanionia uncinata, growing against the clinically relevant Gram‐positive bacteria (including methicillin‐resistant in the activities high arctic wetlands on Spitsbergen Island, Svalbard, Norway, yielded eleven compounds, Staphylococcus aureus) and human pathogenic yeast Candida albicans. including a new one (48) (Figure 5). The in vitro investigation suggested that compound 48 showed Trichoderma polysporum strain OPU1571, recovered from a moss, Sanionia uncinata, growing in a concentration-dependent growth-inhibitory effect on snow rot pathogen Pythium iwayamai at the high arctic wetlands on Spitsbergen Island, Svalbard, Norway, yielded eleven compounds, including 5 daysa [38]. new one (48) (Figure 5). The in vitro investigation suggested that compound 48 showed a Fermentation of the Antarctic ascomycete fungus Geomyces sp. yielded five new asterric acid concentration‐dependent growth‐inhibitory effect on snow rot pathogen Pythium iwayamai at 5 days [38]. derivatives, ethyl asterrate n-butyl asterrate (50), Geomyces and geomycins A–C (51–53) (Figure 6). The Fermentation of the (49), Antarctic ascomycete fungus sp. yielded five new asterric acid derivatives, ethyl asterrate (49), n‐butyl asterrate (50), and geomycins A–C (51–53) (Figure new metabolites were tested for their antibacterial and antifungal activities. Geomycin B 6). The (52) showed new metabolites were tested for their antibacterial and antifungal activities. Geomycin B (52) significant antifungal activity against Aspergillus fumigatus ATCC 10894, with IC50 /MIC values of showed significant antifungal activity against Aspergillus fumigatus ATCC 10894, with IC 50/MIC 0.86/29.5 µM (the positive control fluconazole showed IC50 /MIC values of 7.35/163.4 µM). Geomycin values of 0.86/29.5 μM (the positive control fluconazole showed IC50/MIC values of 7.35/163.4 μM). C (53) displayed moderate antimicrobial activities against the Gram-positive bacteria (Staphylococcus Geomycin C (53) displayed moderate antimicrobial activities against the Gram‐positive bacteria aureus (Staphylococcus aureus ATCC 6538 and Streptococcus pneumoniae CGMCC 1.1692) and Gram‐negative ATCC 6538 and Streptococcus pneumoniae CGMCC 1.1692) and Gram-negative bacterium (Escherichia coli CGMCC 1.2340) [39]. bacterium (Escherichia coli CGMCC 1.2340) [39].
Figure 6. Secondary metabolites derived from the Antarctic fungi (compounds 49–59).
Figure 6. Secondary metabolites derived from the Antarctic fungi (compounds 49–59). Chemical investigation of the marine‐derived fungus Trichoderma asperellum, collected from the
Chemical investigation the marine-derived fungus Trichoderma asperellum, collected sediment of the Antarctic of Penguin Island, resulted in the isolation of six new peptaibols named from the sediment of the Antarctic Penguin Island, resulted in the isolation of six new peptaibols asperelines A–F (54–59) (Figure 6), which are characterized by an acetylated N‐terminus and a residue. The compounds by were against N-terminus fungi containing an uncommon namedC‐terminus asperelines A–F (54–59) (Figure prolinol 6), which are characterized an tested acetylated bacteria, but they showed weak inhibitory activity toward The the early blight pathogen and aand C-terminus containing an only uncommon prolinol residue. compounds were tested againstAlternaria solani, the rice blast Pyricularia oryzae, and the bacteria Staphylococcus aureus and Escherichia fungi and bacteria, but they showed only weak inhibitory activity toward the early blight coli [40]. Further study on the same fungus strain determined thirty‐eight short peptaibols, including pathogen Alternaria solani, the rice blast Pyricularia oryzae, and the bacteria Staphylococcus aureus and thirty‐two new compounds namely asperelines G–Z13 [41].
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Escherichia coli [40]. Further study on the same fungus strain determined thirty-eight short peptaibols, including thirty-two new compounds namely asperelines G–Z13 [41]. Mar. Drugs 2017, 15, 28 8 of 30 Two new epipolythiodioxopiperazines, named chetracins B (60) and C (61), and five new diketopiperazines, named chetracin D (62) and oidioperazines A–D (63–66) (Figure 7), were obtained Two new epipolythiodioxopiperazines, named chetracins B (60) and C (61), and five new from the Antarctic fungus Oidiodendron truncatum GW3-13. An in vitro 3-(4, 5-dimethylthiazol-2-yl) 2, diketopiperazines, named chetracin D (62) and oidioperazines A–D (63–66) (Figure 7), were Mar. Drugs 2017, 15, 28 8 of 30 obtained from the Antarctic fungus Oidiodendron An in vitro 3‐(4, 5-diphenyl tetrazolium bromide (MTT) cytotoxicity assaytruncatum revealed GW3‐13. potent biological activity for 60 in 5‐dimethylthiazol‐2‐yl) 2, 5‐diphenyl tetrazolium bromide (MTT) cytotoxicity assay revealed potent the nanomolar range against a panel of five human cancer lines, HCT-8, BEL-7402, BGC-823, A-549 and Two new epipolythiodioxopiperazines, named chetracins B (60) and C (61), and five new biological activity for 60 in the nanomolar range against a panel of five human cancer lines, HCT‐8, diketopiperazines, D (62) significant and oidioperazines A–D at (63–66) (Figure 7), concentration, were A-2780. New metabolitesnamed 61 andchetracin 62 displayed cytotoxicity a micromolar BEL‐7402, BGC‐823, A‐549 and A‐2780. New metabolites 61 and 62 displayed significant cytotoxicity at from the fungus Oidiodendron truncatum GW3‐13. An 3‐(4, whereas obtained 63–66 showed no Antarctic significant cytotoxicity at 10 µM. Comparison of in thevitro bioactivity data a micromolar concentration, whereas 63–66 showed no significant cytotoxicity at 10 μM. Comparison 5‐dimethylthiazol‐2‐yl) 2, 5‐diphenyl tetrazolium bromide (MTT) cytotoxicity assay revealed potent suggested that the sulfide bridge was a determinant factor for their cytotoxicity, while the number of of the bioactivity data suggested that the sulfide bridge was a determinant factor for their cytotoxicity, biological activity for 60 in the nanomolar range against a panel of five human cancer lines, HCT‐8, sulfur atoms in the bridge did not seem to influence activity [42]. while the number of sulfur atoms in the bridge did not seem to influence activity [42]. BEL‐7402, BGC‐823, A‐549 and A‐2780. New metabolites 61 and 62 displayed significant cytotoxicity at a micromolar concentration, whereas 63–66 showed no significant cytotoxicity at 10 μM. Comparison of the bioactivity data suggested that the sulfide bridge was a determinant factor for their cytotoxicity, while the number of sulfur atoms in the bridge did not seem to influence activity [42].
Figure 7. Secondary metabolites derived from the Antarctic fungi (compounds 60–68).
Figure 7. Secondary metabolites derived from the Antarctic fungi (compounds 60–68).
In 2012, two highly oxygenated polyketides, penilactones A and B (67 and 68) (Figure 7) of Figure 7. Secondary metabolites derived from the Antarctic fungi (compounds 60–68). In related structure but opposite absolute stereochemistry, were isolated from the Antarctic deep‐sea 2012, two highly oxygenated polyketides, penilactones A and B (67 and 68) (Figure 7) of related structure but opposite absolute stereochemistry, were isolated from the Antarctic deep-sea derived derived fungus Penicillium crustosum PRB‐2. The nuclear factor‐κB (NF‐κB) inhibitory activities of 67 In 2012, two highly oxygenated polyketides, penilactones A and B (67 and 68) (Figure 7) of fungus and 68 were tested by means of transient transfection and reporter gene expression assay, and only Penicillium crustosum PRB-2. The nuclear factor-κB (NF-κB) inhibitory activities of 67 and 68 related structure but opposite absolute stereochemistry, were isolated from the Antarctic deep‐sea A plausible 67 showed weak with an inhibitory rate reporter of 40% at a concentration 10 μM. were tested by means ofactivity transient transfection and gene expression of assay, and only 67 showed derived fungus Penicillium crustosum PRB‐2. The nuclear factor‐κB (NF‐κB) inhibitory activities of 67 The penilactones biosynthetic pathway for 67 and 68 was proposed as shown in Scheme 2 [43]. and 68 were tested by means of transient transfection and reporter gene expression assay, and only weak activity with an inhibitory rate of 40% at a concentration of 10 µM. A plausible biosynthetic contain a new carbon skeleton formed from rate two of 3,5‐dimethyl‐2,4‐diol‐acetophenone units and a weak activity with an inhibitory 40% at a 2concentration of 10 μM. A plausible pathway67 forshowed 67 and 68 was proposed as shown in Scheme [43]. The penilactones contain a new γ‐butyrolactone moiety, and have been prepared by a biomimetic synthesis reported the following biosynthetic pathway for 67 and 68 was proposed as shown in Scheme 2 [43]. The penilactones carbon year as shown in Scheme 3 [44]. skeleton formed from two 3,5-dimethyl-2,4-diol-acetophenone units and a γ-butyrolactone contain a new carbon skeleton formed from two 3,5‐dimethyl‐2,4‐diol‐acetophenone units and a
moiety, and have been prepared by a biomimetic synthesis reported the following year as shown in γ‐butyrolactone moiety, and have been prepared by a biomimetic synthesis reported the following Scheme 3year as shown in Scheme 3 [44]. [44].
Scheme 2. Proposed biosynthesis of penilactones A (67) and B (68). Scheme 2. Proposed biosynthesis of penilactones A (67) and B (68).
Scheme 2. Proposed biosynthesis of penilactones A (67) and B (68).
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Scheme 3. Synthesis of ent‐penilactone A (ent‐67) and penilactone B (68). Reagents and conditions: (a) Scheme 3. Synthesis of ent-penilactone A (ent-67) and penilactone B (68). Reagents and conditions: ◦ 71%; (b) HCHO, NaOAc, AcOH, 80 °C, ◦ 75%; (c) HCHO, NaOAc, AcOH, AcOH, 90 °C, (a) Scheme 3. Synthesis of ent‐penilactone A (ent‐67) and penilactone B (68). Reagents and conditions: (a) AcOH, BF BF33.Et .Et2O, 2 O, 90 C, 71%; (b) HCHO, NaOAc, AcOH, 80 C, 75%; (c) HCHO, NaOAc, AcOH, 90 °C, then 110 °C, 46%; (d) toluene, 110 °C, 93%; (e) Ph 3P=C=C=O, toluene, 110 °C, 52%; (f) H , PD/C, ◦ ◦ ◦ 90 AcOH, C, thenBF 110 (d)71%; toluene, 110 C, 93%; (e) Ph toluene, 110 ◦ C, 52%; (f) 2H 3 P=C=C=O, 2 , PD/C, 3.Et2C, O, 46%; 90 °C, (b) HCHO, NaOAc, AcOH, 80 °C, 75%; (c) HCHO, NaOAc, AcOH, MeOH, rt, 99%; (g) dioxane, 110 °C, 86%. ◦ MeOH, rt, 99%; (g) dioxane, 110 C, 86%. 90 °C, then 110 °C, 46%; (d) toluene, 110 °C, 93%; (e) Ph 3P=C=C=O, toluene, 110 °C, 52%; (f) H2, PD/C, MeOH, rt, 99%; (g) dioxane, 110 °C, 86%.
A new chloro‐trinoreremophilane sesquiterpene (69) (Figure 8), three new chlorinated A new chloro-trinoreremophilane sesquiterpene (69) (Figure 8), three new chlorinated eremophilane sesquiterpenes (70–72) (Figure 8), together with a known compound, eremofortine C A new chloro‐trinoreremophilane sesquiterpene (69) (Figure 8), three new chlorinated eremophilane sesquiterpenes (70–72) (Figure 8), together with a known compound, eremofortine (73) (Scheme 4), were isolated from the Antarctic deep‐sea derived fungus, Penicillium sp. PR19N‐1 eremophilane sesquiterpenes (70–72) (Figure 8), together with a known compound, eremofortine C C (73) (Scheme 4), were isolated from the Antarctic deep-sea derived fungus, Penicillium sp. PR19N-1 in 2013. Compound 69 showed moderate cytotoxic activity against HL‐60 and A549 cancer cell lines. (73) (Scheme 4), were isolated from the Antarctic deep‐sea derived fungus, Penicillium sp. PR19N‐1 in 2013. Compound showedmetabolic moderate network cytotoxic of activity HL-60 and A549 cell lines. In addition, the 69 plausible these against isolated products was cancer proposed as in 2013. Compound 69 showed moderate cytotoxic activity against HL‐60 and A549 cancer cell lines. demonstrated in Scheme 4 [45]. Further investigation of this was strain yielded five new In addition, the plausible metabolic network of these isolated products proposed as demonstrated In addition, the plausible metabolic network of these isolated products was proposed as eremophilane‐type sesquiterpenes (74–78) and a new rare lactam‐type eremophilane (79) (Figure 8). in Scheme 4 [45]. Further investigation of this strain yielded five new eremophilane-type sesquiterpenes demonstrated in Scheme 4 [45]. Further investigation of this strain yielded five new Their cytotoxities against HL‐60 and A‐549 human cancer cell lines were valuated, and 78 was the (74–78) and a new rare lactam-type eremophilane (79) (Figure 8). Their cytotoxities against HL-60 and eremophilane‐type sesquiterpenes (74–78) and a new rare lactam‐type eremophilane (79) (Figure 8). most active one with IC 50 value of 5.2 μM against the A‐549 cells [46]. A-549 human cancer cell lines were valuated, and 78 was the most active one with IC50 value of 5.2 µM Their cytotoxities against HL‐60 and A‐549 human cancer cell lines were valuated, and 78 was the against the A-549 cells [46]. most active one with IC50 value of 5.2 μM against the A‐549 cells [46]. OH OH OH
PPO
farnesyl diphosphate
hydroxylation
PPO
farnesyl diphosphate
hydroxylation
isomerization
OH
[O]
OH
O
O
O O 73a
HO
O 73a
Cl
HO O O
O
O
Cl O
O
O
O
H2O
O
[O]
H HCl O
O
H2O
isomerization
H
HCl O
O OH
O O
O
O
OH OH
O
OH
O OH OH
O
O O
O
OH 73b
degradation H 2O 73b acetylation 69 70 [O] deacetylation degradation H 2O acetylation 69 70 [O] deacetylation
hydroxylation epoxidation O
O
O
acetylation [H]
O
HO
acetylation [H]
O
HO
HCl methylation HCl methylation
72 72
O O O 71 71
O
H H
O O
O hydroxylation [O] epoxidation O HO [O] O
O
O
HO O
HCl
O
O epoxidation
O HCl
Scheme 4. Proposed biogenetic network for compounds 69–73.
O epoxidation
Scheme 4. Proposed biogenetic network for compounds 69–73.
Scheme 4. Proposed biogenetic network for compounds 69–73. Two new meroterpenoids, named chrodrimanins I and J (80 and 81) (Figure 8), together with five known biosynthetically related chrodrimanins, were isolated from the culture of the Antarctic Two new meroterpenoids, named chrodrimanins I and J (80 and 81) (Figure 8), together with moss‐derived fungus Penicillium funiculosum GWT2‐24. Distinguished from all of reported Two new meroterpenoids, named chrodrimanins I and J (80 and 81) (Figure 8),the together with five known biosynthetically related chrodrimanins, were isolated from the culture of the Antarctic chrodrimanins, compounds 80 and 81 possess a unique cyclohexanone (E ring) instead of a δ‐lactone fivemoss‐derived known biosynthetically related chrodrimanins, were isolated from the culture of the Antarctic fungus Penicillium funiculosum GWT2‐24. Distinguished from all of the reported moss-derived fungus Penicillium funiculosum GWT2-24. Distinguished from all of the reported chrodrimanins, compounds 80 and 81 possess a unique cyclohexanone (E ring) instead of a δ‐lactone
chrodrimanins, compounds 80 and 81 possess a unique cyclohexanone (E ring) instead of a δ-lactone
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ring. However, only the known compounds exhibited inhibitory activities against influenza virus Mar. Drugs 2017, 15, 28 10 of 30 ring. However, only the known compounds exhibited inhibitory activities against influenza virus A A (H1N1) [47]. (H1N1) [47]. ring. However, only the known compounds exhibited inhibitory activities against influenza virus A Cl Cl Cl Cl (H1N1) [47]. O
O O
Cl
69
HO
O
O OH
HO
OH
HO
O
O
HO
OH
70
O
O
O
HO Cl
O
O
HO O
71
OH
O
OH
69
O
Cl
Cl
O O
HO
O
O O
72
O
O
OH O
70
71
O
O
O
O HO
72
O
O
O
O
OH OH
HO
O
HO
74
HO
75
76
75
76
77
HO
OH 74 O
O
O O
O O
O
O
78
O
O
O O
O
H N
O
H N
O O
O
Chrodrimanin J 81 O
OH
O
O O
HO NO2
OH
HO
O
OH
O
OH CO2Me
I 80 Pseudogymnoascins AChrodrimanin (82) R = OH
OR O O
O O
OR
O
OH
O Chrodrimanin I 80 O
79 O
O
O
O
79
OH
78
OH
O O
O
O
77
O
OH
CO CO22Me H
Pseudogymnoascins A B (82) (83) R =
O
Pseudogymnoascins B C (83) (84) R R ==
O
Pseudogymnoascins C (85) (84) R R == 3-Nitroasterric acid
CO H CO22H
H
CO2H
NO2 O Chrodrimanin J 81 Figure 8. Secondary metabolites derived from the Antarctic fungi (compounds 69–72, 74–85). 3-Nitroasterric acid (85) R69–72, = H Figure 8. Secondary metabolites derived from the Antarctic fungi (compounds 74–85).
Figure 8. Secondary metabolites derived from the Antarctic fungi (compounds 69–72, 74–85). Fermentation of a Pseudogymnoascus sp. fungus isolated from an Antarctic marine sponge,
Fermentation of a Pseudogymnoascus sp. fungus isolated from an Antarctic marine sponge, yielded yielded four new nitroasterric acid derivatives, pseudogymnoascins A–C (82–84) and 3‐nitroasterric Fermentation a along Pseudogymnoascus sp. fungus isolated from an and Antarctic marine sponge, four new nitroasterric acid derivatives, pseudogymnoascins A–C (82–84) and pyriculamide. 3-nitroasterric acid (85) acid (85) (Figure of 8), with two known compounds questin These yielded four new nitroasterric acid derivatives, pseudogymnoascins A–C (82–84) and 3‐nitroasterric (Figure 8), along with two known compounds questin and pyriculamide. These compounds are the compounds are the first nitro derivatives of the known fungal metabolite asterric acid [48]. acid (85) (Figure 8), along with two known compounds questin and pyriculamide. These first nitro derivatives of the known fungal metabolite asterric acid [48].ochraceopones A–E (86–90) Five new highly oxygenated α‐pyrone merosesquiterpenoids, compounds are the first nitro derivatives of the known fungal metabolite asterric acid [48]. (Scheme 5), together with one new double bond isomer of asteltoxin, isoasteltoxin (91) (Figure 9), Five new highly oxygenated α-pyrone merosesquiterpenoids, ochraceopones A–E (86–90) Five new highly oxygenated α‐pyrone merosesquiterpenoids, ochraceopones A–E (86–90) and two known asteltoxin derivatives, asteltoxin and asteltoxin B, were isolated from the Antarctic (Scheme 5), together with one new double bond isomer of asteltoxin, isoasteltoxin (91) (Figure 9), (Scheme 5), together with one new double bond isomer of asteltoxin, isoasteltoxin (91) (Figure 9), Aspergillus ochraceopetaliformis SCSIO 05702. Ochraceopones A–D (86–89) were andsoil‐derived fungus two known asteltoxin derivatives, asteltoxin and asteltoxin B, were isolated from the Antarctic and two known asteltoxin derivatives, asteltoxin and asteltoxin B, were isolated from the Antarctic the first examples of α‐pyrone merosesquiterpenoids possessing a linear tetracyclic carbon skeleton. soil-derived fungus Aspergillus ochraceopetaliformis SCSIO 05702. Ochraceopones A–D (86–89) were soil‐derived fungus Aspergillus ochraceopetaliformis SCSIO 05702. Ochraceopones A–D (86–89) were All isolated compounds were tested for their antiviral, cytotoxic, antibacterial, and the firstthe examples of α-pyrone merosesquiterpenoids possessing a linear tetracyclic carbon skeleton. the first examples of α‐pyrone merosesquiterpenoids possessing a linear tetracyclic carbon skeleton. antitubercular activities. Among the new compounds, 86 and 91 exhibited promising antiviral AllAll the isolated compounds were tested for theirfor antiviral, cytotoxic, antibacterial, and antitubercular the isolated compounds were tested their antiviral, cytotoxic, antibacterial, and viruses. In addition, a possible biosynthetic activities against the H1N1 and H3N2 influenza activities. Among the new compounds, 86 and 91 exhibited promising antiviral activities against the antitubercular activities. Among the new compounds, 86 and 91 exhibited promising antiviral pathway for ochraceopones A–E was proposed in Scheme 5 [49]. H1N1 and H3N2 influenza viruses. In addition, a possible biosynthetic pathway for ochraceopones viruses. In addition, a possible biosynthetic activities against the H1N1 and H3N2 influenza A–E was proposed in Scheme 5 [49]. pathway for ochraceopones A–E was proposed in Scheme 5 [49].
Figure 9. The structure of isoasteltoxin (91) derived from the Antarctic fungus Aspergillus ochraceopetaliformis SCSIO 05702. Figure 9. The structure of isoasteltoxin (91) derived from the Antarctic fungus Aspergillus Figure 9. The structure of isoasteltoxin (91) derived from the Antarctic fungus Aspergillus ochraceopetaliformis SCSIO 05702.
ochraceopetaliformis SCSIO 05702.
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Scheme 5. Postulated biogenetic pathway for ochraceopones A–E (86–90).
Scheme 5. Postulated biogenetic pathway for ochraceopones A–E (86–90).
3. Lichen
3. Lichen
Lichens are symbiotic associations of fungi and algae and/or cyanobacteria that produce unique
Lichens are secondary symbiotic associations of fungi and algae and/or cyanobacteria produce unique characteristic metabolites by comparison to those of higher plants. that Several species of characteristic secondary metabolites by comparison to those of higher plants. Several species lichens have been used for various remedies in folk medicine since ancient time and variety of of lichens haveactive been used various remedies in antimycobacterial, folk medicine since ancientantioxidant time and variety biologically lichen for metabolites, including antiviral, and of biologically active lichen metabolites, including antimycobacterial, antiviral,evolved unique antioxidant and antiherbivore properties, have been described [50,51]. Antarctic lichens may have antiherbivore properties, have been described [50,51]. Antarctic lichens may have evolved unique secondary metabolites to help in surviving the extreme environment in which they live [52–54]. Professor Oh’s group has made great efforts in discovery of new metabolites from the Antarctic secondary metabolites to help in surviving the extreme environment in which they live [52–54]. lichens. From the MeOH of the Antarctic lichen of Stereocaulon alpinum, a new cyclic Professor Oh’s group has extract made great efforts in discovery new metabolites from the Antarctic depsipeptide A (92) (Figure 10) [55], together with three new a usnic acid derivatives lichens. From thestereocalpin MeOH extract of the Antarctic lichen Stereocaulon alpinum, new cyclic depsipeptide usimines A A–C (Figure 10) [56], with were isolated by various chromatographic methods. stereocalpin (92) (93–95) (Figure 10) [55], together three new usnic acid derivatives usimines A–C (93–95) Compound 92 incorporated an unprecedented 5‐hydroxy‐2,4‐dimethyl‐3‐oxo‐octanoic acid in the an (Figure 10) [56], were isolated by various chromatographic methods. Compound 92 incorporated structure, and showed marginal levels of cytotoxicity against three human tumor cell lines, HT‐29, unprecedented 5-hydroxy-2,4-dimethyl-3-oxo-octanoic acid in the structure, and showed marginal B16/F10 and HepG2. In addition, compounds 92–95 moderately inhibited the activity of protein levels of cytotoxicity against three human tumor cell lines, HT-29, B16/F10 and HepG2. In addition, tyrosine phosphatase 1B (PTP1B) in a dose‐dependent manner. Inhibition of PTP1B is predicted to compounds 92–95 moderately inhibited the activity of protein tyrosine phosphatase 1B (PTP1B) in be an excellent, novel therapy to target type 2 diabetes and obesity [57]. Furher investigation of this a dose-dependent manner. Inhibition of PTP1B is predicted to be an excellent, novel therapy to Antarctic lichen recovered seven phenolic lichen metabolites. Among the compounds, the target type 2 diabetes and obesity [57]. Furher investigation of this Antarctic lichen recovered seven depsidone‐type compound, lobaric acid (96) (Figure 10) and two pseudodepsidone‐type phenolic lichen metabolites. Among the compounds, the depsidone-type compound, lobaric acid compounds, 97 and 98 (Figure 10), exhibited potent inhibitory activity against PTP1B with low IC50 (96)values in a non‐competitive manner [58]. In 2013, a new pseudodepsidone‐type metabolite, lobastin (Figure 10) and two pseudodepsidone-type compounds, 97 and 98 (Figure 10), exhibited potent inhibitory activity against PTP1B with low IC50 values in a non-competitive manner [58]. In 2013, a (99) (Figure 10), with antioxidant and antibacterial activity was also reported from this strain [59]. new pseudodepsidone-type metabolite, lobastin (99)A–D (Figure 10), with antioxidant and antibacterial Four new diterpene furanoids, hueafuranoids (100–103) (Figure 10) have been isolated activity was also reported from this strain [59]. from the MeOH extract of the Antarctic lichen Huea sp. Compound 100 showed inhibitory activity against therapeutically targeted protein, PTP1B with an IC50 value of 13.9 μM [60]. Four new diterpene furanoids, hueafuranoids A–D (100–103) (Figure 10) have been isolated from From the Antarctic lichen Ramalina terebrata, the novel compound ramalin (104) (Figure 10) was the MeOH extract of the Antarctic lichen Huea sp. Compound 100 showed inhibitory activity against isolated. The experimental data showed that ramalin displayed potent antioxidant activity and can therapeutically targeted protein, PTP1B with an IC50 value of 13.9 µM [60]. be a strong therapeutic candidate for controlling oxidative stress in cells [61].
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From the Antarctic lichen Ramalina terebrata, the novel compound ramalin (104) (Figure 10) was isolated. The experimental data showed that ramalin displayed potent antioxidant activity and can be a strong therapeutic candidate for controlling oxidative stress in cells [61]. Mar. Drugs 2017, 15, 28 12 of 30 O
O
O
NH
Mar. Drugs 2017, 15, 28 OO
O
OH N
O
O
O
HO
O
OH
O
Stereocalpin A (92)
O
OH O
O N
O
OH
O
H3CO
H3CO
Lobaric acid (96)
HO O Hueafuranoids A (100) 14 Hueafuranoids C (102)
Usimine C (95)
HO 14
(98) R =COOH
14
Hueafuranoids B (101) O Hueafuranoids HO D (103) O
HO OCH3 (99)
O HO
14
OH
HO OCH3 O (99)
OH
O
O
O
O O
OH R
O
O
R
O OCH 3 (97) O R=H
HO
COOH
O O
O
O
14 O
COOH
Usimine CH(95)
HO OH OCH3 (97) R = H 14 (98) R =COOH
OH
N
O
OH
O HO
OH O
Lobaric acid (96)
COOH
O OOH
Usimine A (93) R = CH3 O Usimine O B (94) R = H
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COOH
H OH
HO
OR
HO
H3CO
N
O
OH
OH H
O
HO
OH
OR
O OH Usimine A (93) ROH = CH3 Usimine B (94) R = H
Stereocalpin AN(92) O
OO
O
O
OO
H3CO
N
O
OH NH
OO
OH H
O
O OH OH
O N H
H N
OH
NH2 O (104) OH Ramalin H
O
N HO N H HO HO O NH 2 Figure 10. Secondary metabolites derived from the Antarctic lichen (compounds 92–104). Hueafuranoids B (101) 14 Hueafuranoids Ametabolites (100) 14 Ramalin (104) Figure 10. Secondary derived from the Antarctic lichen (compounds 92–104). Hueafuranoids D (103) Hueafuranoids C (102) O
4. Mosses Figure 10. Secondary metabolites derived from the Antarctic lichen (compounds 92–104). 4. Mosses Mosses represent a relatively untapped natural source to be explored for new bioactive 4. Mosses Mosses represent a relatively untapped natural source to be explored for new bioactive metabolites. Chemical studies of Antarctic moss Polytrichastrum alpinum led to the isolation of two metabolites. Chemical studies of ohioensins Antarctic moss alpinum lednew to the isolation Mosses represent a relatively untapped source to 106) be explored bioactive new benzonaphthoxanthenones, F natural and Polytrichastrum G (105 and (Figure for 11), along with two of two new benzonaphthoxanthenones, ohioensins andfour G (105 and 106)showed (Figurepotent 11), along with two metabolites. Chemical studies of Antarctic moss Polytrichastrum alpinum led to the isolation of two known compounds ohioensins A and C. All of F the compounds inhibitory new benzonaphthoxanthenones, F and G compounds (105 and 106) showed (Figure 11), along with two activity activity against therapeutically targeted protein tyrosine phosphatase 1B (PTP1B). Kinetic analysis of known compounds ohioensins A andohioensins C. All of the four potent inhibitory known compounds ohioensins and C. All of the four compounds showed potent inhibitory PTP1B inhibition by targeted ohioensin F A (105) suggested that benzonaphthoxanthenones inhibited PTP1B against therapeutically protein tyrosine phosphatase 1B (PTP1B). Kinetic analysis of PTP1B activity against therapeutically targeted protein tyrosine phosphatase 1B (PTP1B). Kinetic analysis of activity in a non‐competitive manner [62]. inhibition by ohioensin F (105) suggested that benzonaphthoxanthenones inhibited PTP1B activity in a PTP1B inhibition by ohioensin F (105) suggested that benzonaphthoxanthenones inhibited PTP1B
non-competitive manner [62]. activity in a non‐competitive manner [62].
Figure 11. Secondary metabolites derived from the Antarctic moss (compounds 105, 106). Figure 11. Secondary metabolites derived from the Antarctic moss (compounds 105, 106).
Figure 11. Secondary metabolites derived from the Antarctic moss (compounds 105, 106). 5. Bryozoans 5. Bryozoans
Bryozoans (moss animals and lace corals) have yielded a significant number of bioactive 5. Bryozoans Bryozoans (moss animals and lace corals) have a significant number of bioactive metabolites and have been reviewed elsewhere [63]. yielded However, there is only a single report on
metabolites and have been a reviewed elsewhere [63]. However, there is only single report on Bryozoans (moss animals and corals)In have yielded a significant number of of bioactive secondary metabolites from polar lace bryozoan. 2011, an investigation into a the chemistry the secondary metabolites from a polar bryozoan. In However, 2011, an investigation into the chemistry of the metabolites and have been reviewed elsewhere [63]. there is only a single report on secondary Arctic bryozoan Tegella cf. spitzbergensis resulted in the isolation and structural determination of Arctic bryozoan Tegella cf. spitzbergensis resulted in the isolation and structural determination of metabolites from a polar bryozoan. In 2011, an investigation into the chemistry of the Arctic bryozoan ent‐eusynstyelamide B (107) and three new derivatives, eusynstyelamides D–F (108–110) (Figure 12) ent‐eusynstyelamide B (107) and three new derivatives, eusynstyelamides D–F (108–110) (Figure 12) Ent‐eusynstyelamide is the enantiomer of determination the known brominated tryptophan B Tegella[64]. cf. spitzbergensis resultedB in (107) the isolation and structural of ent-eusynstyelamide [64]. Ent‐eusynstyelamide B (107) is the enantiomer of the known brominated tryptophan metabolite eusynstyelamide B [65]. Antimicrobial activities were reported for 107–110, with MIC (107) and three new derivatives, eusynstyelamides D–F (108–110) 12) [64]. Ent-eusynstyelamide metabolite eusynstyelamide B [65]. Antimicrobial activities were (Figure reported for 107–110, with MIC
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B (107) is the enantiomer of the known brominated tryptophan metabolite eusynstyelamide B [65]. Mar. Drugs 2017, 15, 28 Antimicrobial activities were reported for 107–110, with MIC values as low as 6.25 µg/mL13 of 30 for 107 and 110 against Staphylococcus aureus. Eusynstyelamides were generally more active against Gram-positive values as low as 6.25 μg/mL for 107 and 110 against Staphylococcus aureus. Eusynstyelamides were bacteriagenerally more active against Gram‐positive bacteria than Gram‐negative bacteria [64]. than Gram-negative bacteria [64].
Figure 12. Secondary metabolites derived from the Arctic bryozoan (compounds 107–110).
Figure 12. Secondary metabolites derived from the Arctic bryozoan (compounds 107–110). 6. Cnidarians
6. Cnidarians
Cnidarians are the second largest source (after sponges) of new marine natural products
Cnidarians are the second largest source (after sponges) of new marine natural products reported reported each year, with a predominance of terpenoids [11–13] and are also well represented in the polar regions. In 2003, fractionation of the bioactive extract from the chemically defended Antarctic each year, with a predominance of terpenoids [11–13] and are also well represented in the polar regions. In 2003,gorgonian coral Ainigmaptilon antarcticus yielded two sesquiterpenes, ainigmaptilones A (111) and B fractionation of the bioactive extract from the chemically defended Antarctic gorgonian coral (112) (Figure 13). Ainigmaptilone A has broad spectrum bioactivity toward sympatric predatory and Ainigmaptilon antarcticus yielded two sesquiterpenes, ainigmaptilones A (111) and B (112) (Figure 13). fouling organisms, including antibiotic activity [66]. Ainigmaptilone A has broad spectrum bioactivity toward sympatric predatory and fouling organisms, The ethereal extract of another Antarctic gorgonian Dasystenella acanthina was found to contain including antibiotic activity [66]. three main nonpolar and relatively transient sesquiterpene metabolites, including a new compound, The ethereal extract(113) of another gorgonian Dasystenella found to contain furanoeudesmane (Figure Antarctic 13). Compound 113 was toxic at 46 acanthina μM in a was Gambusia affinis ichthyotoxicity this result, an involvement of these molecules in the defensive three main nonpolar test. and According relativelyto transient sesquiterpene metabolites, including a new compound, mechanisms of the animal could be suggested [67]. furanoeudesmane (113) (Figure 13). Compound 113 was toxic at 46 µM in a Gambusia affinis Seven new steroids, compounds 114–120 (Figure 13), were isolated from the Antarctic octocoral ichthyotoxicity test. According to this result, an involvement of these molecules in the defensive Anthomastus bathyproctus. The in vitro cytotoxicity has been tested against three human tumor cell mechanisms of the animal could be suggested [67]. lines MDA‐MB‐231 (breast adenocarcinoma), A‐549 (lung carcinoma), and HT‐29 (colon Seven new steroids, compounds 114–120 (Figure 13), were isolated from the Antarctic octocoral adenocarcinoma). Compounds 115–118 displayed weak activity as inhibitors of cell growth [68]. AnthomastusChemical investigation of the lipophilic extract of the Antarctic soft coral Alcyonium grandis led bathyproctus. The in vitro cytotoxicity has been tested against three human tumor cell lines to the finding nine unreported sesquiterpenoids, compounds and 121–129 (Figure 13) adenocarcinoma). [69]. These MDA-MB-231 (breastof adenocarcinoma), A-549 (lung carcinoma), HT-29 (colon molecules are members of the illudalane class and in particular belong to the group of Compounds 115–118 displayed weak activity as inhibitors of cell growth [68]. alcyopterosins. Similar illudalanes have been isolated from the sub‐Antartic deep sea soft coral Chemical investigation of the lipophilic extract of the Antarctic soft coral Alcyonium grandis Alcyonium paessleri [70]. Repellency experiments conducted using the omnivorous Antarctic sea star led to the finding of nine unreported sesquiterpenoids, compounds 121–129 (Figure 13) [69]. These Odontaster validus revealed a strong activity in the lipophilic extract of A. grandis against predation molecules members of the illudalane class and in particular belong to the group of alcyopterosins. The total synthesis of some members of the alcyopterosin family has been reported already by [69].are Similar many research groups [71–75]. illudalanes have been isolated from the sub-Antartic deep sea soft coral Alcyonium paessleri [70]. More recently, the isolation and of two new tricyclic sesquiterpenoids, Repellency experiments conducted using thecharacterization omnivorous Antarctic sea star Odontaster validus revealed shagenes A (130) and B (131) (Figure 13) were presented. The two compounds were isolated from an a strong activity in the lipophilic extract of A. grandis against predation [69]. The total synthesis of undescribed soft coral collected from the Scotia Arc in the Southern Ocean. Exploration of the some members of the alcyopterosin family has been reported already by many research groups [71–75]. bioactivity found that shagenes A was active against the visceral leishmaniasis causing parasite, More recently, the isolation and characterization of two new tricyclic sesquiterpenoids, shagenes Leishmania donovani (IC50 value = 5 μM), with no cytotoxicity against the mammalian host [76]. A (130) and In 2012, two halogenated natural products breitfussin A (132) and breitfussin B (133) (Figure 13) B (131) (Figure 13) were presented. The two compounds were isolated from an undescribed soft coral collected theArctic Scotiahydrozoan Arc in the Southern Ocean. Exploration the Island) bioactivity were isolated from from the Thuiria breitfussi collected at Bjørnøya of(Bear [77]. found Recently, Hedberg and co‐workers synthesized breitfussins A and B firstly using Suzuki coupling that shagenes A was active against the visceral leishmaniasis causing parasite, Leishmania donovani (IC50 value = 5 µM), with no cytotoxicity against the mammalian host [76]. In 2012, two halogenated natural products breitfussin A (132) and breitfussin B (133) (Figure 13) were isolated from the Arctic hydrozoan Thuiria breitfussi collected at Bjørnøya (Bear Island) [77].
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Mar. Drugs 2017, 15, 28 Recently, Hedberg and co-workers synthesized breitfussins A and B firstly using Suzuki14 of 30 coupling Mar. Drugs 2017, 15, 28 14 of 30 reactions to join the heteroaromatic rings, thus confirming the assigned structure of these natural reactions to join the heteroaromatic rings, thus confirming the assigned structure of these natural products (Scheme 6) [78]. Soon after, a conceptually distinct synthesis of breitfussin of B through late-stage reactions to join the rings, thus confirming the assigned these natural products (Scheme 6) heteroaromatic [78]. Soon after, a conceptually distinct synthesis structure of breitfussin B through bromination of the breitfussin core was reported by Khan and Chen [79]. products (Scheme 6) [78]. Soon after, a conceptually distinct synthesis of breitfussin B through late‐stage bromination of the breitfussin core was reported by Khan and Chen [79].
late‐stage bromination of the breitfussin core was reported by Khan and Chen [79]. O
H
O
H
O
H
H
O
OH Ainigmaptilones A (111) OH Ainigmaptilones A (111)
OH Ainigmaptilones B (112) OH Ainigmaptilones B (112)
O
R
CO2Me
O
R
CO2Me
H HH H
Furanoeudesmane (113)
O
Furanoeudesmane (113)
H
O (114)
Cl
R2O
Cl R1O (121) R1 = COCH2CH2CH3; R2 = COCH 2CH2CH3 R1O (122) R2 CH = COCH 3 (121) R R11 = = COCH COCH32;CH 2 3; R2 = COCH 2CH2CH3 (123) (122) R R1 = = COCH COCH3;; R R2 = = COCH COCH2CH2CH3 1
3
2
O O(124)
O
(115)
O
(115)
(124)
3
1
3
2
2
2
(117)
H
R1
HH H
CO2Me
OAc
O
CO2Me
H H (119) R1 = OH, R2 = H (120) R R1==OH, H, RR2 ==OH (119) H
O
OH
1
OH
2
(120) R1 = H, R2 = OH
3
H O H O
O
NH N
OO
O O
HN
O
O
HN
N
O O
N H N H
Br
O
Br
Shagenes A (130)
Shagenes B (131)
Shagenes A (130)
Shagenes B (131)
Breitfussin A (132)
HH
Br
NH
O Breitfussin A (132)
HH
R2 R2
R1
(129) R = COCH2CH2CH3
3
(127) R1 = H, R2 = H H O O H O
(117)
RO (128) R = COCH3 RO (129) R R= = COCH COCH2CH2CH3 (128)
H (118) (118)
CO2Me
Cl Cl
H
OAc
(116)
Cl R1O (125) R1 = COCH 3, R2 = COCH 3 R1O (126) R = COCH (125) R11 = COCH33,, R R22 = = COCH COCH23CH2CH3 (127) R2 = ,HR = COCH CH CH (126) R R1 = = H, COCH
O
CO2Me
(116)
(123) R1 = COCH3; R2 = COCH2CH2CH3 R 2O
ClR2O
O
CO2Me
(114)
R2O
H HH H
H CO2Me
Br
NH
O
NH
NO N
O
H
H
H
H
HH
HH
OH
OH
H
Br
Breitfussin B (133)
HH
HH
Br
O Breitfussin B (133)
HO OH
GersemiolOH A (134)
GersemiolOH B (135)
H Gersemiol C OH (136)
Gersemiol A (134)
Gersemiol B (135)
Gersemiol C (136)
HO
OH OH Eunicellol A (137) Eunicellol A (137)
Figure 13. Secondary metabolites derived from the polar cnidarians (compounds 111–137).
Figure 13. Secondary metabolites derived from the polar cnidarians (compounds 111–137). Figure 13. Secondary metabolites derived from the polar cnidarians (compounds 111–137).
Br Br
133 133
OH OH Me a Me a NO2 Br NO2 Br
j j
Br Br
I I OMe OMe
N N
OMe OMe Me b Me b Br NO2 Br NO2
O O
N TIPS N TIPS
Br N Br Boc N i Boc i Br Br
OMe OMe N H N H 132 132 h h N I N I O OMe O OMe
N TIPS N TIPS
c c
OMe OMe
I I
O OB OB O
d d
N TIPS N TIPS
Br Br
O O
B(OH)2 N Boc B(OH)2 N I Boc N I N I N I Boc g O OMe N Boc g O OMe Br Br
N TIPS N TIPS
N N
TIPS N TIPS TIPS TIPS OMe N O O OMe N TIPS N TIPS
Br Br
e e
f f
Br Br
OMe OMe
N N
O O
N TIPS N TIPS
Scheme 6. Synthesis of Breitfussin A (132) and B (133). Reagents and conditions: (a) MeI, Cs2CO3, Scheme 6. Synthesis of Breitfussin A (132) and B (133). Reagents and conditions: (a) MeI, Cs2CO3,
DMF, 82%; (b) ofDimethylformamide acetal Reagents (DMFDMA), DMF, then Cs Zn, Scheme 6. rt, Synthesis Breitfussin A (132)dimethyl and B (133). andPyrrolidine, conditions: (a) MeI, 2 CO3 , DMF, rt, 82%; (b) Dimethylformamide dimethyl acetal (DMFDMA), Pyrrolidine, DMF, then Zn, AcOH/H2O, 80 °C, 61%; (c) Iodine chloride, Pyridine (ICl, Py), CH 2Cl2, then NaH, Three isopropyl DMF, rt, 82%; (b) Dimethylformamide dimethyl acetal (DMFDMA), Pyrrolidine, DMF, then Zn, AcOH/H2O, 80 °C, 61%; (c) Iodine chloride, Pyridine (ICl, Py), CH2Cl2, then NaH, Three isopropyl silicon alkyl chloride (TIPSCl), THF, 81%; (ICl, (d) Py), 1,1′‐Bis(diphenylphosphino)ferrocene] AcOH/H2O, 80 ◦ C, 61%; (c) Iodine chloride, Pyridine CH2 Cl2 , then NaH, Three isopropyl silicon alkyl chloride (TIPSCl), THF, 81%; (d) 1,1′‐Bis(diphenylphosphino)ferrocene] dichloropalladium (Pd(dppf)Cl2), K3PO4, Toluene/H 2O, 80 °C; (e) 10% aq HCl, THF, 0 °C, 89%; (f) 0 -Bis(diphenylphosphino)ferrocene]dichloropalladium silicondichloropalladium alkyl chloride (TIPSCl), THF, 81%; (d) 1,1 (Pd(dppf)Cl(LiHMDS), 2), K3PO4, Toluene/H2O, 80 °C; (e) 10% aq HCl, THF, 0 °C, 89%; (f) Lithium hexamethyldisilazide −78 then I2, −78 °C, 15%; (g) Pd(dppf)Cl 2CO3, ◦ C; °C, ◦ C, 89%;2, Cs (Pd(dppf)Cl K3 PO4 , Toluene/H (e) then 10%I2, aq THF, (f)2CO Lithium Lithium hexamethyldisilazide (LiHMDS), °C, −78 HCl, °C, 15%; (g) 0Pd(dppf)Cl 2, Cs 3, 2 ), 2 O, 80 −78 Dioxane/H2O, rt, 61%; (h) Trimethylsilyl trifluoromethanesulfonate (TMSOTf), Et 3N, CH2Cl2, 0 °C to ◦ C, then I , −78 ◦ C, 15%; (g) Pd(dppf)Cl , Cs CO , hexamethyldisilazide (LiHMDS), − 78 Dioxane/H2O, rt, 61%; (h) Trimethylsilyl trifluoromethanesulfonate (TMSOTf), Et 3N, CH2Cl2, 0 °C to 2 2 2 3 rt, then Tetrabutylammonium fluoride (TBAF), THF, 0 °C, 64%; (i) N‐Bromosuccinimide (NBS), THF, rt, then Tetrabutylammonium fluoride (TBAF), THF, 0 °C, 64%; (i) N‐Bromosuccinimide (NBS), THF, Dioxane/H (TMSOTf), Et3 N, CH2 Cl2 , 0 ◦ C 2 O, rt, 61%; (h) Trimethylsilyl trifluoromethanesulfonate −78 °C to rt, 57%; (j) Trifluoroacetic acid (TFA), CH 2Cl2, 0 °C to rt, then TBAF, THF, 0 °C, 67%. 2, 0 °C to rt, then TBAF, THF, 0 °C, 67%. to rt, −78 °C to rt, 57%; (j) Trifluoroacetic acid (TFA), CH then Tetrabutylammonium fluoride (TBAF), 2Cl THF, 0 ◦ C, 64%; (i) N-Bromosuccinimide (NBS), ◦ THF, −78 C to rt, 57%; (j) Trifluoroacetic acid (TFA), CH2 Cl2 , 0 ◦ C to rt, then TBAF, THF, 0 ◦ C, 67%.
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From the Arctic soft coral Gersemia fruticosa, three new diterpenes named gersemiols A–C (134–136) togetherFrom withthe a new eunicellane eunicellol A (137), been obtained. All compounds Arctic soft coral diterpene, Gersemia fruticosa, three new have diterpenes named gersemiols A–C were tested for their antimicrobial activity against several bacteriaA and fungi. Only was (134–136) together with a new eunicellane diterpene, eunicellol (137), have been eunicellol obtained. A All found to exhibit moderate anti-bacterial activity against methicillin resistant Staphylococcus aureus compounds were tested for their antimicrobial activity against several bacteria and fungi. Only (MRSA) with A MIC value of 24–48 µg/mL [80]. anti‐bacterial activity against methicillin resistant eunicellol was found to exhibit moderate Staphylococcus aureus (MRSA) with MIC value of 24–48 μg/mL [80].
7. Echinoderms
7. Echinoderms
Echinoderms are well known producers of bioactive glycosylated metabolites [11–13], and many Echinoderms well known producers of the bioactive glycosylated [11–13], and new natural productsare have been described from polar examples. In metabolites 2001, two new trisulfated many new natural liouvillosides products have Abeen from the polar examples. In from 2001, the two new triterpene glycosides, (138)described and B (139) (Figure 14), were isolated Antarctic seatrisulfated triterpene glycosides, liouvillosides A (138) and B (139) (Figure 14), were isolated from cucumber Staurocucumis liouvillei. Liouvillosides A and B are two new examples of a small number the Antarctic sea cucumber Staurocucumis liouvillei. Liouvillosides A and B are two new examples of of trisulfated triterpene glycosides from sea cucumbers belonging to the family Cucumariidae. Both a small number of trisulfated triterpene glycosides from sea virus cucumbers the family glycosides were found to be virucidal against herpes simplex type 1 belonging (HSV-1) atto concentrations type 1 Cucumariidae. Both glycosides were found to be virucidal against herpes simplex virus below 10 µg/mL [81]. A novel triterpene holostane disulfated tetrasaccharide olygoglycoside, (HSV‐1) at concentrations below 10 μg/mL [81]. A novel triterpene holostane disulfated turquetoside A (140) (Figure 14), having a rare terminal 3-O-methyl-D-quinovose, was isolated from tetrasaccharide olygoglycoside, turquetoside A (140) (Figure 14), having a rare terminal the Antarctic sea cucumber Staurocucumis turqueti [82]. The occurrence of 3-O-methyl-D-quinovose in 3‐O‐methyl‐D‐quinovose, was isolated from the Antarctic sea cucumber Staurocucumis turqueti [82]. triterpene glycosides in S. turqueti and in the congeneric Antarctic sea cucumber S. liouvillei suggests The occurrence of 3‐O‐methyl‐D‐quinovose in triterpene glycosides in S. turqueti and in the congeneric that the presence of this sugar in carbohydrate chains of triterpene glycosides is a taxonomical character Antarctic sea cucumber S. liouvillei suggests that the presence of this sugar in carbohydrate chains of of the genus Staurocucumis [81,82]. triterpene glycosides is a taxonomical character of the genus Staurocucumis [81,82]. Subsequently, another three new triterpene glycosides, achlioniceosides A1 (141), A2 (142), Subsequently, another three new triterpene glycosides, achlioniceosides A1 (141), A2 (142), and andA3 A3(143) (143)(Figure (Figure14), 14),were wereobtained obtainedfrom fromthe theAntarctic Antarcticsea seacucumber cucumber Achlionice violaecuspidata. Achlionice violaecuspidata. Glycosides 141–143 are the first triterpene glycosides isolated from a sea cucumber belonging to the Glycosides 141–143 are the first triterpene glycosides isolated from a sea cucumber belonging to the order Elasipodida [83]. order Elasipodida [83].
Figure 14. Secondary metabolites derived from the Antarctic sea cucumbers (compounds 138–143).
Figure 14. Secondary metabolites derived from the Antarctic sea cucumbers (compounds 138–143).
8. Molluscs
8. Molluscs
The nudibranch Austrodoris kerguelenensis is distributed widely around the Antarctic coast and The nudibranch kerguelenensis is distributed widely around the (144) Antarctic continental shelves. Austrodoris In 2003, two unprecedented nor‐sesquiterpenes, austrodoral and coast its andoxidised continental shelves. In 2003, acid two unprecedented nor-sesquiterpenes, (144) and its derivative austrodoric (145) (Figure 15), were isolated from austrodoral the skin of the marine oxidised derivative austrodoric acid (145) (Figure 15), were isolated from the skin of the marine dorid dorid A. kerguelenensis, collected in the Antarctic. A role of stress‐metabolites could be suggested for A. kerguelenensis, collected inshort the Antarctic. A role of stress-metabolites be suggested for these these compounds [84]. A and efficient synthesis of 144 and 145 could was reported as shown in
compounds [84]. A short and efficient synthesis of 144 and 145 was reported as shown in Scheme 7 [85].
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Further chemical study of this chemical Antarctic study nudibranch yielded two novel 2-monoacylglycerols (146) and Scheme 7 [85]. Further of this Antarctic nudibranch yielded two novel Scheme 7 7 [85]. [85]. Further Further chemical chemical study study of this Antarctic nudibranch yielded two novel Scheme this Antarctic nudibranch yielded two novel (147) (Figure 15), along with two known 1,2-diacyl glyceryl esters [86]. 2‐monoacylglycerols (146) and (147) (Figure 15), along with two known 1,2‐diacyl glyceryl esters [86]. 2‐monoacylglycerols (146) and (147) (Figure 15), along with two known 1,2‐diacyl glyceryl esters [86]. 2‐monoacylglycerols (146) and (147) (Figure 15), along with two known 1,2‐diacyl glyceryl esters [86].
Austrodoris
Figure 15. Secondary metabolites derived from the Antarctic nudibranch Figure 15. Secondary metabolites derived from the Antarctic nudibranch Austrodoris kerguelenensis Figure 15. Secondary metabolites derived from the Antarctic nudibranch Austrodoris kerguelenensis (compounds 144–147). Figure 15. Secondary metabolites derived from the Antarctic nudibranch Austrodoris (compounds 144–147). kerguelenensis (compounds 144–147).
kerguelenensis (compounds 144–147).
Scheme 7. Synthesis of austrodoral (144) and austrodoric acid (145). Reagents and conditions: (a) Scheme 7. Synthesis of austrodoral (144) and austrodoric acid (145). Reagents and conditions: (a) Scheme 7. Synthesis of austrodoral4, H (144) and austrodoric acid (145). Reagents and conditions: (a) four four steps, 59% [87,88]; (b) OsO 2O, t‐BuOH, trimethylamine N‐oxide, pyridine, reflux, 24 h, 87%; Scheme 7. Synthesis of austrodoral (144) and austrodoric acid (145). Reagents and conditions: (a) four steps, 59% [87,88]; (b) OsO4, H2O, t‐BuOH, trimethylamine N‐oxide, pyridine, reflux, 24 h, 87%; steps,(c) BF 59%3∙OEt [87,88]; OsO4 , H2 O, t-BuOH, trimethylamine N-oxide, pyridine, reflux, 242Cl h,2, 87%; 2, CH2(b) Cl2, 0 °C to rt, 20 min, 95%; (d) NaBH 4, EtOH, rt, 15 min, 97%; (e) Pb(OAc) 4, CH four steps, 59% [87,88]; (b) OsO 4, H2O, t‐BuOH, trimethylamine N‐oxide, pyridine, reflux, 24 h, 87%; (c) BF3∙OEt2, CH2Cl2, 0 °C to rt, 20 min, 95%; (d) NaBH 4, EtOH, rt, 15 min, 97%; (e) Pb(OAc)4, CH2Cl2, ◦ C to 4 , t‐BuOH–H 2 O, reflux, 12 h, 91%. (c) BFrt, 45 min, 92%; (f) NaIO OEt , CH Cl , 0 rt, 20 min, 95%; (d) NaBH , EtOH, rt, 15 min, 97%; (e) Pb(OAc) , CH · 3 2 2 2 4 4 2 Cl2 , (c) BF 3∙OEt2, CH2Cl2, 0 °C to rt, 20 min, 95%; (d) NaBH 4, EtOH, rt, 15 min, 97%; (e) Pb(OAc)4, CH2Cl2, rt, 45 min, 92%; (f) NaIO 4, t‐BuOH–H2O, reflux, 12 h, 91%.
rt, 45 min, 92%; (f) NaIO4 , t-BuOH–H2 O, reflux, 12 h, 91%. rt, 45 min, 92%; (f) NaIO4, t‐BuOH–H2O, reflux, 12 h, 91%. Investigation of the nudibranch A. kerguelenensis collected near the Antarctic Peninsula Investigation of the nudibranch A. kerguelenensis collected near the Antarctic Peninsula resulted in the isolation of three A. new diterpenes, palmadorins A–C (148–150) (Figure 16) [89]. Investigation the nudibranch kerguelenensis collected near the Antarctic Peninsula resulted resulted in the ofisolation of three new diterpenes, palmadorins A–C (148–150) (Figure 16) [89]. Investigation of the nudibranch A. kerguelenensis collected near the Antarctic Peninsula Detailed investigation of this Antarctic nudibranch led to the discovery of a diverse suite of Detailed new in the isolation of three new diterpenes, palmadorins A–C (148–150) (Figure 16) [89]. Detailed of of this Antarctic to the discovery of a diverse suite of new resulted in investigation the isolation three new nudibranch diterpenes, led palmadorins A–C (148–150) (Figure 16) [89]. diterpenoid glyceride esters, palmadorins D–S (151–166) (Figure 16), including one (palmadorin L) investigation of this Antarctic nudibranch led to the discovery of a diverse suite of new diterpenoid diterpenoid glyceride esters, palmadorins D–S (151–166) (Figure 16), including one (palmadorin L) Detailed investigation of this diterpene Antarctic from nudibranch led to the nudibranch. discovery of Palmadorin a diverse suite of new that is the first halogenated this well‐studied A (148), B that is the first halogenated D–S diterpene from (Figure this well‐studied nudibranch. Palmadorin A glyceride esters, palmadorins (151–166) 16), including one (palmadorin L)(148), that B is the diterpenoid glyceride esters, palmadorins D–S (151–166) (Figure 16), including one (palmadorin L) (149), D (151), M (160), N (161), and O (162) inhibit human erythroleukemia (HEL) cells with low (149), D (151), M (160), N (161), and O (162) inhibit human erythroleukemia (HEL) cells with low firstthat halogenated diterpene from this well-studied nudibranch. Palmadorin A (148), B (149), D is the first halogenated diterpene from this well‐studied nudibranch. Palmadorin A (148), B micromolar IC50, and palmadorin M inhibits Jak2, STAT5, and Erk1/2 activation in HEL cells and (151), micromolar IC 50, and palmadorin M inhibits Jak2, STAT5, and Erk1/2 activation in HEL cells and (149), D (151), M (160), N (161), and O (162) inhibit human erythroleukemia (HEL) cells with low M (160), N (161), and O (162) inhibit human erythroleukemia (HEL) cells with low micromolar IC50 , causes apoptosis at 5 mM [90]. causes apoptosis at 5 mM [90]. IC50 palmadorin M inhibits Jak2, STAT5, and Erk1/2 activation in causes HEL cells and andmicromolar palmadorin M, and inhibits Jak2, STAT5, and Erk1/2 activation in HEL cells and apoptosis O O O OR O4 R
20 at 5causes apoptosis at 5 mM [90]. mM [90]. 20 17
H H
R1 R1
20
3 3
R1
H 19 18 19 18
3
Palmadorin R1 Palmadorin R 191 A (148) H 18 H A B (148) (149) H Palmadorin RH B 1 C (149) (150) H AC (148) D (150) (151) HH H (151) H=O H BD (149) E (152) (152) H=O CE (150) F (153) H (153) H DF (151) G (154) H=O (154) =O =O EG (152) H (155) H H (155) H=O H F (153) I (156) (156) =O =O G IJ(154) (157) =O (157) H JK (155) (158) H=O =O K (158) =O I (156) =O J (157) =O K (158) =O H H 4
HO 4H HO 18 Cl Cl 18 4
17
17
16 16
R2
16R2
4
O R4
R3 R3 OH ROH 3
OH
RR R3 R4 Other 2 2 R2 R R Other 4,18 H CH23OH H4 4,18 OH H H CH2OAc 4,18 H CH H 2 4,18 RH R R4 Other CH 3,4 2 OH CH322OAc OH H H 3,4 4,18 OH CH OH CH HH OH H 4,18 22OH H CH H 2 4,18 4,18 H CH2H 3,4 H H2OH OH HOAc CH CH 2OH 3,4 3,4 OH H CH OH 3,4 OH H22OH 2OH CH OH CHH 3,4 4,18 OH H CH22OH OH 3,4 H HH CH H CH 2OH 3,4 3,4 H H CH OH 3,4 2 OH H 2OAcCH2HOH OH CH 3,4 3,4 OH 3,4 OH HH2OAcCH OH =O CH CH2H OH 2 3,4 CHH 3,4 3,4 2OH H=O HH2OH CH OH CH 2OH 3,4 OH CH OH H 3,4 3,4 2OH OH HH =O CH CH22OAc 3,4 =O CH2OH H 3,4 =O H CH2OH 3,4 OH CH2OHO H O 3,4 =O CH2OH H O OH O OH OOH OH
O L (159) Palmadorin OH Palmadorin L (159) OH
20 20 9 9 5 20 5
R3 R3 R4 RR4
O O
R1 R1
O OR2O OH R1 R2 OH
3
O R2 OH R4 Palmadorin R1 R2 R3 R4 H Palmadorin R=CH R4 3 M (160) CHR21OH R H2 2 19 OH M (160) 18 CH =CH N (161) H2 CHH2OH =CH22 N =CH Palmadorin R1 CHH2ROH R3 22 R4 2 O (161) (162) CHH =CH 2OAc O (162) CH H OH =CH 2OAc 2 CH M(163) (160) CH =CH P H 2OHCH2H 2 3 P HH CH CH CH3 2OH N (163) (161) CH =CHCH Q (164) H 2OH 2 3 2OH Q H OAcCH2H OH O (164) (162) CH =CHCH 2 2 3 P (163) H CH2OH O CH3 Q (164) H CH2OH O CH3 O O OH O O O OH OR OR H O O H Palmadorin R (165) R = Ac OH Palmadorin (165) R ROR =H Ac Palmadorin R S (166) = Palmadorin S (166) R = H H H 9
18 19H 18 195
Palmadorin R (165) R = Ac O H Palmadorin S (166) R = HH O Granuloside (167) Granuloside (167)
H
Other Other 5 55 5 Other 5 5 5 5 5 5 5 5 5 5 5
O O
OH O OH O
Figure 16. Secondary metabolites derived from the Antarctic nudibranch (compounds 148–167). HO Figure 16. Secondary metabolites derived from the Antarctic nudibranch (compounds 148–167). Cl
18
Palmadorin L (159)
Granuloside (167)
OH
Figure 16. Secondary metabolites derived from the Antarctic nudibranch (compounds 148–167). Figure 16. Secondary metabolites derived from the Antarctic nudibranch (compounds 148–167).
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Recently, a new homosesterterpene named granuloside (167) (Figure 16), was characterized from the Antarctic nudibranch Charcotia granulosa. Granuloside was the(Figure first linear homosesterterpene Recently, a new homosesterterpene named granuloside (167) 16), was characterized from ever the reported Antarctic and, nudibranch granulosa. Granuloside was structure the first linear skeleton despite theCharcotia low molecular complexity, its chemical poses many homosesterterpene skeleton ever reported and, despite the low molecular complexity, its chemical questions about its biogenesis and origin in the nudibranch [91]. structure poses many questions about its biogenesis and origin in the nudibranch [91].
9. Sponges 9. Sponges
Marine sponges are the largest source of new marine natural products reported annually [11–13] Marine sponges are the of largest source of new marine natural [92]. products reported annually and have provided a rich array biologically important compounds There are a large number [11–13] and have provided a rich array of biologically important compounds [92]. There are a large of studies on sponges from warm or tropical waters, whereas little is known about the chemistry of number of studies on or sponges from warm Actually, or tropical waters, whereas little is known can about the sponges from the Arctic Antarctic waters. polar species of marine sponges also be a chemistry of sponges from the Arctic or Antarctic waters. Actually, polar species of marine sponges rich source of biologically and structurally interesting molecules. can also be a rich source of biologically and structurally interesting molecules. Pyridinium alkaloids are widely distributed in marine sponges of different genera. In 2003, Pyridinium alkaloids are widely distributed in marine sponges of different genera. In 2003, chemical investigation of the Arctic sponge Haliclona viscosa led to the isolation of a new trimeric chemical investigation of the Arctic sponge Haliclona viscosa led to the isolation of a new trimeric 3-alkyl pyridinium alkaloid, viscosamine (168) (Figure 17) [93]. Further investigation of this sponge 3‐alkyl pyridinium alkaloid, viscosamine (168) (Figure 17) [93]. Further investigation of this sponge yielded one new 3-alkyl pyridinium alkaloid, viscosaline (169) (Figure 17) [94], and two new yielded one new 3‐alkyl pyridinium alkaloid, viscosaline (169) (Figure 17) [94], and two new 3-alkyltetrahy-dropyridine alkaloids, haliclamines C (170) and D (171) (Figure 17) [95]. In 2009, new 3‐alkyltetrahy‐dropyridine alkaloids, haliclamines C (170) and D (171) (Figure 17) [95]. In 2009, new haliclamines E (172) and F (173) (Figure 17)17) were subsequently obtained from this Arctic sponge [96]. haliclamines E (172) and F (173) (Figure were subsequently obtained from this Arctic sponge Compound 169 showed activity in the feeding deterrence assay against the amphipod Anonyx nugax [96]. Compound 169 showed activity in the feeding deterrence assay against the amphipod Anonyx andnugax and the starfish Asterias rubens from the North Sea [97]. Compounds 169 and 170 showed a the starfish Asterias rubens from the North Sea [97]. Compounds 169 and 170 showed a strong inhibition against two bacterial strains isolated from the vicinity of the sponge [95,97]. The synthesis strong inhibition against two bacterial strains isolated from the vicinity of the sponge [95,97]. The synthesis of the Arctic sponge alkaloids were also achieved by two groups [97,98]. of the Arctic sponge alkaloids were also achieved by two groups [97,98].
Figure 17. Secondary metabolites derived from the Arctic sponge Haliclona viscosa (compounds 168–173). Figure 17. Secondary metabolites derived from the Arctic sponge Haliclona viscosa (compounds 168–173).
A new sesterterpene, caminatal (174), and two novel sesterterpenes, oxaspirosuberitenone (175) A new sesterterpene, caminatal (174), and two novel sesterterpenes, oxaspirosuberitenone (175) and and 19‐episuberitenone (176) (Scheme 8) were obtained from the Antarctic sponge Suberites 19-episuberitenone (176) (Scheme 8) were obtained from the Antarctic sponge Suberites caminatus [99,100]. caminatus [99,100]. Their possible biogenesis were proposed as shown in Scheme 8. Their possible biogenesis were proposed as shown in Scheme 8. Four new diterpenoids, 177–180 (Figure 18) were isolated from the Antarctic sponge Dendrilla Four new diterpenoids, 177–180 (Figure 18) were isolated from the Antarctic sponge Dendrilla membranosa. Compound 177 was a nor‐diterpene gracilane skeleton derivative, while 178–180 are membranosa. Compound 177 was a nor-diterpene gracilane skeleton derivative, while 178–180 are C-20 C‐20 aplysulphurane‐type diterpenes [101]. aplysulphurane-type diterpenes [101]. Three new sesterterpenes of the suberitane class, suberitenones C (181) and D (182) and Three new sesterterpenes of the suberitane class, suberitenones C (181) and D (182) and suberiphenol (183) (Figure 18), were isolated from the sponge Suberites sp. collected from Antarctica. suberiphenol (183)the (Figure were isolated thecytotoxic sponge Suberites sp. human collected from Antarctica. Unfortunately, new 18), compounds were from neither against the leukemia K562 Unfortunately, the new compounds were neither cytotoxic against the human leukemia K562 cell-line cell‐line nor antimicrobial against B. subtilis, C. albicans, E. coli and S. aureus [102]. Five new steroids, norselic acids A–E (184–188) (Figure 18), were isolated from the sponge Crella nor antimicrobial against B. subtilis, C. albicans, E. coli and S. aureus [102]. sp. collected in Antarctica. Norselic acid A displayed antibiotic activity against methicillin‐resistant Five new steroids, norselic acids A–E (184–188) (Figure 18), were isolated from the sponge Crella sp. Staphylococcus aureus, S. aureus, antibiotic vancomycin‐resistant Enterococcus faecium and collected in Antarctica.methicillin‐sensitive Norselic acid A displayed activity against methicillin-resistant Candida albicans, and reduced consumption of food pellets by sympatric mesograzers. Compounds Staphylococcus aureus, methicillin-sensitive S. aureus, vancomycin-resistant Enterococcus faecium and 184–188 were also active against the Leishmania parasite with low micromolar activity [103].
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Candida albicans, and reduced consumption of food pellets by sympatric mesograzers. Compounds + activity [103]. 184–188Mar. Drugs 2017, 15, 28 were also active againstOHthe Leishmania parasite with low micromolar 18 of 30 OH OH H OH + H
OH
+ H +
H+
+ OH
- H+ - H+
H+ H+
H+
OH
O +
H
+
- H+ +
-H
O
O
O
[O]
O
O
H
+
[O]
H
H
H
HO
OH [O]
OAc O Caminatal (174)
O
OAc Caminatal (174)
[O]
+ OH
O OH
H
H
OAc
OAc
+ OH
O
OH
OH
O
+
O
+
HO
OH
H H
OH
[O]
HO
[O]
OAc OAc 19-Episuberitenone (176)
19-Episuberitenone (176)
OAc
H+
H
+ H+, -H+
+ H+, -H+
H
O H
O O
H
OAc
H+
H
O H HH H
OH
H OH
OAc
OAc Oxaspirosuberitenone (175) Oxaspirosuberitenone (175)
Scheme 8. 8. Possible (174), oxaspirosuberitenone oxaspirosuberitenone (175) (175) Scheme Possible biogenesis biogenesis of of caminatal caminatal (174), and and Scheme 8. Possible biogenesis of caminatal (174), oxaspirosuberitenone (175) and 19-episuberitenone (176). 19‐episuberitenone (176). 19‐episuberitenone (176).
Figure 18. Secondary metabolites derived from the Antarctic sponges (compounds 177–189) and the Arctic sponge (compounds 190–193).
Figure 18. Secondary metabolites derived from the Antarctic sponges (compounds 177–189) and the Figure 18. Secondary metabolites derived from the Antarctic sponges (compounds 177–189) and the Arctic sponge (compounds 190–193). Arctic sponge (compounds 190–193).
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Darwinolide (189), a novel spongian diterpene, was characterized from the Antarctic sponge Dendrilla membranosa. Darwinolide displayed antibiofilm activity against MRSA with no mammalian cytotoxicity, and may present a suitable scaffold for the development of novel antibiofilm agents to treat drug resistant bacterial infections [104]. Barettin (190), 8,9-dihydrobarettin (191), bromoconicamin (192) and a novel brominated marine indole (193) (Figure 18) were isolated from the sponge Geodia barretti collected off the Norwegian coast. The compounds were evaluated as inhibitors of electric eel acetylcholinesterase. Compounds 190 and 191 displayed significant inhibition of the enzyme, 192 was less potent against acetylcholinesterase, and 193 was inactive. Based on the inhibitory activity, a library of 22 simplified synthetic analogs was designed and prepared to probe the role of the brominated indole. From the structure–activity investigation, it was shown that the brominated indole motif is not sufficient to generate a high acetylcholinesterase inhibitory activity, even when combined with natural cationic ligands for the acetylcholinesterase active site. The four natural compounds were also analysed for butyrylcholinesterase inhibitory activity and shown to display comparable activities [105]. 10. Tunicates Tunicates comprise >2800 species and have yielded a diverse array of bioactive metabolites [10,106], including anticancer agents such as didemnin B from Trididemnum solidum, diazonamide from Diazona angulata, and the approved anticancer drug Ecteinascidin 743 (Yondelis™) from Ecteinascidia turbinata [107,108]. Bioassay-guided fractionation of CH2Cl2/MeOH extracts of the tunicate Aplidium cyaneum collected in Antarctica led to the isolation of aplicyanins A–F (194–199) (Figure 19), a group of alkaloids containing a bromoindole nucleus and a 6-tetra-hydropyrimidine substituent at C-3. Cytotoxic activity in the submicromolar range as well as antimitotic properties were found for compounds 195, 197, and 199, whereas compounds 194 and 196 proved to be inactive at the highest concentrations tested and compound 198 displayed only mild cytotoxic properties. The results clearly suggested a key role for the presence of the acetyl group at N-16 in the biological activity of this family of compounds [109]. Five new ecdysteroids, hyousterones A–D (200–203) and abeohyousterone (204) (Figure 19), were isolated from the Antarctic tunicate Synoicum adareanum by Baker and co-workers. Abeohyousterone (204) has moderate cytotoxicity toward several cancer cell lines. Hyousterones bearing the 14β-hydroxy group (200 and 202) were weakly cytotoxic, while the 14α-hydroxy hyousterones (201 and 203) were devoid of cytotoxicity [110]. Further chemical investigation of the same Antarctic tunicate S. adareanum yielded five new bioactive macrolides, palmerolide A (205) and D–G (206–209) (Figure 19). Most of these palmerolides were potent V-ATPase inhibitors and had sub-micromolar activity against melanoma [111,112]. Especially, palmerolide A remained the most potent of this series of natural products against melanoma cells. In the National Cancer Institute (NCI) sixty-cell panel, palmerolide A did not display cytotoxicity below 1 µM against any non-melanoma cell lines. In vivo activity of palmerolide A in mice has been confirmed in the NCI’s hollow fiber assay [113]. Structural features of palmerolide A such as the carbamate and the vinyl amide moieties led the Baker group to hypothesize a bacterial origin for this polyketide. One finding that supported the possibility was the identification of polyketide synthase (PKS) genes, similar to bryostatin biosynthetic genes [114]. Due to promising biological activity and limited access to natural supplies, as well as their challenging structures, palmerolide A and congeneric structures are important targets for chemical synthesis. Recent advances in the synthesis of the palmerolides have been reviewed by Lisboa and Dudley [115]. To date, three total syntheses [116–120] of palmerolide A have been reported. Four groups disclosed formal syntheses [121–126], and various synthetic approaches have also been described [127–135]. The synthesis of the reported structure of palmerolide C has also been achieved, and a structural revision has been proposed [136].
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Figure 19. Secondary metabolites derived from the Antarctic tunicates (compounds 194–209). Figure 19. Secondary metabolites derived from the Antarctic tunicates (compounds 194–209). Figure 19. Secondary metabolites derived from the Antarctic tunicates (compounds 194–209). In 2009, bioassay‐guided fractionation fractionation of of the the Antarctic species, led led to the In 2009, bioassay-guided Antarctic ascidian ascidianAplidium Aplidium species, to the In 2009, bioassay‐guided fractionation of the Antarctic ascidian Aplidium species, led to the characterization of two new biologically active meroterpene derivatives, rossinones A (210) and B characterization of two new biologically active meroterpene derivatives, rossinones A (210) and B (211) characterization of two new biologically active meroterpene derivatives, rossinones A (210) and B (211) (Figure 20). The rossinones exhibited antiinflammatory, antiviral and antiproliferative (Figure 20). The rossinones exhibited antiinflammatory, antiviral and antiproliferative activities [137]. (211) (Figure 20). The rossinones exhibited antiinflammatory, antiviral and antiproliferative activities [137]. In additon, rossinone B (211) was proven to take part in the whole‐colony chemical In additon, rossinone B (211) was proven to take part in the whole-colony chemical defense of The following year, a activities [137]. In additon, rossinone B (211) was proven to take part in the whole‐colony chemical defense of Aplidium falklandicum, repelling both sea stars and amphipods [138]. Aplidium falklandicum, repelling both sea stars and amphipods [138]. The following year, a biomimetic The following year, a defense of Aplidium falklandicum, repelling both sea stars and amphipods [138]. biomimetic total synthesis of (±)‐rossinone B was achieved through a highly efficient strategy as totalshown synthesis of ( ± )-rossinone B was achieved through a highly efficient strategy as shown biomimetic total synthesis of (±)‐rossinone was novel achieved through a highly efficient strategy as in in Scheme 9 [139]. Two years later, B three rossinone‐related meroterpenes (212–214) Scheme 9 [139]. Two years later, three novel rossinone-related meroterpenes (212–214) (Figure shown in Scheme 9 [139]. Two years later, three novel rossinone‐related meroterpenes (212–214) 20) (Figure 20) were obtained from the Antarctic ascidian Aplidium fuegiense. The new compounds were were obtained from the Antarctic ascidian Aplidium fuegiense. The new compounds were found to be (Figure 20) were obtained from the Antarctic ascidian Aplidium fuegiense. The new compounds were found to be selectively localized in the viscera of the ascidian [140]. found to be selectively localized in the viscera of the ascidian [140]. selectively localized in the viscera of the ascidian [140]. OHC OHC
h h
O
O
OTMS
O
O
NC
a
TBDPSO TBDPSO
211 211
NC
a
OTMS b
TBDPSO TBDPSO
TBDPSO TBDPSO
OH O OH O O O H O O H O O
H H
g g
OH OH
O O
O O
c
OTMS
b
OTMS
OH OH O f O f
OMe OMe OH OH
c
OMe OMe OMe OMe
OAc OAc
d d
O O
OMe OMe OMe OMe MOMO MOMO
OH OH
OH OH O O
e e
OMOM OMOM
OMe OMe OMe OMe
MOMO MOMO
OH OH
OAc OAc O O
Scheme 9. Synthesis of rossinone B (211). Reagents and conditions: (a) Trimethylsilyl cyanide Scheme 9. Synthesis of rossinone B (211). Reagents and conditions: (a) Trimethylsilyl cyanide (TMSCN), NEt 3, CH3of CN, 99%; (b) LiHMDS, THF, −78 °C, then 3‐methyl‐2‐butenal, TMS migration, Scheme 9. Synthesis rossinone B (211). Reagents and conditions: (a) Trimethylsilyl cyanide (TMSCN), NEt 3, CH3CN, 99%; (b) LiHMDS, THF, −78 °C, then 3‐methyl‐2‐butenal, TMS migration, 75%; (c) 1 N HCl, THF, then 2O/py, then HF, CH 3CN, then 2,2‐Dimethoxypropane (DMP), (TMSCN), NEt3 , CH3 CN, 99%; (b)Ac LiHMDS, THF, −78 ◦ C, then 3-methyl-2-butenal, TMS migration, 75%; (c) 1 N HCl, THF, then Ac2O/py, then HF, CH3CN, then 2,2‐Dimethoxypropane (DMP), 4‐(Dicyanomethylene)‐2‐methyl‐6‐(4‐dimethylaminostyryl)‐4H‐pyran (DCM), 51%; (d) nBuLi, −78 °C, 75%; (c) 1 N HCl, THF, then Ac2 O/py, then HF, CH3 CN, then 2,2-Dimethoxypropane (DMP), 4‐(Dicyanomethylene)‐2‐methyl‐6‐(4‐dimethylaminostyryl)‐4H‐pyran (DCM), 51%; (d) nBuLi, −78 °C, 88%; (e) K2CO3/MeOH, 79%; (f) 6 N HNO3, then AgO, 90%; (g) toluene, sealed 150 °C; 4-(Dicyanomethylene)-2-methyl-6-(4-dimethylaminostyryl)-4H-pyran (DCM), 51%;tube, (d) nBuLi, −(h) 78 ◦ C, 88%; (e) K 2CO3/MeOH, 79%; (f) 6 N HNO3, then AgO, 90%; (g) toluene, sealed tube, 150 °C; (h) CH3OH/H2O, TsOH, 80 °C, 31%. ◦ 88%;CH (e) K2 CO 3 /MeOH, 79%; (f) 6 N HNO3 , then AgO, 90%; (g) toluene, sealed tube, 150 C; 3OH/H 2O, TsOH, 80 °C, 31%.
(h) CH3 OH/H2 O, TsOH, 80 ◦ C, 31%.
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From the sub-Arctic ascidian Synoicum pulmonaria collected off the Norwegian coast,21 of 30 three new Mar. Drugs 2017, 15, 28 brominated guanidinium oxazolidinones were isolated, named synoxazolidinones A–C (215–217) From the sub‐Arctic ascidian Synoicum pulmonaria collected off the Norwegian coast, three new (Figure 20) [141–143]. The backbone of the compounds contains a 4-oxazolidinone ring rarely brominated oxazolidinones were isolated, (215–217) and seen in natural guanidinium products. Synoxazolidinones A (215)named and Bsynoxazolidinones (216) exhibitedA–C antibacterial (Figure 20) [141–143]. The backbone of the compounds contains a 4‐oxazolidinone ring rarely seen antifungal activities, and 215 displayed higher activity than 216 because of the chlorine atom in its in natural products. Synoxazolidinones A (215) and B (216) exhibited antibacterial and antifungal structure [141]. Synoxazolidinone C could inhibit the growth of Gram-positive bacteria Staphylococcus activities, and 215 displayed higher activity than 216 because of the chlorine atom in its structure aureus[141]. Synoxazolidinone C could inhibit the growth of Gram‐positive bacteria Staphylococcus aureus and methicillin-resistant S. aureus at a concentration of 10 µg/mL [142]. In addition, 215 and 217 a broadS. and high toward adhesion and growth 16217 known and displayed methicillin‐resistant aureus at a activity concentration of 10 the μg/mL [142]. In addition, 215 of and displayed a broad and high activity microalgae, toward the adhesion and growth of 16 known biofouling species of marine bacteria, and crustaceans. Compound 217biofouling was the most of marine bacteria, microalgae, crustaceans. Compound was the most active [144]. activespecies compound and was comparable to and the commercial antifouling217 product Sea-Nine-211 compound and was comparable to the commercial antifouling product Sea‐Nine‐211 [144]. Pulmonarins A (218) and B (219) (Figure 20) were two new dibrominated marine acetylcholinesterase Pulmonarins A (218) and B (219) (Figure 20) were two new dibrominated marine inhibitors that were also isolated from this sub-Arctic ascidian. Both 218 and 219 displayed acetylcholinesterase inhibitors that were also isolated from this sub‐Arctic ascidian. Both 218 and reversible, noncompetitive acetylcholinesterase inhibition comparable to several known natural 219 displayed reversible, noncompetitive acetylcholinesterase inhibition comparable to several acetylcholinesterase inhibitiors [145]. inhibitiors In addition, the were generally against known natural acetylcholinesterase [145]. In pulmonarins addition, the pulmonarins were active generally the adhesion and growth of several bacteria [144]. active against the adhesion and growth of several bacteria [144].
FigureFigure 20. Secondary metabolites derived from the Antarctic tunicates (compounds 210–214) and the 20. Secondary metabolites derived from the Antarctic tunicates (compounds 210–214) and the Arctic tunicate (compounds 215–219).
Arctic tunicate (compounds 215–219). 11. Conclusions
11. Conclusions
As demonstrated by this review, polar organisms have yielded an impressive array of novel
As demonstrated polar organisms have yielded anactivities impressive array the of novel compounds (Table by 1) this with review, complex structures and potent biological including compounds (Table 1) with complex structures and potent biological activities including the cytotoxic cytotoxic cyclic acylpeptides, mixirins A–C (1–3), from the Arctic marine bacterium Bacillus sp. [15]; unusual mixirins antibacterial lindgomycin (46) bacterium from the Bacillus culture sp.broth of unusual a cyclic the acylpeptides, A–C polyketide, (1–3), from the Arctic marine [15]; the Lindgomycetaceae strain [36]; the antioxidant (104) from the Antarctic lichen antibacterial polyketide, lindgomycin (46) fromcompound the cultureramalin broth of a Lindgomycetaceae strain [36]; the new antiparasitic tricyclic sesquiterpenoids, shagenes A (130) and B (131) Ramalina terebrata [61]; the antioxidant compound ramalin (104) from the Antarctic lichen Ramalina terebrata [61]; the new from an undescribed Antarctic soft coral [76]; and the new macrolides, palmerolide A (205) and D–G antiparasitic tricyclic sesquiterpenoids, shagenes A (130) and B (131) from an undescribed Antarctic (206–209) with potent V‐ATPase inhibitory and sub‐micromolar activity against melanoma from the soft coral [76]; and the new macrolides, palmerolide A (205) and D–G (206–209) with potent V-ATPase Antarctic tunicate Synoicum adareanum [111,112]. inhibitoryThe andnatural sub-micromolar activity against melanoma from the a Antarctic tunicate Synoicum products derived from polar regions appear to have high hit rate regarding adareanum [111,112]. biological activity, varying from cytotoxic, enzyme inhibitory, antioxidant, antiparasitic, antiviral to antibacterial and so on. Secondary metabolism polar habitats largely by ecological The natural products derived from polar regionsin appear to have ais high hit driven rate regarding biological requirements of the producing organism. Successful organisms antiparasitic, will often have specific to metabolic activity, varying from cytotoxic, enzyme inhibitory, antioxidant, antiviral antibacterial that produce unique natural products that bestow ecological advantage, of the and sopathways on. Secondary metabolism infunctional polar habitats is largely driven by ecological requirements increasing the possibility of finding pharmaceutical lead molecules. producing organism. Successful organisms will often have specific metabolic pathways that produce unique functional natural products that bestow ecological advantage, increasing the possibility of finding pharmaceutical lead molecules.
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Table 1. Novel natural products isolated from polar organisms. PHYLUM/Class
Species
Compounds
Bioactivity
Region
References
Bacillus sp.
1–3
Cytotoxic
Arctic
[15]
MICROORGANISMS Bacteria
Salegentibacter sp. Pseudoalteromonas haloplanktis Nostoc sp. Janthinobacterium sp. Pseudomonas sp. Actinomyces
Antimicrobial and cytotoxic
Arctic
[16,17]
Rradical scavenging
Antarctic
[18]
18 19, 20 21, 22
Antibacterial Antimycobacterial Antibacterial
Antarctic Antarctic Antarctic
[19] [20] [21]
Streptomyces sp.
23–25
Nocardiopsis sp. Nocardia dassonvillei Streptomyces nitrosporeus
Streptomyces griseus Streptomyces griseus Microbispora aerata Nocardiopsis sp.
26 27 28, 29 30 31 32 33 34 35, 36
Anti-angiogenesis Antifungal and cytotoxic Antiviral Enzyme inhibitory Enzyme inhibitory and cytotoxic Antibacterial Neuroprotective Antiproliferative and cytotoxic
Penicillium algidum
37
Anticancer
38–40 41 42 43–45 46, 47 48 49, 50 51–53 54–59 60–62 63–66 67, 68 69 70–78 79 80, 81 82–85 86–90 91
Cytotoxicity Antibacterial Cytotoxicity Immunosuppression Antibacterial Antifungal
Streptomyces sp.
Fungi
4–14 15 16, 17
Eutypella sp. Lindgomycetaceae Trichoderma polysporum Geomyces sp. Trichoderma asperellum Oidiodendron truncatum Penicillium crustosu m Penicillium sp. Penicillium funiculosum Pseudogymnoascus sp. Aspergillus ochraceopetaliformis
Antifungal and antibacterial Antifungal
Arctic
[22]
Arctic Arctic Arctic
[23] [24] [25]
Arctic
[27]
Antarctic Antarctic Antarctic Antarctic
[28] [29] [30] [31]
Arctic
[32]
Arctic
[33–35]
Arctic Arctic
[36,37] [38]
Antarctic
[39]
Antarctic
[40]
Cytotoxic
Antarctic
[42]
NF-κB inhibitory Moderate cytotoxic
Antarctic
[43]
Antarctic
[45,46]
Antarctic Antarctic
[47] [48]
Antiviral
Antarctic
[49]
Cytotoxic
Stereocaulon alpinum
92 93–98 99
Cytotoxic and enzyme inhibitory Enzyme inhibitory Antioxidant and antibacterial
Antarctic
[55–59]
Huea sp. Ramalina terebrata
100–103 104
Enzyme inhibitory Antioxidant
Antarctic Antarctic
[60] [61]
Polytrichastrum alpinum
105, 106
Enzyme inhibitory
Antarctic
[62]
BRYOZOANS
Tegella cf. spitzbergensis
107–110
Antibacterial
Arctic
[64]
CNIDARIANS
Ainigmaptilon antarcticus
111, 112
Predation inhibitory
Antarctic
[66]
Dasystenella acanthina Anthomastus bathyproctus Alcyonium grandis Undescribed octocoral Thuiria breitfussi
113
Ichthyotoxic
Antarctic
[67]
114–120
Weak cytotoxic
Antarctic
[68]
Antiparasitic
Antarctic Antarctic Arctic
[69] [76] [77]
Arctic
[80]
Antarctic
[81]
LICHEN
MOSS
121–129 130, 131 132, 133 134–136 137
Antibacterial
Staurocucumis liouvillei
138, 139
Antiviral
Staurocucumis turqueti Achlionice violaecuspidata
140 141–143
Antarctic Antarctic
[82] [83]
Austrodoris kerguelenensis
144–147
Antarctic
[84,85]
Gersemia fruticosa ECHINODERMS
MOLLUSCS
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Table 1. Cont. PHYLUM/Class
Species Austrodoris kerguelenensis Charcotia granulosa
SPONGES
Bioactivity
Region
References
148–166
Erythroleukemia inhibitory
Antarctic
[89]
167
Antarctic
[91]
Haliclona viscosa
168–173
Arctic
[93–96]
Suberites caminatus Dendrilla membranosa Suberites sp. Crella sp. Dendrilla membranosa
174–176 177–180 181–183 184–188 189 190 191–193
Antibacterial and antifungal Antibacterial
Antarctic Antarctic Antarctic Antarctic Antarctic
[99,100] [101] [102] [103] 104]
Enzyme inhibitory
Arctic
[105]
Antarctic
[109]
Antarctic
[110–112]
Antarctic
[137]
Antarctic
[140]
Arctic
[141–145]
Geodia barretti TUNICATES
Compounds
Aplidium cyaneum
194–199
Antimitotic Moderate cytotoxic
Synoicum adareanum
200–203 204 205–209
Aplidium sp.
210, 211
Aplidium fuegiense
212–214 215–217
Synoicum pulmonaria
218, 219
Cytotoxic and enzyme inhibitory Antiinflammatory, antiviral and antiproliferative Antibacterial and antifungal Enzyme inhibitory and antibacterial
However, when compared to the large number of polar microorganisms which have been reported, very few have been screened for the production of interesting secondary metabolites. This situation may be attributed to the difficulties in cultivating polar microorganisms, some of which cannot survive under normal laboratory conditions and therefore cannot be cultured using traditional techniques. As yet, the potential of this area remains virtually untapped. Nowadays, advances in laboratory techniques have led to cultivation of some previously inaccessible extremophiles. Moreover, new tools developed recently in the fields of bioinformatics [146], analytics [147], and molecular biology [148], in combination with rapid improvement in sequencing technology, might herald a new era of research into this specific source. Acknowledgments: The authors express thanks to the people who helped with this work. This work was financed by NSFC grant (21602152, 81403036), Shandong Provincial Natural Science Foundation (ZR2016BB01, ZR2014HM048), Shandong Provincial Key Research and Development Program (2016GSF202002), Shandong Provincial Medical Science and Technology Development Project (2013WS0321), Taian Science and Technology Development Project (2016NS1214), Shandong Provincial Education Department Project (J15LM56), National Undergraduate Training Program for Innovation and Entrepreneurship (201610439263) and Taishan Medical University High-level Development Project (2015GCC15). Author Contributions: Yuan Tian and Yan-Ling Li contributed equally in the writing of this manuscript. Feng-Chun Zhao collected all the references. Conflicts of Interest: The authors declare no conflict of interest.
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