Article

Palmerolide A, a Cytotoxic Macrolide from the Antarctic Tunicate Synoicum a dareanum

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Abstract

Palmerolide A, a 20-membered macrocyclic polyketide bearing carbamate and vinyl amide functionality, was isolated from the tunicate Synoicum adareanum collected from the vicinity of Palmer Station on the Antarctic Peninsula. Palmerolide A displays potent and selective cytotoxicity toward melanoma (UACC-66 LC50 = 0.018 muM) and appears to operate via inhibition (IC50 = 2 nM) of V-ATPase.

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... These enzymes appear to have an impact on angiogenesis, apoptosis, cell proliferation, and tumor metatastisis (10). A number of marine macrolides inhibit V-ATPases, including lobatamides, chondropsins, iejimalides, and several of the palmerolides (14)(15)(16)(17)(18). ...
... Palmerolide A (Fig. 1) is the principal secondary metabolite isolated from Synoicum adareanum, an ascidian which can be found in abundance at depths of 10 to 40 m in the coastal waters near Palmer Station, Antarctica (17). Palmerolide A is a macrolide polyketide that possesses potent bioactivity against malignant melanoma cell lines while demonstrating minimal cytotoxicity against other cell lines (17). ...
... Palmerolide A (Fig. 1) is the principal secondary metabolite isolated from Synoicum adareanum, an ascidian which can be found in abundance at depths of 10 to 40 m in the coastal waters near Palmer Station, Antarctica (17). Palmerolide A is a macrolide polyketide that possesses potent bioactivity against malignant melanoma cell lines while demonstrating minimal cytotoxicity against other cell lines (17). The NCI's COMPARE algorithm was used to correlate experimental findings with a database for prediction of the biochemical mechanism by identifying the mechanism of action of palmerolide A as a vacuolar-ATPase (V-ATPase) inhibitor (28). ...
Preprint
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Polyketides are a complex family of natural products that often serve competitive or pro-survival purposes but can also demonstrate bioactivity in human diseases as, for example cholesterol lowering agents, anti-infectives, or anti-tumor agents. Marine invertebrates and microbes are a rich source of polyketides. Palmerolide A, a polyketide isolated from the Antarctic ascidian Synoicum adareanum , is a vacuolar-ATPase inhibitor with potent bioactivity against melanoma cell lines. The biosynthetic gene clusters (BGC) responsible for production of secondary metabolites are encoded in the genomes of the producers as discrete genomic elements. A putative palmerolide BGC was identified from a S. adareanum metagenome based on a high degree of congruence with a chemical structure-based retrobiosynthetic prediction. Protein family homology analysis, conserved domain searches, and active site and motif identification were used to identify and propose the function of the 75 kb trans -acyltransferase (AT) polyketide synthase-non-ribosomal synthase (PKS-NRPS) domains responsible for the synthesis of palmerolide A. Though PKS systems often act in a predictable co-linear sequence, this BGC includes multiple trans -acting enzymatic domains, a non-canonical condensation termination domain, a bacterial luciferase-like monooxygenase (LLM), and multiple copies found within the metagenome-assembled genome (MAG) of Candidatus Synoicohabitans palmerolidicus. Detailed inspection of the five highly similar pal BGC copies suggests the potential for biosynthesis of other members of the palmerolide chemical family. This is the first delineation of a biosynthetic gene cluster from an Antarctic species. These findings have relevance for fundamental knowledge of PKS combinatorial biosynthesis and could enhance drug development efforts of palmerolide A through heterologous gene expression. Significance Statement Complex interactions exist between microbiomes and their hosts. Increasingly, defensive metabolites that have been attributed to host biosynthetic capability are now being recognized as products of associated microbes. These unique metabolites often have bioactivity in targets of human disease and can be purposed as pharmaceuticals. The molecular machinery for production of palmerolide A, a macrolide that is potent and selective against melanoma, was discovered as a genomic cluster in the microbiome of an Antarctic ascidian. Multiple non-identical copies of this genomic information provide clues to differences in specific enzymatic domains and point to Nature’s ability to perform combinatorial biosynthesis in situ . Harnessing this genetic information may pave a path for development of a palmerolide-based drug.
... 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. ...
... As demonstrated by this review, polar organisms have yielded an impressive array of novel compounds (Table 1) with complex structures and potent biological activities including the cytotoxic cyclic acylpeptides, mixirins A-C (1-3), from the Arctic marine bacterium Bacillus sp. [15]; the unusual antibacterial polyketide, lindgomycin (46) from the culture broth of a Lindgomycetaceae strain [36]; the antioxidant compound ramalin (104) from the Antarctic lichen Ramalina terebrata [61]; the new antiparasitic tricyclic sesquiterpenoids, shagenes A (130) and B (131) from an undescribed Antarctic soft coral [76]; and the new macrolides, palmerolide A (205) and D-G (206-209) with potent V-ATPase inhibitory and sub-micromolar activity against melanoma from the Antarctic tunicate Synoicum adareanum [111,112]. ...
... Moderate cytotoxic Antarctic [110][111][112] ...
Article
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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.
... Furthermore, only a small number of deep-water tunicates have been analyzed chemically due to the difficulties in accessing deep-sea habitats. Most of the compounds isolated from tunicates are nitrogen-containing, with the most common being aromatic alkaloids and macrocyclic metabolites [6][7][8][9][10]. ...
... Species of the genus Synoicum have been found in both shallow and deep-water around the world [11]. Most species of Synoicum spp. that have been studied chemically are from tropical shallow waters and only a few are from cold water habitats [9,10,12,13]. The existing literature shows that this genus of ascidians produce a variety of secondary metabolites, which are structurally diverse and include, but are not limited to, alkaloids, peptides, and polyketides [14][15][16][17]. ...
... The existing literature shows that this genus of ascidians produce a variety of secondary metabolites, which are structurally diverse and include, but are not limited to, alkaloids, peptides, and polyketides [14][15][16][17]. These secondary metabolites have shown anti-inflammatory, anti-microbial, and cytotoxic activity [10,[14][15][16][17][18]. ...
Article
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Five new alkaloids have been isolated from the lipophilic extract of the Antarctic tunicate Synoicum sp. Deep-sea specimens of Synoicum sp. were collected during a 2011 cruise of the R/V Nathanial B. Palmer to the southern Scotia Arc, Antarctica. Crude extracts from the invertebrates obtained during the cruise were screened in a zebrafish-based phenotypic assay. The Synoicum sp. extract induced embryonic dysmorphology characterized by axis truncation, leading to the isolation of aminopyrimidine substituted indolone (1–4) and indole (5–12) alkaloids. While the primary bioactivity tracked with previously reported meridianins A–G (5–11), further investigation resulted in the isolation and characterization of australindolones A–D (1–4) and the previously unreported meridianin H (12).
... This study was specifically motivated by our desire to understand the biosynthetic origins of a natural product, palmerolide A, given its potent anticancer activity (28), that is found to be associated with the polyclinid Antarctic ascidian, Synoicum adareanum ( Fig. 1A and B). Ascidians are known to be rich sources of bioactive natural products (9). ...
... Palmerolide A has anticancer properties with selective activity against melanoma when tested in the National Cancer Institute 60-cell-line panel (28). This result is of particular interest, as there are few natural product therapeutics for this devastating form of cancer. ...
... Several questions remain with regard to the in situ function of palmerolide A (a eukaryotic V-ATPase inhibitor in human cell line assays [28]) in this cryohabitat: how and why is it bioaccumulated by the host? Overall, the study of natural products in high-latitude marine ecosystems is in its infancy. ...
Article
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Palmerolide A has potential as a chemotherapeutic agent to target melanoma. We interrogated the microbiome of the Antarctic ascidian, Synoicum adareanum , using a cultivation-independent high-throughput sequencing and bioinformatic strategy.
... Alcyonium antarcticum (formerly, A. paessleri) and Synoicum adareanum are both reported to be rich in secondary metabolites. The soft coral A. antarcticum produces sesquiterpenes that are unusual in bearing nitrate ester functional groups [14], while the ascidian, S. adareanum, is known to produce a family of macrolide polyketides, the palmerolides, which have potent activity against melanoma [15]. The role of the microbial community in contributing to host defensive chemistry, microbechemistry interactions and niche optimization, as well as microbe-microbe interactions, are unknown in these high-latitude environments. ...
... The patellazoles, marine macrolides from the ascidian Lissoclinum patella, bioaccumulate in the ascidian tissues to concentrations up to seven orders of magnitude higher than their cytotoxic dose in mammalian cell lines [49,50]. Additionally, there are other instances in which bioaccumulation in ascidian host tissues suggests metabolic cooperation of producer and host as well as compound translocation from producer to host [15,51,52]. Although the PalA levels were normalized to grams of dry lobe weight, tissue-specific spatial localization is a potentially confounding factor in the statistical analyses investigating the ASV:PalA relationship. ...
Article
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Polar marine ecosystems hold the potential for bioactive compound biodiscovery, based on their untapped macro- and microorganism diversity. Characterization of polar benthic marine invertebrate-associated microbiomes is limited to few studies. This study was motivated by our interest in better understanding the microbiome structure and composition of the ascidian, Synoicum adareanum, in which palmerolide A (PalA), a bioactive macrolide with specificity against melanoma, was isolated. PalA bears structural resemblance to a hybrid nonribosomal peptide-polyketide that has similarities to microbially-produced macrolides. We conducted a spatial survey to assess both PalA levels and microbiome composition in S. adareanum in a region of the Antarctic Peninsula near Anvers Island (64° 46'S, 64° 03'W). PalA was ubiquitous and abundant across a collection of 21 ascidians (3 subsamples each) sampled from seven sites across the Anvers Island Archipelago. The microbiome composition (V3–V4 16S rRNA gene sequence variants) of these 63 samples revealed a core suite of 21 bacterial amplicon sequence variants (ASVs)—20 of which were distinct from regional bacterioplankton. ASV co-occurrence analysis across all 63 samples yielded subgroups of taxa that may be interacting biologically (interacting subsystems) and, although the levels of PalA detected were not found to correlate with specific sequence variants, the core members appeared to occur in a preferred optimum and tolerance range of PalA levels. These results, together with an analysis of the biosynthetic potential of related microbiome taxa, describe a conserved, high-latitude core microbiome with unique composition and substantial promise for natural product biosynthesis that likely influences the ecology of the holobiont.
... As part of our ongoing search for new compounds with antimicrobial activity from marine invertebrates, the aqueous extract of the colonial ascidian Synoicum turgens was examined for its content of AMPs. Synoicum species have previously awarded several bioactive secondary metabolites, including the cytotoxic palmerolide macrolides [30,31], the β-carboline guanidine alkaloid tiruchanduramine with α-glucosidase inhibitory activity [32,33], and the synoxazolidinones and pulmonarines with various bioactivities from S. pulmonaria [34][35][36][37]. To the best of our knowledge, no AMPs have been isolated and characterized from Synoicum species. ...
... Peptide sample was then combined 1:1 with cold (4 • C) 10 mM tris(2-carboxyethyl)phosphine (11.4 mg/mL) solution in 0.17 M citrate buffer (pH 3.0). One sample of turgencin B was incubated at 40 • C, a second sample at room temperature, and a third sample at 4 • C. Aliquots of 50 µL were taken out at different timepoints (10,20,30,45,60,90, 120 and 240 min) from all three samples. Upon sampling, each reaction solution was immediately added to 0.6 mg of pre-prepared N-ethylmaleimide (NEM) and incubated for 15 min at 37 • C before acidification through addition of 300 µL of 1% FA. ...
Article
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This study reports the isolation of two novel cysteine-rich antibacterial peptides, turgencin A and turgencin B, along with their oxidized derivatives, from the Arctic marine colonial ascidian Synoicum turgens. The peptides are post-translationally modified, containing six cysteines with an unusual disulfide connectivity of Cys1-Cys6, Cys2-Cys5, and Cys3-Cys4 and an amidated C-terminus. Furthermore, the peptides contain methionine residues resulting in the isolation of peptides with different degrees of oxidation. The most potent peptide, turgencin AMox1 with one oxidized methionine, displayed antimicrobial activity against both Gram-negative and Gram-positive bacteria with a minimum inhibitory concentration (MIC) as low as 0.4 µM against selected bacterial strains. In addition, the peptide inhibited the growth of the melanoma cancer cell line A2058 (IC50 = 1.4 µM) and the human fibroblast cell line MRC-5 (IC50 = 4.8 µM). The results from this study show that natural peptides isolated from marine tunicates have the potential to be promising drug leads.
... led to the isolation of biselides C (498), D (499) and E (500) which exhibited cytotoxicity against human cancer cells NCI-H460 and MDA-MB-231 [304]. Cytotoxic palmerolide A (501) was obtained from the Antarctic tunicate Synoicum adareanum [305] and its stereochemistry was revised and confirmed by synthesis [306,307]. investigation of the D. sp. ...
... led to the isolation of biselides C (498), D (499) and E (500) which exhibited cytotoxicity against human cancer cells NCI-H460 and MDA-MB-231 [304]. Cytotoxic palmerolide A (501) was obtained from the Antarctic tunicate Synoicum adareanum [305] and its stereochemistry was revised and confirmed by synthesis [306,307]. ...
Article
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Macrolides are a significant family of natural products with diverse structures and bioactivities. Considerable effort has been made in recent decades to isolate additional macrolides and characterize their chemical and bioactive properties. The majority of macrolides are obtained from marine organisms, including sponges, marine microorganisms and zooplankton, cnidarians, mollusks, red algae, bryozoans, and tunicates. Sponges, fungi and dinoflagellates are the main producers of macrolides. Marine macrolides possess a wide range of bioactive properties including cytotoxic, antibacterial, antifungal, antimitotic, antiviral, and other activities. Cytotoxicity is their most significant property, highlighting that marine macrolides still encompass many potential antitumor drug leads. This extensive review details the chemical and biological diversity of 505 macrolides derived from marine organisms which have been reported from 1990 to 2020.
... Hodgsonal, a sesquiterpene isolated exclusively from the notum and papillae of B. hodgsoni (Iken et al., 1998), showed repellence against O. validus (Avila et al., 2000). Doris kerguelenensis was proved to possess a variety of diterpene diacylglycerols in the notum (Gavagnin et al., 1995;1999a, b;2003a, b;Diyabalanage et al., 2006;Maschek et al., 2012), some of them displaying anti-predatory activity against O. validus (Iken et al., 2002). These metabolites are synthesised through diverse metabolic routes with a remarkable variability among individuals (Cutignano et al., 2011). ...
... Hodgsonal, a sesquiterpene isolated exclusively from the notum and dorsal papillae of B. hodgsoni (Iken et al., 1998), showed repellence against the sympatric sea star predator Odontaster validus (Avila et al., 2000). Doris kerguelenensis was proven to possess a wide variety of terpene acylglycerols in the notum (Gavagnin et al., 1995(Gavagnin et al., , 1999a(Gavagnin et al., ,b, 2003aDiyabalanage et al., 2006;Cutignano et al., 2011;Maschek et al., 2012), some of them proven to display anti-predatory activity against O. validus (Iken et al., 2002). The metabolites of D. kerguelenensis are synthesized through diverse metabolic routes with a remarkable variability among individuals of even the same population (Cutignano et al., 2011). ...
Thesis
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This thesis covers three important aspects of Antarctic heterobranchs: ecology, taxonomy, and systematics. The first section deals with ecological interactions of several nudibranchs. In Chapter 1, we chemically characterize a new natural product (a homosesterterpene) called granuloside, from Charcotia granulosa Vayssière, 1906; remarkably, this is the first record of this type of compound in marine organisms. In Chapter 2, we assess the origin, function, and distribution of granuloside in this nudibranch; we found glandular structures probably responsible for storing granuloside, as a defensive mechanism against predators, like the sympatric starfish, Odontaster validus Koehler, 1906. We also hypothesize that granuloside is de novo biosynthesized by C. granulosa. This chapter reflects how organisms from polar latitudes have similar defensive strategies to those of temperate and tropical zones. In Chapter 3, a new species of ectosymbiont copepod, Anthessius antarcticus n. sp., living on C. granulosa is described. This is the first record of such association in Antarctica and the first time that this copepod genus has been found living on a nudibranch. In Chapter 4, we study the development of two anthobranchs, Doris kerguelenensis (Bergh, 1884) and Bathydoris hodgsoni Eliot, 1907, both with intracapsular development; we provide new data on the egg masses characteristics, and embryos morphology and anatomy, throughout their development; we also studied at which ontogenetic stage their natural products appear. We concluded that both nudibranchs exhibit developmental periods of up to several years; their embryos are physically defended by a thick egg capsule, while juveniles already rely on de novo biosynthesized defensive compounds. In the second section of this thesis, our interdisciplinary taxonomic and systematic studies, including histology, tomography, electron microscopy, and molecular tools, allowed us to describe three new species of heterobranchs. In Chapter 5, we provide integrative taxonomic evidence for the establishment of a new family (Newnesiidae), and the description of a new species of Cephalaspidea (Newnesia joani n. sp.) with eurybathic and circumpolar distribution; this discovery traces the origin of the cephalaspideans (distributed worldwide) to Antarctica. In Chapter 6, we performed a three-dimensional (3D) anatomical reconstruction and compared the two nudibranchs Doto antarctica and the new species Doto carinova n. sp.; their phylogeny reveals intriguing questions concerning the development of the reproductive system in this genus; 3D reconstructions reveal also the presence of probable giant neurons associated with the nervous system, which were unknown in this genus so far. Finally, in Chapter 7 we provide new evidence of bipolar geographic distributions by describing a new species of nudibranch, Doridunculus punkus n. sp., using only non-destructive tomographic techniques. Our results highlight both the need and the relevance of multidisciplinary approaches to study biodiversity and ecological interactions in heterobranch molluscs from a poorly studied area of the planet, such as Antarctica.
... Antarctic Tunicates are also a chemically rich group, with many bioactivities described [8,13,15,[18][19][20][21][24][25][26]45,88,[149][150][151][152][153][154][155][156][157]. Here, however, the species tested were not repellent in the assays against crabs, except for the hydrophilic extract of the colonial Synoicum adareanum. ...
... This contrasts with previous results in assays with Antarctic predators, where they were repellent [8,13,15,16,[18][19][20][21][24][25][26]45,88]. S. adareanum possesses many chemicals, such as polyketides palmerolides (7) (Figure 4) [150,151,154,155]. The hydrophilic fraction may also contain these or perhaps other compounds that could produce this repellence. ...
Article
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Many Antarctic marine benthic macroinvertebrates are chemically protected against predation by marine natural products of different types. Antarctic potential predators mostly include sea stars (macropredators) and amphipod crustaceans (micropredators) living in the same areas (sympatric). Recently, alien species (allopatric) have been reported to reach the Antarctic coasts, while deep-water crabs are suggested to be more often present in shallower waters. We decided to investigate the effect of the chemical defenses of 29 representative Antarctic marine benthic macroinvertebrates from seven different phyla against predation by using non-native allopatric generalist predators as a proxy for potential alien species. The Antarctic species tested included 14 Porifera, two Cnidaria, two Annelida, one Nemertea, two Bryozooa, three Echinodermata, and five Chordata (Tunicata). Most of these Antarctic marine benthic macroinvertebrates were chemically protected against an allopatric generalist amphipod but not against an allopatric generalist crab from temperate waters. Therefore, both a possible recolonization of large crabs from deep waters or an invasion of non-native generalist crab species could potentially alter the fundamental nature of these communities forever since chemical defenses would not be effective against them. This, together with the increasing temperatures that elevate the probability of alien species surviving, is a huge threat to Antarctic marine benthos.
... On the other hand, organisms that live in extreme conditions and found in the marine environment have also been widely explored. Palmerolide A is a potent cytotoxic macrolide isolated from Synoicum adareanum, a circumpolar tunicate from Antarctica displaying a potent anti-cancer activity against melanoma cell lines [40]. ...
Chapter
Natural products are often described for their 'privileged' scaffold, allowing them to work as ligands for a diverse array of enzymes and receptors. There is actually a link that can explain why natural products can display good results as enzyme inhibitors. Despite the general potential of natural products in drug discovery, there are still some drawbacks that can hinder pharmaceutical development. Microencapsulation is an approach used in a drug delivery system. Novel drug delivery systems not only increase the therapeutic value by reducing toxicity and increasing the bioavailability, but also overcome non-compliance to the therapeutic by reducing repeated drug administrations. The strategies are often solutions for most of the problems regarding lack of bioavailability of natural products as drug leads. The strategy of repurposing approved drugs is a promising approach that could enhance the potential of natural products. Besides the financial advantages, repurposing has also safety rewards.
... Also, in smaller amounts, they present some non-nitrogenous compounds, such as lactones, terpenoids or quinones (Blunt et al., 2018). Antarctic ascidians coming from shallow and deep bottoms present bioactive natural products such as palmerolide A, a group of ecdysteroids, meridianins, aplicyanins and rossinones (Diyabalanage et al., 2006;Miyata et al., 2007;Seldes et al., 2007;Appleton et al., 2009). It is often unclear whether the tunicates are the true producers of the molecules or if associated microbes may play a role in their chemical ecology . ...
... It has potent cytotoxicity against melanoma cells (UACC-62, MI14, SK-MEL-5, LOX IMVI), colon cancer cell line HCC-2998 and renal cancer cell line RXF 393. It was also found to be V-ATPase inhibitor [90,91]. Another ascidian, Lissoclinum patella, produces patellazoles A-C (2-4); these natural compounds have strong cytotoxicity against HCT-116 tumour cells [92]. ...
Article
Full-text available
Ascidians are a class of sessile filter-feeding invertebrates, that provide unique and fertile niches harboring various microorganisms, such as bacteria, actinobacteria, cyanobacteria and fungi. Over 1000 natural products, including alkaloids, cyclic peptides, and polyketides, have been isolated from them, which display diverse properties, such as antibacterial, antifungal, antitumor, and anti-inflammatory activities. Strikingly, direct evidence has confirmed that ~8% of natural products from ascidians are actually produced by symbiotic microorganisms. In this review, we present 150 natural products from microorganisms associated with ascidians that have been reported up to 2017.
... More than 90% of the ocean exists at temperatures below 3 °C, yet only 2% of natural products are reported from marine organisms collected in these regions [1,2], reflecting, in part, that such environments remain difficult to access. Despite the lack of attention, important biologically active compounds continue to be found [3][4][5][6][7][8][9]. ...
Article
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: An Antarctic coral belonging to the order Pennatulacea, collected during the 2013 austral autumn by trawl from 662 to 944 m depth, has yielded three new briarane diterpenes, bathyptilone A-C (1–3) along with a trinorditerpene, enbepeanone A (4), which bears a new carbon skeleton. Structure elucidation was facilitated by one- and two-dimensional NMR spectroscopy, mass spectrometry and confirmed by X-ray crystallography. The three compounds were screened in four cancer cell lines. Bathyptilone A displayed selective nanomolar cytotoxicity against the neurogenic mammalian cell line Ntera-2.
... It has long been a tenet of natural products discovery research that examination of unexplored and unusual source organisms, or those from unique environments, provides opportunities for finding novel natural products. Recent examples of such habitats include caves (19), hydrothermal vents (20), Arctic (17) and Antarctic waters (21), plant endophytes (22,23), and vertebrate (24)(25)(26) and invertebrate (27) microbiota. To examine the relationship between organism type and chemical diversity we subdivided the dataset into subgroups within two major designations (bacterial and marine). ...
Article
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Significance Natural products research seems to be at a critical juncture in terms of its relevance to modern biological science. We have evaluated this landscape of chemical diversity to ask key questions, including the following. How has the rate of discovery of new natural products progressed over the past 70 y? Has natural product structural novelty changed as a function of time? Has the rate of novel discovery declined in recent years? Does exploring novel taxonomic space afford an advantage in terms of novel compound discovery? Is it possible to estimate how close we are to describing all of the chemical space covered by natural products? And, finally, is there still value in exploring natural products space for novel biologically active natural products?
... Palmerolide D exhibited a 10-fold decrease in inhibiting V-ATPase compared to palmerolide A, but its cytotoxicity showed a 10-fold increase. 127,128 The same Antarctic tunicate Synoicum adareanum that produced palmerolide A 127 and palmerolides D-G, 128 yielded the previously reported ecdysteroid diaulusterol B along with ve new ones, named hyousterones A-D (367-370), and abeohyousterone (371). The structures of the new metabolites were elucidated by means of thorough spectroscopic techniques while their relative congurations were determined through NOESY and ROESY experiments. ...
Article
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Covering the literature on cold-water marine natural products from 2006 to 2016. This is an update report on marine natural products isolated from cold-water organisms in the last decade, following the previous review that covered the literature up to 2005. Emphasis is given to the biological activities as well as the spectroscopic methods used for the structure elucidation of the new metabolites isolated from cold-water habitats.
... Major compounds in the NA extract were long fatty acids and lyso-PAF, but other compounds with previously reported antiproliferative activity, such as the diterpene spongian-16-one [40], the chlorophyll ethyl pheophorbide A [88,112], palmerolide A (a macrocyclic polyketide) [85,86], and rhizovarin D (an indole diterpene) [89], were present in large amounts. Finally, the most abundant compounds in the NB extract were spongian-16-one and a porphyrin derivative, pyropheophorbide A, both of which have been reported to possess antiproliferative activity [40,88,112]. ...
Article
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Marine compounds are a potential source of new anticancer drugs. In this study, the antiproliferative effects of 20 invertebrate marine extracts on three colon cancer cell models (HGUE-C-1, HT-29, and SW-480) were evaluated. Extracts from two nudibranchs (Phyllidia varicosa, NA and Dolabella auricularia, NB), a holothurian (Pseudocol ochirus violaceus, PS), and a soft coral (Carotalcyon sp., CR) were selected due to their potent cytotoxic capacities. The four marine extracts exhibited strong antiproliferative effects and induced cell cycle arrest at the G2/M transition, which evolved into early apoptosis in the case of the CR, NA, and NB extracts and necrotic cell death in the case of the PS extract. All the extracts induced, to some extent, intracellular ROS accumulation, mitochondrial depolarization, caspase activation, and DNA damage. The compositions of the four extracts were fully characterized via HPLC-ESI-TOF-MS analysis, which identified up to 98 compounds. We propose that, among the most abundant compounds identified in each extract, diterpenes, steroids, and sesqui- and seterterpenes (CR); cembranolides (PS); diterpenes, polyketides, and indole terpenes (NA); and porphyrin, drimenyl cyclohexanone, and polar steroids (NB) might be candidates for the observed activity. We postulate that reactive oxygen species (ROS) accumulation is responsible for the subsequent DNA damage, mitochondrial depolarization, and cell cycle arrest, ultimately inducing cell death by either apoptosis or necrosis.
... In 2009, Hall and co-workers applied the oxa [4 + 2] cycloaddition/allylboration to a total synthesis of palmerolide A (79), 42 a complex macrolide with selective antimelanoma activity. 43 Construction of the "east" fragment 80 featured the chiral secondary boronate 81 as a key intermediate (Scheme 20). This synthetic strategy exploited the "self-allylboration" product 44 that was initially feared to form uncontrollably via As part of an effort to provide new methods to access these structures, Hall and co-workers recently achieved a regioselective and stereospecific Suzuki−Miyaura cross-coupling of piperidine-and pyran-derived allylboronates with aryl and alkenyl organobromides (Scheme 22A). ...
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... Haloquadratum walsbyi was used as an outgroup. Core (green diamonds) and dynamic (blue 1191 diamonds) ASVs are shown, along with cultivated isolates from the Synoicum adareanum 1192 microbiome (light blue triangles) and cloned rRNA gene sequences from an earlier study with S. 1193 adareanum collected in 2006(Riesenfeld et al. 2008. [note upon final submission, this figure 1194 will appear as a standalone PDF in which it will be in full size] 1195 author/funder. ...
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The ascidian, S. adareanum, from the Antarctic Peninsula near Anvers Island, is known to produce a bioactive compound, palmerolide A (PalA) that has specific activity to melanoma, a particularly invasive and metastatic form of skin cancer. The combined non-ribosomal peptide polyketide structure of PalA has similarities to microbially-produced macrolides which motivated this study utilizing culture-dependent and -independent investigations coupled with PalA detection to improve our understanding of the host-associated microbiome and relationship to PalA. Cultivation efforts yielded seven different bacteria, none of which produced PalA under the conditions tested. The genome sequence was mined for one of the most abundant members of the microbiome, Pseudovibrio sp. str. TunPSC04-5.I4, revealing eight biosynthetic gene clusters, none supporting the potential for PalA biosynthesis. PalA was ubiquitous and abundant across a collection of 21 ascidians (3 subsamples each) sampled from seven sites across the Anvers Island archipelago. These 63 samples were used to assess microbiome composition (V3-V4 16S rRNA gene sequence variants) which revealed a core suite of 21 bacteria, 20 of which were distinct from regional bacterioplankton. Co-occurrence analysis yielded several subsystems that may interact functionally and, although the levels of PalA detected were not found to correlate with specific sequence variants, the core members appeared to occur in a preferred optimum and tolerance range of PalA levels. Sequence variant relative abundance and biosynthetic potential of related organisms pointed to a subset of the core membership as potential PalA producers which provides a gateway to identifying the producer of palmerolides in future work.
... Palmerolide-A was identified from the tunicate Synoicum adareanum isolated from the Antarctic area. It has been shown to inhibit V-ATPase resulting in strong and specific cytotoxicity on melanoma cell line UACC-66 [81]. Many years later (2020), Murray and colleagues investigated the Synoicum adareanum microbiome composition to increase knowledge of the palmerolide-A biosynthetic pathway [82] and opened a new perspective on this precious marine natural product (MNP). ...
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... An additional secondary metabolite is Palmerolide A (PalA), with cytotoxicity against melanoma, isolated from the colonial ascidian Synoicum adareanum [77]. The levels of PalA in S. adareanum were abundant and ubiquitous, along with a core and stable microbiome [65]. ...
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Giovanni Appendino was born in Carmagnola, Italy, in 1995. After graduating from the University of Torino in 1979, he did post-Laurea work with Professor Pierre De Clercq (University of Gent, Belgium), working on the total synthesis of gibberellic acids. In 1983, he became lecturer and in 1998 associated professor at his alma mater. Since 2000, he is full professor of organic chemistry at the Università del Piemonte Orientale, Faculty of Pharmacy and since 2006, chief scientific adviser of Indena S.p.A., Milano. Professor Appendino’s research interests are in the realm of bioactive natural products (isolation, chemical modification, and total synthesis). He has published over 250 original articles in this area and in 1991 he received the Rhône–Poulenc Rorer Award of the Phytochemical Society of Europe for his studies on isoprenoids.
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A stereoselective synthesis of the highly advanced intermediates towards the revised structure of palmerolide C and 10–ent–palmerolide C are described in this paper. The required key fragments C1–C6, C7–C14 and C15–C23 have been successfully assembled in a convergent manner to access the C1–C23 framework bearing all the five stereocenters present in the natural product. The synthesis involves Julia–Kocienski reaction, Yamaguchi esterification, Takai olefination and regioselective epoxide opening as key steps. The proposed route is flexible and could also be applied to the synthesis of structurally related palmerolides.
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From deep ocean trenches and the geographical poles to outer space, organisms can be found living in remarkably extreme conditions. This book provides a captivating account of these systems and their extraordinary inhabitants, ‘extremophiles’. A diverse, multidisciplinary group of experts discuss responses and adaptations to change; biodiversity, bioenergetic processes, and biotic and abiotic interactions; polar environments; and life and habitability, including searching for biosignatures in the extraterrestrial environment. The editors emphasise that understanding these systems is important for increasing our knowledge and utilizing their potential, but this remains an understudied area. Given the threat to these environments and their biota caused by climate change and human impact, this timely book also addresses the urgency to document these systems. It will help graduate students and researchers in conservation, marine biology, evolutionary biology, environmental change and astrobiology better understand how life exists in these environments and its susceptibility or resilience to change.
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Plant-based systems continue to play an essential role in health care, and their use by different cultures is extensively documented. This chapter reviews the continuing value of natural products as sources of potential chemotherapeutic agents. While the contributions of natural secondary metabolites to modern medicine are abundantly clear, the question of their origins has long intrigued chemists and biochemists. Six major hypotheses are summarized here. Structural diversity is not the only reason why natural products are of interest to drug developers, since they often provide highly selective and specific biological activities based on mechanisms of action. The natural products approach can thus be seen as complementary to the synthetic approach, each providing access to (initially) different lead structures. The task of the natural products researcher is thus to select these compounds of pharmacological interest from the “natural combinatorial libraries” produced by extraction of organisms. There are four major elements in the design of any successful natural-products–based drug discovery program: acquisition of biomass, effective screening, bioactivity- driven fractionation, and rapid and effective structure elucidation. The selection of plant samples often raises the question of the ethnobotanical/ethnopharmacological approach versus a random approach. Structure elucidation of the bioactive constituent depends almost exclusively on the application of modern instrumental methods, particularly high-field NMR and MS. Novel methods of chemical syntheses that have the potential to produce base “natural product” molecules that can be optimized for specific medicinal chemistry purposes are also reported.
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Mosher's (H-1) method to elucidate the absolute configuration of secondary alcohols was reexamined by use of high-field FT NMR spectroscopy, which enables assignment of most of the protons of complex molecules. There is a systematic arrangement of DELTA-delta (delta-S - delta-R) values obtained for the (R)- and (S)-MTPA esters of (-)-menthol, (-)-borneol, cholesterol, and ergosterol, the absolute configurations of which are known. Analysis of the DELTA-delta values of these compounds led to a rule that could predict the absolute configurations of natural products. When this rule was applied to some marine terpenoids including cembranolides and xenicanes, their absolute configurations were assigned and a part of the results were confirmed by X-ray structural analyses. In the case of sipholenol A, which has a sterically hindered OH group, this rule is inapplicable. But the problem is overcome by inverting the OH group to a less sterically hindered position; the resulting epimer gives systematically arranged DELTA-delta values, which enabled the elucidation of the absolute configuration. Comparison of the present method with Mosher's F-19 method indicates that the latter one using F-19 NMR lacks in reliability.