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Mar. Drugs, Volume 12, Issue 4 (April 2014), Pages 1699-2340

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Open AccessArticle Nature’s Lab for Derivatization: New and Revised Structures of a Variety of Streptophenazines Produced by a Sponge-Derived Streptomyces Strain
Mar. Drugs 2014, 12(4), 1699-1714; doi:10.3390/md12041699
Received: 19 December 2013 / Revised: 7 February 2014 / Accepted: 17 February 2014 / Published: 25 March 2014
Cited by 4 | PDF Full-text (509 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Eight streptophenazines (A–H) have been identified so far as products of Streptomyces strain HB202, which was isolated from the sponge Halichondria panicea from the Baltic Sea. The variation of bioactivities based on small structural changes initiated further studies on new derivatives. Three new
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Eight streptophenazines (A–H) have been identified so far as products of Streptomyces strain HB202, which was isolated from the sponge Halichondria panicea from the Baltic Sea. The variation of bioactivities based on small structural changes initiated further studies on new derivatives. Three new streptophenazines (I–K) were identified after fermentation in the present study. In addition, revised molecular structures of streptophenazines C, D, F and H are proposed. Streptophenazines G and K exhibited moderate antibacterial activity against the facultative pathogenic bacterium Staphylococcus epidermidis and against Bacillus subtilis. All tested compounds (streptophenazines G, I–K) also showed moderate activities against PDE 4B. Full article
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Open AccessArticle Synthesis and Evaluation of Some New Aza-B-homocholestane Derivatives as Anticancer Agents
Mar. Drugs 2014, 12(4), 1715-1731; doi:10.3390/md12041715
Received: 26 December 2013 / Revised: 24 February 2014 / Accepted: 26 February 2014 / Published: 25 March 2014
Cited by 6 | PDF Full-text (928 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Using analogues of some marine steroidal oximes as precursors, a series of aza-B-homocholestane derivatives possessing different substituted groups at the 3-position of the steroidal nucleus were synthesized. Their biological activity against cancer cell proliferation was determined with multiple cancer cell lines.
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Using analogues of some marine steroidal oximes as precursors, a series of aza-B-homocholestane derivatives possessing different substituted groups at the 3-position of the steroidal nucleus were synthesized. Their biological activity against cancer cell proliferation was determined with multiple cancer cell lines. Aza-B-homocholestane derivatives possessing 3-hydroxyl, 3-hydroximino and 3-thiosemicarbazone groups displayed remarkable cytotoxicity to cancer cells via apoptosis inducing mechanism. Compounds 5, 10, 12, 15 and 18 exhibited better potency to inhibit cancer cell proliferation. In addition, compound 15 was further evaluated with three dimensional (3D) multicellular spheroids assay to determine its potency against spheroid growth. The structure-activity relationship (SAR) generated in the studies is valuable for the design of novel chemotherapeutic agents. Full article
Open AccessArticle Vibrio vulnificus MO6-24/O Lipopolysaccharide Stimulates Superoxide Anion, Thromboxane B2, Matrix Metalloproteinase-9, Cytokine and Chemokine Release by Rat Brain Microglia in Vitro
Mar. Drugs 2014, 12(4), 1732-1756; doi:10.3390/md12041732
Received: 28 December 2013 / Revised: 26 February 2014 / Accepted: 26 February 2014 / Published: 26 March 2014
Cited by 2 | PDF Full-text (785 KB) | HTML Full-text | XML Full-text
Abstract
Although human exposure to Gram-negative Vibrio vulnificus (V. vulnificus) lipopolysaccharide (LPS) has been reported to result in septic shock, its impact on the central nervous system’s innate immunity remains undetermined. The purpose of this study was to determine whether V. vulnificus
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Although human exposure to Gram-negative Vibrio vulnificus (V. vulnificus) lipopolysaccharide (LPS) has been reported to result in septic shock, its impact on the central nervous system’s innate immunity remains undetermined. The purpose of this study was to determine whether V. vulnificus MO6-24/O LPS might activate rat microglia in vitro and stimulate the release of superoxide anion (O2), a reactive oxygen species known to cause oxidative stress and neuronal injury in vivo. Brain microglia were isolated from neonatal rats, and then treated with either V. vulnificus MO6-24/O LPS or Escherichia coli O26:B6 LPS for 17 hours in vitro. O2 was determined by cytochrome C reduction, and matrix metalloproteinase-2 (MMP-2) and MMP-9 by gelatinase zymography. Generation of cytokines tumor necrosis factor alpha (TNF-α), interleukin-1 alpha (IL-1α), IL-6, and transforming growth factor-beta 1 (TGF-β1), chemokines macrophage inflammatory protein (MIP-1α)/chemokine (C-C motif) ligand 3 (CCL3), MIP-2/chemokine (C-X-C motif) ligand 2 (CXCL2), monocyte chemotactic protein-1 (MCP-1)/CCL2, and cytokine-induced neutrophil chemoattractant-2alpha/beta (CINC-2α/β)/CXCL3, and brain-derived neurotrophic factor (BDNF), were determined by specific immunoassays. Priming of rat microglia by V. vulnificus MO6-24/O LPS in vitro yielded a bell-shaped dose-response curve for PMA (phorbol 12-myristate 13-acetate)-stimulated O2 generation: (1) 0.1–1 ng/mL V. vulnificus LPS enhanced O2 generation significantly but with limited inflammatory mediator generation; (2) 10–100 ng/mL V. vulnificus LPS maximized O2 generation with concomitant release of thromboxane B2 (TXB2), matrix metalloproteinase-9 (MMP-9), and several cytokines and chemokines; (3) 1000–100,000 ng/mL V. vulnificus LPS, with the exception of TXB2, yielded both attenuated O2 production, and a progressive decrease in MMP-9, cytokines and chemokines investigated. Thus concentration-dependent treatment of neonatal brain microglia with V. vulnificus MO6-24/O LPS resulted in a significant rise in O2 production, followed by a progressive decrease in O2 release, with concomitant release of lactic dehydrogenase (LDH), and generation of TXB2, MMP-9, cytokines and chemokines. We hypothesize that the inflammatory mediators investigated may be cytotoxic to microglia in vitro, by an as yet undetermined autocrine mechanism. Although V. vulnificus LPS was less potent than E. coli LPS in vitro, inflammatory mediator release by the former was clearly more efficacious. Finally, we hypothesize that should V. vulnificus LPS gain entry into the CNS, it would be possible that microglia might become activated, resulting in high levels of O2 as well as neuroinflammatory TXB2, MMP-9, cytokines and chemokines. Full article
(This article belongs to the Special Issue Marine Lipopolysaccharides)
Open AccessArticle Synthesis and Anti-Tuberculosis Activity of the Marine Natural Product Caulerpin and Its Analogues
Mar. Drugs 2014, 12(4), 1757-1772; doi:10.3390/md12041757
Received: 7 January 2014 / Revised: 6 February 2014 / Accepted: 27 February 2014 / Published: 27 March 2014
Cited by 5 | PDF Full-text (697 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Caulerpin (1a), a bis-indole alkaloid from the marine algal Caulerpa sp., was synthesized in three reaction steps with an overall yield of 11%. The caulerpin analogues (1b1g) were prepared using the same synthetic pathway with overall yields
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Caulerpin (1a), a bis-indole alkaloid from the marine algal Caulerpa sp., was synthesized in three reaction steps with an overall yield of 11%. The caulerpin analogues (1b1g) were prepared using the same synthetic pathway with overall yields between 3% and 8%. The key reaction involved a radical oxidative aromatic substitution involving xanthate (3) and 3-formylindole compounds (4a4g). All bis-indole compounds synthesized were evaluated against the Mycobacterium tuberculosis strain H37Rv, and 1a was found to display excellent activity (IC50 0.24 µM). Full article
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Open AccessArticle Peridinin from the Marine Symbiotic Dinoflagellate, Symbiodinium sp., Regulates Eosinophilia in Mice
Mar. Drugs 2014, 12(4), 1773-1787; doi:10.3390/md12041773
Received: 10 December 2013 / Revised: 25 February 2014 / Accepted: 28 February 2014 / Published: 27 March 2014
PDF Full-text (528 KB) | HTML Full-text | XML Full-text
Abstract
Peridinin and fucoxanthin, which are natural carotenoids isolated from a symbiotic dinoflagellate, Symbiodinium sp., and a brown alga, Petalonia fascia, respectively, were compared for inhibitory effects on delayed-type hypersensitivity in mice. The number of eosinophils at the site of inflammation and in
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Peridinin and fucoxanthin, which are natural carotenoids isolated from a symbiotic dinoflagellate, Symbiodinium sp., and a brown alga, Petalonia fascia, respectively, were compared for inhibitory effects on delayed-type hypersensitivity in mice. The number of eosinophils at the site of inflammation and in peripheral blood was compared for the administration of peridinin and fucoxanthin applied by painting and intraperitoneally. Peridinin, but not the structurally-related fucoxanthin, significantly suppressed the number of eosinophils in both the ear lobe and peripheral blood. Furthermore, peridinin applied topically, but not administered intraperitoneally, suppressed the level of eotaxin in the ears of sensitized mice. Fucoxanthin weakly suppressed the concentration of eotaxin in ears only by intraperitoneal administration. Although both carotenoids inhibited the migration of eosinophils toward eotaxin, the inhibitory effect of peridinin was higher than that of fucoxanthin. Peridinin may be a potential agent for suppressing allergic inflammatory responses, such as atopic dermatitis, in which eosinophils play a major role in the increase of inflammation. Full article
(This article belongs to the Special Issue Marine Carotenoids (Special Issue))
Open AccessArticle A Practical Strategy to Discover New Antitumor Compounds by Activating Silent Metabolite Production in Fungi by Diethyl Sulphate Mutagenesis
Mar. Drugs 2014, 12(4), 1788-1814; doi:10.3390/md12041788
Received: 13 December 2013 / Revised: 21 February 2014 / Accepted: 5 March 2014 / Published: 27 March 2014
Cited by 14 | PDF Full-text (1162 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Many fungal biosynthetic pathways are silent in standard culture conditions, and activation of the silent pathways may enable access to new metabolites with antitumor activities. The aim of the present study was to develop a practical strategy for microbial chemists to access silent
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Many fungal biosynthetic pathways are silent in standard culture conditions, and activation of the silent pathways may enable access to new metabolites with antitumor activities. The aim of the present study was to develop a practical strategy for microbial chemists to access silent metabolites in fungi. We demonstrated this strategy using a marine-derived fungus Penicillium purpurogenum G59 and a modified diethyl sulphate mutagenesis procedure. Using this strategy, we discovered four new antitumor compounds named penicimutanolone (1), penicimutanin A (2), penicimutanin B (3), and penicimutatin (4). Structures of the new compounds were elucidated by spectroscopic methods, especially extensive 2D NMR analysis. Antitumor activities were assayed by the MTT method using human cancer cell lines. Bioassays and HPLC-photodiode array detector (PDAD)-UV and HPLC-electron spray ionization (ESI)-MS analyses were used to estimate the activated secondary metabolite production. Compounds 2 and 3 had novel structures, and 1 was a new compound belonging to a class of very rare natural products from which only four members are so far known. Compounds 13 inhibited several human cancer cell lines with IC50 values lower than 20 μM, and 4 inhibited the cell lines to some extent. These results demonstrated the effectiveness of this strategy to discover new compounds by activating silent fungal metabolic pathways. These discoveries provide rationale for the increased use of chemical mutagenesis strategies in silent fungal metabolite studies. Full article
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Open AccessArticle Seven New and Two Known Lipopeptides as well as Five Known Polyketides: The Activated Production of Silent Metabolites in a Marine-Derived Fungus by Chemical Mutagenesis Strategy Using Diethyl Sulphate
Mar. Drugs 2014, 12(4), 1815-1838; doi:10.3390/md12041815
Received: 24 December 2013 / Revised: 12 February 2014 / Accepted: 17 February 2014 / Published: 28 March 2014
Cited by 20 | PDF Full-text (1192 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
AD-2-1 is an antitumor fungal mutant obtained by diethyl sulfate mutagenesis of a marine-derived Penicillium purpurogenum G59. The G59 strain originally did not produce any metabolites with antitumor activities in MTT assays using K562 cells. Tracing newly produced metabolites under guidance of MTT
[...] Read more.
AD-2-1 is an antitumor fungal mutant obtained by diethyl sulfate mutagenesis of a marine-derived Penicillium purpurogenum G59. The G59 strain originally did not produce any metabolites with antitumor activities in MTT assays using K562 cells. Tracing newly produced metabolites under guidance of MTT assay and TLC analysis by direct comparison with control G59 extract, seven new (17) and two known (89) lipopeptides were isolated together with five known polyketides 1014 from the extract of mutant AD-2-1. Structures of the seven new compounds including their absolute configurations were determined by spectroscopic and chemical evidences and named as penicimutalides A–G (17). Seven known compounds were identified as fellutamide B (8), fellutamide C (9), 1′-O-methylaverantin (10), averantin (11), averufin (12), nidurufin (13), and sterigmatocystin (14). In the MTT assay, 114 inhibited several human cancer cell lines to varying extents. All the bioassays and HPLC-photodiode array detector (PDAD)-UV and HPLC-electron spray ionization (ESI)-MS analyses demonstrated that the production of 114 in the mutant AD-2-1 was caused by the activated production of silent metabolites in the original G59 fungal strain. Present results provided additional examples for effectiveness of the chemical mutagenesis strategy using diethyl sulphate mutagenesis to discover new compounds by activating silent metabolites in fungal isolates. Full article
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Open AccessArticle Structure Activity Relationship of Brevenal Hydrazide Derivatives
Mar. Drugs 2014, 12(4), 1839-1858; doi:10.3390/md12041839
Received: 8 February 2014 / Revised: 10 March 2014 / Accepted: 12 March 2014 / Published: 28 March 2014
Cited by 2 | PDF Full-text (604 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Brevenal is a ladder frame polyether produced by the dinoflagellate Karenia brevis. This organism is also responsible for the production of the neurotoxic compounds known as brevetoxins. Ingestion or inhalation of the brevetoxins leads to adverse effects such as gastrointestinal maladies and
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Brevenal is a ladder frame polyether produced by the dinoflagellate Karenia brevis. This organism is also responsible for the production of the neurotoxic compounds known as brevetoxins. Ingestion or inhalation of the brevetoxins leads to adverse effects such as gastrointestinal maladies and bronchoconstriction. Brevenal shows antagonistic behavior to the brevetoxins and shows beneficial attributes when administered alone. For example, in an asthmatic sheep model, brevenal has been shown to increase tracheal mucosal velocity, an attribute which has led to its development as a potential treatment for Cystic Fibrosis. The mechanism of action of brevenal is poorly understood and the exact binding site has not been elucidated. In an attempt to further understand the mechanism of action of brevenal and potentially develop a second generation drug candidate, a series of brevenal derivatives were prepared through modification of the aldehyde moiety. These derivatives include aliphatic, aromatic and heteroaromatic hydrazide derivatives. The brevenal derivatives were tested using in vitro synaptosome binding assays to determine the ability of the compounds to displace brevetoxin and brevenal from their native receptors. A sheep inhalation model was used to determine if instillation of the brevenal derivatives resulted in bronchoconstriction. Only small modifications were tolerated, with larger moieties leading to loss of affinity for the brevenal receptor and bronchoconstriction in the sheep model. Full article
Open AccessArticle Marine Natural Products Acting on the Acetylcholine-Binding Protein and Nicotinic Receptors: From Computer Modeling to Binding Studies and Electrophysiology
Mar. Drugs 2014, 12(4), 1859-1875; doi:10.3390/md12041859
Received: 20 December 2013 / Revised: 20 February 2014 / Accepted: 11 March 2014 / Published: 28 March 2014
Cited by 7 | PDF Full-text (1122 KB) | HTML Full-text | XML Full-text
Abstract
For a small library of natural products from marine sponges and ascidians, in silico docking to the Lymnaea stagnalis acetylcholine-binding protein (AChBP), a model for the ligand-binding domains of nicotinic acetylcholine receptors (nAChRs), was carried out and the possibility of complex formation was
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For a small library of natural products from marine sponges and ascidians, in silico docking to the Lymnaea stagnalis acetylcholine-binding protein (AChBP), a model for the ligand-binding domains of nicotinic acetylcholine receptors (nAChRs), was carried out and the possibility of complex formation was revealed. It was further experimentally confirmed via competition with radioiodinated α-bungarotoxin ([125I]-αBgt) for binding to AChBP of the majority of analyzed compounds. Alkaloids pibocin, varacin and makaluvamines С and G had relatively high affinities (Ki 0.5–1.3 μM). With the muscle-type nAChR from Torpedo californica ray and human neuronal α7 nAChR, heterologously expressed in the GH4C1 cell line, no competition with [125I]-αBgt was detected in four compounds, while the rest showed an inhibition. Makaluvamines (Ki ~ 1.5 μM) were the most active compounds, but only makaluvamine G and crambescidine 359 revealed a weak selectivity towards muscle-type nAChR. Rhizochalin, aglycone of rhizochalin, pibocin, makaluvamine G, monanchocidin, crambescidine 359 and aaptamine showed inhibitory activities in electrophysiology experiments on the mouse muscle and human α7 nAChRs, expressed in Xenopus laevis oocytes. Thus, our results confirm the utility of the modeling studies on AChBPs in a search for natural compounds with cholinergic activity and demonstrate the presence of the latter in the analyzed marine biological sources. Full article
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Open AccessArticle NMR-Based Metabolomic Analysis of Spatial Variation in Soft Corals
Mar. Drugs 2014, 12(4), 1876-1890; doi:10.3390/md12041876
Received: 12 December 2013 / Revised: 6 February 2014 / Accepted: 27 February 2014 / Published: 28 March 2014
Cited by 1 | PDF Full-text (1015 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Soft corals are common marine organisms that inhabit tropical and subtropical oceans. They are shown to be rich source of secondary metabolites with biological activities. In this work, soft corals from two geographical locations were investigated using 1H-NMR spectroscopy coupled with multivariate
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Soft corals are common marine organisms that inhabit tropical and subtropical oceans. They are shown to be rich source of secondary metabolites with biological activities. In this work, soft corals from two geographical locations were investigated using 1H-NMR spectroscopy coupled with multivariate statistical analysis at the metabolic level. A partial least-squares discriminant analysis showed clear separation among extracts of soft corals grown in Sanya Bay and Weizhou Island. The specific markers that contributed to discrimination between soft corals in two origins belonged to terpenes, sterols and N-containing compounds. The satisfied precision of classification obtained indicates this approach using combined 1H-NMR and chemometrics is effective to discriminate soft corals collected in different geographical locations. The results revealed that metabolites of soft corals evidently depended on living environmental condition, which would provide valuable information for further relevant coastal marine environment evaluation. Full article
(This article belongs to the Special Issue Metabolomics - Applications in Marine Natural Products Chemistry)
Open AccessArticle Combined Effects of Nitrogen Concentration and Seasonal Changes on the Production of Lipids in Nannochloropsis oculata
Mar. Drugs 2014, 12(4), 1891-1910; doi:10.3390/md12041891
Received: 16 January 2014 / Revised: 26 February 2014 / Accepted: 10 March 2014 / Published: 31 March 2014
Cited by 8 | PDF Full-text (585 KB) | HTML Full-text | XML Full-text
Abstract
Instead of sole nutrient starvation to boost algal lipid production, we addressed nutrient limitation at two different seasons (autumn and spring) during outdoor cultivation in flat panel photobioreactors. Lipid accumulation, biomass and lipid productivity and changes in fatty acid composition of Nannochloropsis oculata
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Instead of sole nutrient starvation to boost algal lipid production, we addressed nutrient limitation at two different seasons (autumn and spring) during outdoor cultivation in flat panel photobioreactors. Lipid accumulation, biomass and lipid productivity and changes in fatty acid composition of Nannochloropsis oculata were investigated under nitrogen (N) limitation (nitrate:phosphate N:P 5, N:P 2.5 molar ratio). N. oculata was able to maintain a high biomass productivity under N-limitation compared to N-sufficiency (N:P 20) at both seasons, which in spring resulted in nearly double lipid productivity under N-limited conditions (0.21 g L−1 day−1) compared to N-sufficiency (0.11 g L−1 day−1). Saturated and monounsaturated fatty acids increased from 76% to nearly 90% of total fatty acids in N-limited cultures. Higher biomass and lipid productivity in spring could, partly, be explained by higher irradiance, partly by greater harvesting rate (~30%). Our results indicate the potential for the production of algal high value products (i.e., polyunsaturated fatty acids) during both N-sufficiency and N-limitation. To meet the sustainability challenges of algal biomass production, we propose a dual-system process: Closed photobioreactors producing biomass for high value products and inoculum for larger raceway ponds recycling waste/exhaust streams to produce bulk chemicals for fuel, feed and industrial material. Full article
Open AccessArticle Theonellamide G, a Potent Antifungal and Cytotoxic Bicyclic Glycopeptide from the Red Sea Marine Sponge Theonella swinhoei
Mar. Drugs 2014, 12(4), 1911-1923; doi:10.3390/md12041911
Received: 10 February 2014 / Revised: 12 March 2014 / Accepted: 13 March 2014 / Published: 1 April 2014
Cited by 16 | PDF Full-text (975 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
In our search for bioactive metabolites from marine organisms, we have investigated the polar fraction of the organic extract of the Red Sea sponge Theonella swinhoei. Successive chromatographic separations and final HPLC purification of the potent antifungal fraction afforded a new bicyclic
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In our search for bioactive metabolites from marine organisms, we have investigated the polar fraction of the organic extract of the Red Sea sponge Theonella swinhoei. Successive chromatographic separations and final HPLC purification of the potent antifungal fraction afforded a new bicyclic glycopeptide, theonellamide G (1). The structure of the peptide was determined using extensive 1D and 2D NMR and high-resolution mass spectral determinations. The absolute configuration of theonellamide G was determined by chemical degradation and 2D NMR spectroscopy. Theonellamide G showed potent antifungal activity towards wild and amphotericin B-resistant strains of Candida albicans with IC50 of 4.49 and 2.0 μM, respectively. Additionally, it displayed cytotoxic activity against the human colon adenocarcinoma cell line (HCT-16) with IC50 of 6.0 μM. These findings provide further insight into the chemical diversity and biological activities of this class of compounds. Full article
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Open AccessArticle Spirocyclic Drimanes from the Marine Fungus Stachybotrys sp. Strain MF347
Mar. Drugs 2014, 12(4), 1924-1938; doi:10.3390/md12041924
Received: 9 January 2014 / Revised: 24 February 2014 / Accepted: 11 March 2014 / Published: 1 April 2014
Cited by 12 | PDF Full-text (957 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
A novel spirocyclic drimane coupled by two drimane fragment building blocks 2 and a new drimane 1 were identified in mycelia and culture broth of Stachybotrys sp. MF347. Their structures were established by spectroscopic means. This is the first example of spirocyclic drimane
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A novel spirocyclic drimane coupled by two drimane fragment building blocks 2 and a new drimane 1 were identified in mycelia and culture broth of Stachybotrys sp. MF347. Their structures were established by spectroscopic means. This is the first example of spirocyclic drimane coupled by a spirodihydrobenzofuranlactam unit and a spirodihydroisobenzofuran unit; and the connecting position being N-C instead of an N and N connecting unit. Strain MF347 produced also the known spirocyclic drimanes stachybocin A (12) and stachybocin B (11) featured by two sesquiterpene-spirobenzofuran structural units connected by a lysine residue; the known spirocyclic drimanes chartarlactam O (5); chartarlactam K (6); F1839A (7); stachybotrylactam (8); stachybotramide (9); and 2α-acetoxystachybotrylactam acetate (10); as well as ilicicolin B (13), a known sesquiterpene. The relative configuration of two known spirobenzofuranlactams (3 and 4) was determined. All compounds were subjected to biological activity tests. The spirocyclic drimane 2, 11, and 12, as well as the sesquiterpene 13, exhibited antibacterial activity against the clinically relevant methicillin-resistant Staphylococcus aureus (MRSA). Full article
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Open AccessArticle The Marine Fungal Metabolite, Dicitrinone B, Induces A375 Cell Apoptosis through the ROS-Related Caspase Pathway
Mar. Drugs 2014, 12(4), 1939-1958; doi:10.3390/md12041939
Received: 28 January 2014 / Revised: 11 March 2014 / Accepted: 18 March 2014 / Published: 2 April 2014
Cited by 12 | PDF Full-text (2399 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Dicitrinone B, a rare carbon-bridged citrinin dimer, was isolated from the marine-derived fungus, Penicillium citrinum. It was reported to have antitumor effects on tumor cells previously; however, the details of the mechanism remain unclear. In this study, we found that dicitrinone B
[...] Read more.
Dicitrinone B, a rare carbon-bridged citrinin dimer, was isolated from the marine-derived fungus, Penicillium citrinum. It was reported to have antitumor effects on tumor cells previously; however, the details of the mechanism remain unclear. In this study, we found that dicitrinone B inhibited the proliferation of multiple tumor types. Among them, the human malignant melanoma cell, A375, was confirmed to be the most sensitive. Morphologic evaluation, cell cycle arrest and apoptosis rate analysis results showed that dicitrinone B significantly induced A375 cell apoptosis. Subsequent observation of reactive oxygen species (ROS) accumulation and mitochondrial membrane potential (MMP) reduction revealed that the apoptosis induced by dicitrinone B may be triggered by over-producing ROS. Further studies indicated that the apoptosis was associated with both intrinsic and extrinsic apoptosis pathways under the regulation of Bcl-2 family proteins. Caspase-9, caspase-8 and caspase-3 were activated during the process, leading to PARP cleavage. The pan-caspase inhibitor, Z-VAD-FMK, could reverse dicitrinone B-induced apoptosis, suggesting that it is a caspase-dependent pathway. Our data for the first time showed that dicitrinone B inhibits the proliferation of tumor cells by inducing cell apoptosis. Moreover, compared with the first-line chemotherapy drug, 5-fluorouracil (5-Fu), dicitrinone B showed much more potent anticancer efficacy, suggesting that it might serve as a potential antitumor agent. Full article
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Open AccessArticle Antifouling Activity of Synthetic Alkylpyridinium Polymers Using the Barnacle Model
Mar. Drugs 2014, 12(4), 1959-1976; doi:10.3390/md12041959
Received: 23 December 2013 / Revised: 26 February 2014 / Accepted: 26 February 2014 / Published: 2 April 2014
Cited by 6 | PDF Full-text (941 KB) | HTML Full-text | XML Full-text
Abstract
Polymeric alkylpyridinium salts (poly-APS) isolated from the Mediterranean marine sponge, Haliclona (Rhizoniera) sarai, effectively inhibit barnacle larva settlement and natural marine biofilm formation through a non-toxic and reversible mechanism. Potential use of poly-APS-like compounds as antifouling agents led to the chemical synthesis
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Polymeric alkylpyridinium salts (poly-APS) isolated from the Mediterranean marine sponge, Haliclona (Rhizoniera) sarai, effectively inhibit barnacle larva settlement and natural marine biofilm formation through a non-toxic and reversible mechanism. Potential use of poly-APS-like compounds as antifouling agents led to the chemical synthesis of monomeric and oligomeric 3-alkylpyridinium analogues. However, these are less efficient in settlement assays and have greater toxicity than the natural polymers. Recently, a new chemical synthesis method enabled the production of poly-APS analogues with antibacterial, antifungal and anti-acetylcholinesterase activities. The present study examines the antifouling properties and toxicity of six of these synthetic poly-APS using the barnacle (Amphibalanus amphitrite) as a model (cyprids and II stage nauplii larvae) in settlement, acute and sub-acute toxicity assays. Two compounds, APS8 and APS12-3, show antifouling effects very similar to natural poly-APS, with an anti-settlement effective concentration that inhibits 50% of the cyprid population settlement (EC50) after 24 h of 0.32 mg/L and 0.89 mg/L, respectively. The toxicity of APS8 is negligible, while APS12-3 is three-fold more toxic (24-h LC50: nauplii, 11.60 mg/L; cyprids, 61.13 mg/L) than natural poly-APS. This toxicity of APS12-3 towards nauplii is, however, 60-fold and 1200-fold lower than that of the common co-biocides, Zn- and Cu-pyrithione, respectively. Additionally, exposure to APS12-3 for 24 and 48 h inhibits the naupliar swimming ability with respective IC50 of 4.83 and 1.86 mg/L. Full article
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Open AccessArticle New Terpenes from the Egyptian Soft Coral Sarcophyton ehrenbergi
Mar. Drugs 2014, 12(4), 1977-1986; doi:10.3390/md12041977
Received: 31 December 2013 / Revised: 11 March 2014 / Accepted: 14 March 2014 / Published: 2 April 2014
Cited by 9 | PDF Full-text (969 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Chemical investigations of the Egyptian soft coral Sarcophyton ehrenbergi have led to the isolation of compounds 13 as well as the previously reported marine cembranoid diterpene sarcophine (4). Structures were elucidated by comprehensive NMR and HRMS experimentation. Isolated compounds
[...] Read more.
Chemical investigations of the Egyptian soft coral Sarcophyton ehrenbergi have led to the isolation of compounds 13 as well as the previously reported marine cembranoid diterpene sarcophine (4). Structures were elucidated by comprehensive NMR and HRMS experimentation. Isolated compounds were in vitro assayed for cytotoxic activity against human hepatocarcinoma (HepG2) and breast adenocarcinoma (MCF-7) cell lines. Full article
Open AccessArticle Neritinaceramides A–E, New Ceramides from the Marine Bryozoan Bugula neritina Inhabiting South China Sea and Their Cytotoxicity
Mar. Drugs 2014, 12(4), 1987-2003; doi:10.3390/md12041987
Received: 23 January 2014 / Revised: 2 March 2014 / Accepted: 13 March 2014 / Published: 2 April 2014
Cited by 4 | PDF Full-text (970 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Five new ceramides, neritinaceramides A (1), B (2), C (3), D (4) and E (5), together with six known ceramides (611), two known alkyl glycerylethers (12 and 13
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Five new ceramides, neritinaceramides A (1), B (2), C (3), D (4) and E (5), together with six known ceramides (611), two known alkyl glycerylethers (12 and 13) and a known nucleoside (14), were isolated from marine bryozoan Bugula neritina, which inhabits the South China Sea. The structures of the new compounds were elucidated as (2S,3R,3′S,4E,8E,10E)-2-(hexadecanoylamino)-4,8,10-octadecatriene-l,3,3′-triol (1), (2S,3R,2′R,4E,8E,10E)-2-(hexadecanoylamino)-4,8,10-octadecatriene-l,3,2′-triol (2), (2S,3R,2′R,4E,8E,10E)-2-(octadecanoylamino)-4,8,10-octadecatriene-l,3,2′-triol (3), (2S,3R,3′S,4E,8E)-2-(hexadecanoylamino)-4,8-octadecadiene-l,3,3′-triol (4) and (2S,3R,3′S,4E)-2-(hexadecanoylamino)-4-octadecene-l,3,3′-triol (5) on the basis of extensive spectral analysis and chemical evidences. The characteristic C-3′S hydroxyl group in the fatty acid moiety in compounds 1, 4 and 5, was a novel structural feature of ceramides. The rare 4E,8E,10E-triene structure in the sphingoid base of compounds 13, was found from marine bryozoans for the first time. The new ceramides 15 were evaluated for their cytotoxicity against HepG2, NCI-H460 and SGC7901 tumor cell lines, and all of them exhibited selective cytotoxicity against HepG2 and SGC7901 cells with a range of IC50 values from 47.3 μM to 58.1 μM. These chemical and cytotoxic studies on the new neritinaceramides A–E (15) added to the chemical diversity of B. neritina and expanded our knowledge of the chemical modifications and biological activity of ceramides. Full article
(This article belongs to the collection Bioactive Compounds from Marine Invertebrates)
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Open AccessArticle Variegatusides: New Non-Sulphated Triterpene Glycosides from the Sea Cucumber Stichopus variegates Semper
Mar. Drugs 2014, 12(4), 2004-2018; doi:10.3390/md12042004
Received: 11 December 2013 / Revised: 29 January 2014 / Accepted: 7 February 2014 / Published: 2 April 2014
Cited by 6 | PDF Full-text (907 KB) | HTML Full-text | XML Full-text
Abstract
Four new triterpene glycosides, variegatusides C–F (14), together with three structurally known triterpene glycosides, variegatusides A and B (5, 6), and holothurin B (7), were isolated from the sea cucumber Stichopus variegates Semper (Holothuriidae),
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Four new triterpene glycosides, variegatusides C–F (14), together with three structurally known triterpene glycosides, variegatusides A and B (5, 6), and holothurin B (7), were isolated from the sea cucumber Stichopus variegates Semper (Holothuriidae), collected from the South China Sea. Their structures were elucidated on the basis of extensive spectral analysis (nuclear magnetic resonance (NMR) and electrospray ionization mass spectrometry (ESIMS)) and chemical evidence. Variegatusides C–F exhibit the same structural feature consisting of the presence of a 23-hydroxyl group at the holostane-type triterpene aglycone side chain. Variegatuside C (1) has a double bond (24, 25) in this same chain, while variegatuside D (2) exhibits a 8(9)-ene bond in the holostane-type triterpene aglycone, which has not been extracted from other sea cucumber species. Compound 4 is a native compound from the sea cucumber S. variegates Semper, which has been reported to be desacetylstichloroside B1. Except for holothurin B, these glycosides have no sulfate group in their sugar chain and show potent antifungal activities in vitro biotests. Full article
(This article belongs to the collection Bioactive Compounds from Marine Invertebrates)
Open AccessArticle Cyanobacteria from Terrestrial and Marine Sources Contain Apoptogens Able to Overcome Chemoresistance in Acute Myeloid Leukemia Cells
Mar. Drugs 2014, 12(4), 2036-2053; doi:10.3390/md12042036
Received: 26 January 2014 / Revised: 13 March 2014 / Accepted: 18 March 2014 / Published: 3 April 2014
Cited by 4 | PDF Full-text (963 KB) | HTML Full-text | XML Full-text
Abstract
In this study, we investigated forty cyanobacterial isolates from biofilms, gastropods, brackish water and symbiotic lichen habitats. Their aqueous and organic extracts were used to screen for apoptosis-inducing activity against acute myeloid leukemia cells. A total of 28 extracts showed cytotoxicity against rat
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In this study, we investigated forty cyanobacterial isolates from biofilms, gastropods, brackish water and symbiotic lichen habitats. Their aqueous and organic extracts were used to screen for apoptosis-inducing activity against acute myeloid leukemia cells. A total of 28 extracts showed cytotoxicity against rat acute myeloid leukemia (IPC-81) cells. The design of the screen made it possible to eliminate known toxins, such as microcystins and nodularin, or known metabolites with anti-leukemic activity, such as adenosine and its analogs. A cytotoxicity test on human embryonic kidney (HEK293T) fibroblasts indicated that 21 of the 28 extracts containing anti-acute myeloid leukemia (AML) activity showed selectivity in favor of leukemia cells. Extracts L26-O and L30-O were able to partly overcome the chemotherapy resistance induced by the oncogenic protein Bcl-2, whereas extract L1-O overcame protection from the deletion of the tumor suppressor protein p53. In conclusion, cyanobacteria are a prolific resource for anti-leukemia compounds that have potential for pharmaceutical applications. Based on the variety of cellular responses, we also conclude that the different anti-leukemic compounds in the cyanobacterial extracts target different elements of the death machinery of mammalian cells. Full article
Open AccessArticle Placotylene A, an Inhibitor of the Receptor Activator of Nuclear Factor-κB Ligand-Induced Osteoclast Differentiation, from a Korean Sponge Placospongia sp.
Mar. Drugs 2014, 12(4), 2054-2065; doi:10.3390/md12042054
Received: 10 February 2014 / Revised: 28 February 2014 / Accepted: 19 March 2014 / Published: 3 April 2014
Cited by 5 | PDF Full-text (979 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
A new inhibitor, placotylene A (1), of the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation, and a regioisomer of placotylene A, placotylene B (2), were isolated from a Korean marine sponge Placospongia sp. The chemical structures of
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A new inhibitor, placotylene A (1), of the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation, and a regioisomer of placotylene A, placotylene B (2), were isolated from a Korean marine sponge Placospongia sp. The chemical structures of placotylenes A and B were elucidated on the basis of 1D and 2D NMR, along with MS spectral analysis and revealed as an iodinated polyacetylene class of natural products. Placotylene A (1) displayed inhibitory activity against RANKL-induced osteoclast differentiation at 10 μM while placotylene B (2) did not show any significant activity up to 100 μM, respectively. Full article
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Open AccessArticle Phallusiasterols A and B: Two New Sulfated Sterols from the Mediterranean Tunicate Phallusia fumigata and Their Effects as Modulators of the PXR Receptor
Mar. Drugs 2014, 12(4), 2066-2078; doi:10.3390/md12042066
Received: 11 December 2013 / Revised: 27 February 2014 / Accepted: 27 February 2014 / Published: 3 April 2014
Cited by 3 | PDF Full-text (925 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Purification of the apolar extracts of the marine ascidian Phallusia fumigata, afforded two new sulfated sterols, phallusiasterols A (1) and B (2). The structures of the new compounds have been elucidated using mass spectrometry and NMR experiments. The
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Purification of the apolar extracts of the marine ascidian Phallusia fumigata, afforded two new sulfated sterols, phallusiasterols A (1) and B (2). The structures of the new compounds have been elucidated using mass spectrometry and NMR experiments. The effects of phallusiasterols A and B as modulators of pregnane-X-receptor (PXR) have been investigated. These studies revealed that phallusiasterol A induces PXR transactivation in HepG2 cells and stimulates the expression of the PXR target genes CYP3A4 and MDR1 in the same cell line. Molecular docking calculations suggested the theoretical binding mode of phallusiasterol A with hPXR and revealed that phallusiasterol A fitted well in the LBD of PXR. Full article
Open AccessCommunication Phenolic Polyketides from the Co-Cultivation of Marine-Derived Penicillium sp. WC-29-5 and Streptomyces fradiae 007
Mar. Drugs 2014, 12(4), 2079-2088; doi:10.3390/md12042079
Received: 15 January 2014 / Revised: 24 February 2014 / Accepted: 21 March 2014 / Published: 4 April 2014
Cited by 5 | PDF Full-text (762 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Penicillium sp. WC-29-5 was co-cultured with Streptomyces fradiae 007 to produce five natural products (13, 4a and 4b) that were isolated and characterized by spectroscopic analysis. Interestingly, these compounds were found to be different from those produced in
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Penicillium sp. WC-29-5 was co-cultured with Streptomyces fradiae 007 to produce five natural products (13, 4a and 4b) that were isolated and characterized by spectroscopic analysis. Interestingly, these compounds were found to be different from those produced in discrete fungal and bacterial controls. Among these compounds, the absolute configurations of compounds 4a and 4b were determined for the first time by X-ray single crystal diffraction experiments and electronic circular dichroism (ECD) calculations. An evaluation of the cytotoxic activities of these compounds revealed that 4b was moderately cytotoxic towards HL-60 and H1975 tumor cells with IC50 values of 3.73 and 5.73 µM, respectively, whereas compound 4a was only moderately cytotoxic towards H1975 cells with an IC50 value of 3.97 µM. Full article
Open AccessArticle Molecular Response to Toxic Diatom-Derived Aldehydes in the Sea Urchin Paracentrotus lividus
Mar. Drugs 2014, 12(4), 2089-2113; doi:10.3390/md12042089
Received: 7 February 2014 / Revised: 21 March 2014 / Accepted: 25 March 2014 / Published: 4 April 2014
Cited by 10 | PDF Full-text (698 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Diatoms are dominant photosynthetic organisms in the world’s oceans and represent a major food source for zooplankton and benthic filter-feeders. However, their beneficial role in sustaining marine food webs has been challenged after the discovery that they produce secondary metabolites, such as polyunsaturated
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Diatoms are dominant photosynthetic organisms in the world’s oceans and represent a major food source for zooplankton and benthic filter-feeders. However, their beneficial role in sustaining marine food webs has been challenged after the discovery that they produce secondary metabolites, such as polyunsaturated aldehydes (PUAs), which negatively affect the reproductive success of many invertebrates. Here, we report the effects of two common diatom PUAs, heptadienal and octadienal, which have never been tested before at the molecular level, using the sea urchin, Paracentrotus lividus, as a model organism. We show that both PUAs are able to induce teratogenesis (i.e., malformations), as already reported for decadienal, the better-studied PUA of this group. Moreover, post-recovery experiments show that embryos can recover after treatment with all three PUAs, indicating that negative effects depend both on PUA concentrations and the exposure time of the embryos to these metabolites. We also identify the time range during which PUAs exert the greatest effect on sea urchin embryogenesis. Finally, we report the expression levels of thirty one genes (having a key role in a broad range of functional responses, such as stress, development, differentiation, skeletogenesis and detoxification processes) in order to identify the common targets affected by PUAs and their correlation with morphological abnormalities. This study opens new perspectives for understanding how marine organisms afford protection from environmental toxicants through an integrated network of genes. Full article
Open AccessArticle Insights and Ideas Garnered from Marine Metabolites for Development of Dual-Function Acetylcholinesterase and Amyloid-β Aggregation Inhibitors
Mar. Drugs 2014, 12(4), 2114-2131; doi:10.3390/md12042114
Received: 10 December 2013 / Revised: 27 February 2014 / Accepted: 12 March 2014 / Published: 4 April 2014
Cited by 4 | PDF Full-text (2061 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Due to the diversity of biological activities that can be found in aquatic ecosystems, marine metabolites have been an active area of drug discovery for the last 30 years. Marine metabolites have been found to inhibit a number of enzymes important in the
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Due to the diversity of biological activities that can be found in aquatic ecosystems, marine metabolites have been an active area of drug discovery for the last 30 years. Marine metabolites have been found to inhibit a number of enzymes important in the treatment of human disease. Here, we focus on marine metabolites that inhibit the enzyme acetylcholinesterase, which is the cellular target for treatment of early-stage Alzheimer’s disease. Currently, development of anticholinesterase drugs with improved potency, and drugs that act as dual acetylcholinesterase and amyloid-β aggregation inhibitors, are being sought to treat Alzheimer’s disease. Seven classes of marine metabolites are reported to possess anti-cholinesterase activity. We compared these metabolites to clinically-used acetylcholinesterase inhibitors having known mechanisms of inhibition. We performed a docking simulation and compared them to published experimental data for each metabolite to determine the most likely mechanism of inhibition for each class of marine inhibitor. Our results indicate that several marine metabolites bind to regions of the acetylcholinesterase active site that are not bound by the clinically-used drugs rivastigmine, galanthamine, donepezil, or tacrine. We use the novel poses adopted for computational drug design of tighter binding anticholinesterase drugs likely to act as inhibitors of both acetylcholinesterase activity and amyloid-β aggregation inhibition. Full article
(This article belongs to the collection Bioactive Compounds from Marine Invertebrates)
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Open AccessArticle Action of Clathrodin and Analogues on Voltage-Gated Sodium Channels
Mar. Drugs 2014, 12(4), 2132-2143; doi:10.3390/md12042132
Received: 3 January 2014 / Revised: 21 February 2014 / Accepted: 25 March 2014 / Published: 4 April 2014
Cited by 4 | PDF Full-text (744 KB) | HTML Full-text | XML Full-text
Abstract
Clathrodin is a marine alkaloid and believed to be a modulator of voltage-gated sodium (NaV) channels. Since there is an urgent need for small molecule NaV channel ligands as novel therapeutics, clathrodin could represent an interesting lead compound. Therefore, clathrodin
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Clathrodin is a marine alkaloid and believed to be a modulator of voltage-gated sodium (NaV) channels. Since there is an urgent need for small molecule NaV channel ligands as novel therapeutics, clathrodin could represent an interesting lead compound. Therefore, clathrodin was reinvestigated for its potency and NaV channel subtype selectivity. Clathrodin and its synthetic analogues were subjected to screening on a broad range of NaV channel isoforms, both in voltage clamp and patch clamp conditions. Even though clathrodin was not found to exert any activity, some analogues were capable of modulating the NaV channels, hereby validating the pyrrole-2-aminoimidazole alkaloid structure as a core structure for future small molecule-based NaV channel modulators. Full article
(This article belongs to the Special Issue Alkaloid Analogs)
Open AccessCommunication Cladieunicellins M–Q, New Eunicellins from Cladiella sp.
Mar. Drugs 2014, 12(4), 2144-2155; doi:10.3390/md12042144
Received: 3 March 2014 / Revised: 20 March 2014 / Accepted: 27 March 2014 / Published: 8 April 2014
Cited by 4 | PDF Full-text (690 KB) | HTML Full-text | XML Full-text
Abstract
Five new 7α-hydroxyeunicellin-based diterpenoids, designated as cladieunicellins M–Q (15), were isolated from a Formosan octocoral Cladiella sp. The structures of 15 were elucidated on the basis of spectroscopic methods and by comparison of the data with those
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Five new 7α-hydroxyeunicellin-based diterpenoids, designated as cladieunicellins M–Q (15), were isolated from a Formosan octocoral Cladiella sp. The structures of 15 were elucidated on the basis of spectroscopic methods and by comparison of the data with those of the related metabolites. Cytotoxicity of metabolites 15 against the human leukemia Molt 4 and HL 60 is also described. Among them, compounds 1, 3 and 5 exhibited moderate cytotoxicity toward Molt 4 cells with IC50 values 16.43, 14.17 and 15.55 μM, respectively. Preliminary SAR (structure activity relationship) information was obtained from these compounds and their analogues. Full article
Open AccessArticle Two New Cytotoxic Indole Alkaloids from a Deep-Sea Sediment Derived Metagenomic Clone
Mar. Drugs 2014, 12(4), 2156-2163; doi:10.3390/md12042156
Received: 7 February 2014 / Revised: 7 March 2014 / Accepted: 10 March 2014 / Published: 8 April 2014
Cited by 5 | PDF Full-text (555 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Two new indole alkaloids, metagenetriindole A (1) and metagenebiindole A (2), were identified from deep-sea sediment metagenomic clone derived Escherichia coli fermentation broth. The structures of new compounds were elucidated by spectroscopic methods. The two new indole alkaloids demonstrated moderately cytotoxic activity against
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Two new indole alkaloids, metagenetriindole A (1) and metagenebiindole A (2), were identified from deep-sea sediment metagenomic clone derived Escherichia coli fermentation broth. The structures of new compounds were elucidated by spectroscopic methods. The two new indole alkaloids demonstrated moderately cytotoxic activity against CNE2, Bel7402 and HT1080 cancer cell lines in vitro. Full article
Open AccessArticle Pelagia noctiluca (Scyphozoa) Crude Venom Injection Elicits Oxidative Stress and Inflammatory Response in Rats
Mar. Drugs 2014, 12(4), 2182-2204; doi:10.3390/md12042182
Received: 23 January 2014 / Revised: 20 March 2014 / Accepted: 21 March 2014 / Published: 10 April 2014
Cited by 9 | PDF Full-text (1301 KB) | HTML Full-text | XML Full-text
Abstract
Cnidarian toxins represent a rich source of biologically active compounds. Since they may act via oxidative stress events, the aim of the present study was to verify whether crude venom, extracted from the jellyfish Pelagia noctiluca, elicits inflammation and oxidative stress processes,
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Cnidarian toxins represent a rich source of biologically active compounds. Since they may act via oxidative stress events, the aim of the present study was to verify whether crude venom, extracted from the jellyfish Pelagia noctiluca, elicits inflammation and oxidative stress processes, known to be mediated by Reactive Oxygen Species (ROS) production, in rats. In a first set of experiments, the animals were injected with crude venom (at three different doses 6, 30 and 60 µg/kg, suspended in saline solution, i.v.) to test the mortality and possible blood pressure changes. In a second set of experiments, to confirm that Pelagia noctiluca crude venom enhances ROS formation and may contribute to the pathophysiology of inflammation, crude venom-injected animals (30 µg/kg) were also treated with tempol, a powerful antioxidant (100 mg/kg i.p., 30 and 60 min after crude venom). Administration of tempol after crude venom challenge, caused a significant reduction of each parameter related to inflammation. The potential effect of Pelagia noctiluca crude venom in the systemic inflammation process has been here demonstrated, adding novel information about its biological activity. Full article
(This article belongs to the collection Bioactive Compounds from Marine Invertebrates)
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Open AccessArticle Simple and Rapid Quality Control of Sulfated Glycans by a Fluorescence Sensor Assay—Exemplarily Developed for the Sulfated Polysaccharides from Red Algae Delesseria sanguinea
Mar. Drugs 2014, 12(4), 2205-2227; doi:10.3390/md12042205
Received: 26 January 2014 / Revised: 28 February 2014 / Accepted: 24 March 2014 / Published: 10 April 2014
Cited by 3 | PDF Full-text (851 KB) | HTML Full-text | XML Full-text
Abstract
Sulfated polysaccharides (SP) from algae are of great interest due to their manifold biological activities. Obstacles to commercial (especially medical) application include considerable variability and complex chemical composition making the analysis and the quality control challenging. The aim of this study was to
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Sulfated polysaccharides (SP) from algae are of great interest due to their manifold biological activities. Obstacles to commercial (especially medical) application include considerable variability and complex chemical composition making the analysis and the quality control challenging. The aim of this study was to evaluate a simple microplate assay for screening the quality of SP. It is based on the fluorescence intensity (FI) increase of the sensor molecule Polymer-H by SP and was originally developed for direct quantification of SP. Exemplarily, 65 SP batches isolated from the red alga Delesseria sanguinea (D.s.-SP) and several other algae polysaccharides were investigated. Their FI increase in the Polymer-H assay was compared with other analytical parameters. By testing just one concentration of a D.s.-SP sample, quality deviations from the reference D.s.-SP and thus both batch-to-batch variability and stability can be detected. Further, structurally distinct SP showed to differ in their concentration-dependent FI profiles. By using corresponding reference compounds, the Polymer-H assay is therefore applicable as identification assay with high negative predictability. In conclusion, the Polymer-H assay showed to represent not only a simple method for quantification, but also for characterization identification and differentiation of SP of marine origin. Full article
(This article belongs to the Special Issue Marine Glycoconjugates)
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Open AccessArticle Maritime Halophyte Species from Southern Portugal as Sources of Bioactive Molecules
Mar. Drugs 2014, 12(4), 2228-2244; doi:10.3390/md12042228
Received: 26 January 2014 / Revised: 28 February 2014 / Accepted: 28 March 2014 / Published: 10 April 2014
Cited by 6 | PDF Full-text (834 KB) | HTML Full-text | XML Full-text
Abstract
Extracts of five halophytes from southern Portugal (Arthrocnemum macrostachyum, Mesembryanthemum edule, Juncus acutus, Plantago coronopus and Halimione portulacoides), were studied for antioxidant, anti-inflammatory and in vitro antitumor properties. The most active extracts towards the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical were
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Extracts of five halophytes from southern Portugal (Arthrocnemum macrostachyum, Mesembryanthemum edule, Juncus acutus, Plantago coronopus and Halimione portulacoides), were studied for antioxidant, anti-inflammatory and in vitro antitumor properties. The most active extracts towards the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical were the methanol extracts of M. edule (IC50 = 0.1 mg/mL) and J. acutus (IC50 = 0.4 mg/mL), and the ether extracts of J. acutus (IC50 = 0.2 mg/mL) and A. macrostachyum (IC50 = 0.3 mg/mL). The highest radical scavenging activity (RSA) against the 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical was obtained in the ether extract of J. acutus (IC50 = 0.4 mg/mL) and H. portulacoides (IC50 = 0.9 mg/mL). The maximum total phenolic content (TPC) was found in the methanol extract of M. edule (147 mg gallic acid equivalents (GAE)/g) and in the ether extract of J. acutus (94 mg GAE/g). Significant decreases in nitric oxide (NO) production were observed after incubation of macrophages with lipopolysaccharide (LPS) and the chloroform extract of H. portulacoides (IC50 = 109 µg/mL) and the hexane extract of P. coronopus (IC50 = 98.0 µg/mL). High in vitro cytotoxic activity and selectivity was obtained with the ether extract of J. acutus. Juncunol was identified as the active compound and for the first time was shown to display selective in vitro cytotoxicity towards various human cancer cells. Full article
Open AccessArticle Modification of Chitin with Kraft Lignin and Development of New Biosorbents for Removal of Cadmium(II) and Nickel(II) Ions
Mar. Drugs 2014, 12(4), 2245-2268; doi:10.3390/md12042245
Received: 4 February 2014 / Revised: 6 March 2014 / Accepted: 12 March 2014 / Published: 10 April 2014
Cited by 15 | PDF Full-text (1715 KB) | HTML Full-text | XML Full-text
Abstract
Novel, functional materials based on chitin of marine origin and lignin were prepared. The synthesized materials were subjected to physicochemical, dispersive-morphological and electrokinetic analysis. The results confirm the effectiveness of the proposed method of synthesis of functional chitin/lignin materials. Mechanism of chitin modification
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Novel, functional materials based on chitin of marine origin and lignin were prepared. The synthesized materials were subjected to physicochemical, dispersive-morphological and electrokinetic analysis. The results confirm the effectiveness of the proposed method of synthesis of functional chitin/lignin materials. Mechanism of chitin modification by lignin is based on formation of hydrogen bonds between chitin and lignin. Additionally, the chitin/lignin materials were studied from the perspective of waste water treatment. The synthetic method presented in this work shows an attractive and facile route for producing low-cost chitin/lignin biosorbents with high efficiency of nickel and cadmium adsorption (88.0% and 98.4%, respectively). The discovery of this facile method of synthesis of functional chitin/lignin materials will also have a significant impact on the problematic issue of the utilization of chitinous waste from the seafood industry, as well as lignin by-products from the pulp and paper industry. Full article
(This article belongs to the Special Issue Marine Biomaterials)
Open AccessArticle Effects of Chitin and Sepia Ink Hybrid Hemostatic Sponge on the Blood Parameters of Mice
Mar. Drugs 2014, 12(4), 2269-2281; doi:10.3390/md12042269
Received: 25 January 2014 / Revised: 18 March 2014 / Accepted: 25 March 2014 / Published: 10 April 2014
Cited by 4 | PDF Full-text (623 KB) | HTML Full-text | XML Full-text
Abstract
Chitin and sepia ink hybrid hemostatic sponge (CTSH sponge), a new biomedical material, was extensively studied for its beneficial biological properties of hemostasis and stimulation of healing. However, studies examining the safety of CTSH sponge in the blood system are lacking. This experiment
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Chitin and sepia ink hybrid hemostatic sponge (CTSH sponge), a new biomedical material, was extensively studied for its beneficial biological properties of hemostasis and stimulation of healing. However, studies examining the safety of CTSH sponge in the blood system are lacking. This experiment aimed to examine whether CTSH sponge has negative effect on blood systems of mice, which were treated with a dosage of CTSH sponge (135 mg/kg) through a laparotomy. CTSH sponge was implanted into the abdominal subcutaneous and a laparotomy was used for blood sampling from abdominal aortic. Several kinds of blood parameters were detected at different time points, which were reflected by coagulation parameters including thrombin time (TT), prothrombin time (PT), activated partial thromboplatin time (APTT), fibrinogen (FIB) and platelet factor 4 (PF4); anticoagulation parameter including antithrombin III (AT-III); fibrinolytic parameters including plasminogen (PLG), fibrin degradation product (FDP) and D-dimer; hemorheology parameters including blood viscosity (BV) and plasma viscosity (PV). Results showed that CTSH sponge has no significant effect on the blood parameters of mice. The data suggested that CTSH sponge can be applied in the field of biomedical materials and has potential possibility to be developed into clinical drugs of hemostatic agents. Full article
(This article belongs to the Special Issue Marine Biomaterials)
Open AccessArticle The Marine-Derived Sipholenol A-4-O-3′,4′-Dichlorobenzoate Inhibits Breast Cancer Growth and Motility in Vitro and in Vivo through the Suppression of Brk and FAK Signaling
Mar. Drugs 2014, 12(4), 2282-2304; doi:10.3390/md12042282
Received: 11 February 2014 / Revised: 1 April 2014 / Accepted: 1 April 2014 / Published: 14 April 2014
Cited by 6 | PDF Full-text (1709 KB) | HTML Full-text | XML Full-text
Abstract
Sipholenol A is a natural sipholane triterpenoid isolated from the Red Sea sponge, Callyspongia siphonella. Previous studies showed the antimigratory and antiproliferative activities of the semisynthetic sipholenol A esters against breast cancer cell lines. This study investigated the effects of sipholenol A-4-
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Sipholenol A is a natural sipholane triterpenoid isolated from the Red Sea sponge, Callyspongia siphonella. Previous studies showed the antimigratory and antiproliferative activities of the semisynthetic sipholenol A esters against breast cancer cell lines. This study investigated the effects of sipholenol A-4-O-3′,4′-dichlorobenzoate (SPA) on the growth, migration and invasion of diverse human breast cancer cells. Results showed that SPA inhibited the growth of the human breast cancer cells, MDA-MB-231, MCF-7, BT-474 and T-47D, in a dose-dependent manner. Immunofluorescent analysis showed that SPA significantly reduced Ki-67-positive cells in MDA-MB-231 cells. Flow cytometry and Western blot analyses revealed that SPA treatment suppressed MDA-MB-231 cell growth by inducing cell cycle arrest at the G1 phase. In addition, SPA suppressed breast cancer cell migration, invasion and decreased Brk and FAK activation in a dose-dependent manner. Molecular docking study suggested a perfect fitting at the FAK’s FERM domain, inhibiting the main autophosphorylation site, Y397, which was further confirmed by Western blot analysis. Most known small molecule FAK inhibitors target the kinase domain, creating several off-target side effects. The in vivo studies showed that SPA treatment suppressed breast tumor growth and Ki-67, CD31, p-Brk and p-FAK expression in orthotopic breast cancer in nude mice. In conclusion, SPA inhibited the growth, invasion and migration of breast cancer cells possibly via deactivating Brk and FAK signaling, suggesting good potential for therapeutic use to control invasive breast cancer. Full article
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Open AccessArticle Design, Synthesis and Biological Evaluation of Tasiamide Analogues as Tumor Inhibitors
Mar. Drugs 2014, 12(4), 2308-2325; doi:10.3390/md12042308
Received: 26 December 2013 / Revised: 5 March 2014 / Accepted: 18 March 2014 / Published: 22 April 2014
Cited by 2 | PDF Full-text (1041 KB) | HTML Full-text | XML Full-text
Abstract
Eighteen analogues of the marine cytotoxic linear peptide tasiamide were designed, synthesized and screened for their inhibitory activities against the growth of human nasopharyngeal carcinoma (KB) and human non-small cell lung tumor (A549) cell lines. The results indicated that minor modifications of the
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Eighteen analogues of the marine cytotoxic linear peptide tasiamide were designed, synthesized and screened for their inhibitory activities against the growth of human nasopharyngeal carcinoma (KB) and human non-small cell lung tumor (A549) cell lines. The results indicated that minor modifications of the C-terminuswith aromatic groups were tolerated, with the IC50 values between 1.29 and 12.88 μM against these two cancer cell lines. Truncation, minor modifications at the N-terminus or elimination of the N-methyl groups in N-Me-d-Gln and/or N-Me-d-Phe residues resulted in inactive analogues. Full article
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Open AccessArticle A New Benzofuran Glycoside and Indole Alkaloids from a Sponge-Associated Rare Actinomycete, Amycolatopsis sp.
Mar. Drugs 2014, 12(4), 2326-2340; doi:10.3390/md12042326
Received: 30 January 2014 / Revised: 17 March 2014 / Accepted: 28 March 2014 / Published: 22 April 2014
Cited by 8 | PDF Full-text (1112 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Three new secondary metabolites, amycofuran (1), amycocyclopiazonic acid (2), and amycolactam (3), were isolated from the sponge-associated rare actinomycete Amycolatopsis sp. Based on combined spectroscopic analyses, the structures of 13 were determined to be a
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Three new secondary metabolites, amycofuran (1), amycocyclopiazonic acid (2), and amycolactam (3), were isolated from the sponge-associated rare actinomycete Amycolatopsis sp. Based on combined spectroscopic analyses, the structures of 13 were determined to be a new benzofuran glycoside and new indole alkaloids related to cyclopiazonic acids, a class that has previously only been reported in fungi. The absolute configurations of 1 and 3 were deduced by ECD calculations, whereas that of 2 was determined using the modified Mosher method. Amycolactam (3) displayed significant cytotoxicity against the gastric cancer cell line SNU638 and the colon cancer cell line HCT116. Full article
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Review

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Open AccessReview Potential Anti-HPV and Related Cancer Agents from Marine Resources: An Overview
Mar. Drugs 2014, 12(4), 2019-2035; doi:10.3390/md12042019
Received: 22 February 2014 / Revised: 10 March 2014 / Accepted: 14 March 2014 / Published: 3 April 2014
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Abstract
Recently, the studies on the prevention and treatment of human papillomavirus (HPV) which is closely related to the cervical cancer and other genital diseases are attracting more and more attention all over the world. Marine-derived polysaccharides and other bioactive compounds have been shown
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Recently, the studies on the prevention and treatment of human papillomavirus (HPV) which is closely related to the cervical cancer and other genital diseases are attracting more and more attention all over the world. Marine-derived polysaccharides and other bioactive compounds have been shown to possess a variety of anti-HPV and related cancer activities. This paper will review the recent progress in research on the potential anti-HPV and related cancer agents from marine resources. In particular, it will provide an update on the anti-HPV actions of heparinoid polysaccharides and bioactive compounds present in marine organisms, as well as the therapeutic vaccines relating to marine organisms. In addition, the possible mechanisms of anti-HPV actions of marine bioactive compounds and their potential for therapeutic application will also be summarized in detail. Full article
Open AccessReview Briarane Diterpenoids Isolated from Gorgonian Corals between 2011 and 2013
Mar. Drugs 2014, 12(4), 2164-2181; doi:10.3390/md12042164
Received: 22 January 2014 / Revised: 20 March 2014 / Accepted: 21 March 2014 / Published: 10 April 2014
Cited by 10 | PDF Full-text (697 KB) | HTML Full-text | XML Full-text
Abstract
The structures, names, bioactivities and references of 138 briarane-type diterpenoids, including 87 new compounds, are summarized in this review. All the briarane-type compounds mentioned in this review article were obtained from gorgonian corals including the genus Briareum, Dichotella, Junceella and Verrucella
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The structures, names, bioactivities and references of 138 briarane-type diterpenoids, including 87 new compounds, are summarized in this review. All the briarane-type compounds mentioned in this review article were obtained from gorgonian corals including the genus Briareum, Dichotella, Junceella and Verrucella. Some of these compounds showed potential bioactivities. Full article

Other

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Open AccessCorrection Correction: Kallifatidis, G. et al. The Marine Natural Product Manzamine A Targets Vacuolar ATPases and Inhibits Autophagy in Pancreatic Cancer Cells. Mar. Drugs 2013, 11, 3500–3516
Mar. Drugs 2014, 12(4), 2305-2307; doi:10.3390/md12042305
Received: 12 March 2014 / Accepted: 27 March 2014 / Published: 21 April 2014
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Abstract
We found two errors in our previous published paper [1]. Figure 4A has a mistake in the units in the labels, where it shows mM instead of micromolar (µM). A correctly labeled Figure 4A ensues. In Figures 2 and 4, the size bar
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We found two errors in our previous published paper [1]. Figure 4A has a mistake in the units in the labels, where it shows mM instead of micromolar (µM). A correctly labeled Figure 4A ensues. In Figures 2 and 4, the size bar scale is micrometers (µm). We apologize for the inconvenience caused to our readers. [...] Full article

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