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1.  New Meroterpenoids from the Endophytic Fungus Aspergillus flavipes AIL8 Derived from the Mangrove Plant Acanthus ilicifolius 
Marine Drugs  2015;13(1):237-248.
Four new meroterpenoids (2–5), along with three known analogues (1, 6, and 7) were isolated from mangrove plant Acanthus ilicifolius derived endophytic fungus Aspergillus flavipes. The structures of these compounds were elucidated by NMR and MS analysis, the configurations were assigned by CD data, and the stereochemistry of 1 was confirmed by X-ray crystallography analysis. A possible biogenetic pathway of compounds 1–7 was also proposed. All compounds were evaluated for antibacterial and cytotoxic activities.
PMCID: PMC4306934  PMID: 25574738
meroterpenoid; Aspergillus flavipes; endophytic fungus
2.  Marine-Derived Quorum-Sensing Inhibitory Activities Enhance the Antibacterial Efficacy of Tobramycin against Pseudomonas aeruginosa 
Marine Drugs  2014;13(1):1-28.
Bacterial epiphytes isolated from marine eukaryotes were screened for the production of quorum sensing inhibitory compounds (QSIs). Marine isolate KS8, identified as a Pseudoalteromonas sp., was found to display strong quorum sensing inhibitory (QSI) activity against acyl homoserine lactone (AHL)-based reporter strains Chromobacterium violaceum ATCC 12472 and CV026. KS8 supernatant significantly reduced biofilm biomass during biofilm formation (−63%) and in pre-established, mature P. aeruginosa PAO1 biofilms (−33%). KS8 supernatant also caused a 0.97-log reduction (−89%) and a 2-log reduction (−99%) in PAO1 biofilm viable counts in the biofilm formation assay and the biofilm eradication assay respectively. The crude organic extract of KS8 had a minimum inhibitory concentration (MIC) of 2 mg/mL against PAO1 but no minimum bactericidal concentration (MBC) was observed over the concentration range tested (MBC > 16 mg/mL). Sub-MIC concentrations (1 mg/mL) of KS8 crude organic extract significantly reduced the quorum sensing (QS)-dependent production of both pyoverdin and pyocyanin in P. aeruginosa PAO1 without affecting growth. A combinatorial approach using tobramycin and the crude organic extract at 1 mg/mL against planktonic P. aeruginosa PAO1 was found to increase the efficacy of tobramycin ten-fold, decreasing the MIC from 0.75 to 0.075 µg/mL. These data support the validity of approaches combining conventional antibiotic therapy with non-antibiotic compounds to improve the efficacy of current treatments.
PMCID: PMC4306922  PMID: 25546516
antibiotic resistance; antimicrobial synergy; quorum sensing inhibitors; marine bacteria; biofilm; marine biodiscovery; tobramycin; Pseudomonas aeruginosa
3.  Marine Compound Xyloketal B Reduces Neonatal Hypoxic-Ischemic Brain Injury 
Marine Drugs  2014;13(1):29-47.
Neonatal hypoxic-ischemic encephalopathy causes neurodegeneration and brain injury, leading to sensorimotor dysfunction. Xyloketal B is a novel marine compound isolated from a mangrove fungus Xylaria species (no. 2508) with unique antioxidant effects. In this study, we investigated the effects and mechanism of xyloketal B on oxygen-glucose deprivation-induced neuronal cell death in mouse primary cortical culture and on hypoxic-ischemic brain injury in neonatal mice in vivo. We found that xyloketal B reduced anoxia-induced neuronal cell death in vitro, as well as infarct volume in neonatal hypoxic-ischemic brain injury model in vivo. Furthermore, xyloketal B improved functional behavioral recovery of the animals following hypoxic-ischemic insult. In addition, xyloketal B significantly decreased calcium entry, reduced the number of TUNEL-positive cells, reduced the levels of cleaved caspase-3 and Bax proteins, and increased the level of Bcl-2 protein after the hypoxic-ischemic injury. Our findings indicate that xyloketal B is effective in models of hypoxia-ischemia and thus has potential as a treatment for hypoxic-ischemic brain injury.
PMCID: PMC4306923  PMID: 25546517
hypoxic-ischemic injury; infarct volume; neuroprotection; oxygen glucose deprivation; primary neuronal cell culture; neonatal stroke; behavioral tests; marine drug
4.  Intestinal Absorption of Fucoidan Extracted from the Brown Seaweed, Cladosiphon okamuranus 
Marine Drugs  2014;13(1):48-64.
The aim of this study was to examine the absorption of fucoidan through the intestinal tract. Fucoidan (0.1, 0.5, 1.0, 1.5 and 2.0 mg/mL) was added to Transwell inserts containing Caco-2 cells. The transport of fucoidan across Caco-2 cells increased in a dose-dependent manner up to 1.0 mg/mL. It reached a maximum after 1 h and then rapidly decreased. In another experiment, rats were fed standard chow containing 2% fucoidan for one or two weeks. Immunohistochemical staining revealed that fucoidan accumulated in jejunal epithelial cells, mononuclear cells in the jejunal lamina propria and sinusoidal non-parenchymal cells in the liver. Since we previously speculated that nitrosamine may enhance the intestinal absorption of fucoidan, its absorption was estimated in rats administered N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in their drinking water. Rats were fed 0.2% fucoidan chow (BBN + 0.2% fucoidan rats), 2% fucoidan chow (BBN + 2% fucoidan rats) and standard chow for eight weeks. The uptake of fucoidan through the intestinal tract seemed to be low, but was measurable by our ELISA method. Fucoidan-positive cells were abundant in the small intestinal mucosa of BBN + 2% fucoidan rats. Most fucoidan-positive cells also stained positive for ED1, suggesting that fucoidan was incorporated into intestinal macrophages. The uptake of fucoidan by Kupffer cells was observed in the livers of BBN + 2% fucoidan rats. In conclusion, the absorption of fucoidan through the small intestine was demonstrated both in vivo and in vitro.
PMCID: PMC4306924  PMID: 25546518
fucoidan; intestinal absorption; macrophage; Kupffer cells; Caco-2 cells
5.  Augmenting Anti-Cancer Natural Products with a Small Molecule Adjuvant 
Marine Drugs  2014;13(1):65-75.
Aquatic microbes produce diverse secondary metabolites with interesting biological activities. Cytotoxic metabolites have the potential to become lead compounds or drugs for cancer treatment. Many cytotoxic compounds, however, show undesirable toxicity at higher concentrations. Such undesirable activity may be reduced or eliminated by using lower doses of the cytotoxic compound in combination with another compound that modulates its activity. Here, we have examined the cytotoxicity of four microbial metabolites [ethyl N-(2-phenethyl) carbamate (NP-1), Euglenophycin, Anabaenopeptin, and Glycolipid 652] using three in vitro cell lines [human breast cancer cells (MCF-7), mouse neuroblastoma cells (N2a), and rat pituitary epithelial cells (GH4C1)]. The compounds showed variable cytotoxicity, with Euglenophycin displaying specificity for N2a cells. We have also examined the modulatory power of NP-1 on the cytotoxicity of the other three compounds and found that at a permissible concentration (125 µg/mL), NP-1 sensitized N2a and MCF-7 cells to Euglenophycin and Glycolipid 652 induced cytotoxicity.
PMCID: PMC4306925  PMID: 25548974
anti-cancer agents; cytotoxicity; natural products; toxins; adjuvant; small molecule
6.  Sulfated Galactofucan from the Brown Alga Saccharina latissima—Variability of Yield, Structural Composition and Bioactivity 
Marine Drugs  2014;13(1):76-101.
The fucose-containing sulfated polysaccharides (SP) from brown algae exhibit a wide range of bioactivities and are, therefore, considered promising candidates for health-supporting and medicinal applications. A critical issue is their availability in high, reproducible quality. The aim of the present study was to fractionate and characterize the SP extracted from Saccharina latissima (S.l.-SP) harvested from two marine habitats, the Baltic Sea and North Atlantic Ocean, in May, June and September. The fractionation of crude S.l.-SP by anion exchange chromatography including analytical investigations revealed that S.l.-SP is composed of a homogeneous fraction of sulfated galactofucan (SGF) and a mixture of low-sulfated, uronic acid and protein containing heteropolysaccharides. Furthermore, the results indicated that S.l. growing at an intertidal zone with high salinity harvested at the end of the growing period delivered the highest yield of S.l.-SP with SGF as the main fraction (67%). Its SGF had the highest degree of sulfation (0.81), fucose content (86.1%) and fucose/galactose ratio (7.8) and was most active (e.g., elastase inhibition: IC50 0.21 μg/mL). Thus, S.l. from the North Atlantic harvested in autumn proved to be more appropriate for the isolation of S.l.-SP than S.l. from the Baltic Sea and S.l. harvested in spring, respectively. In conclusion, this study demonstrated that habitat and harvest time of brown algae should be considered as factors influencing the yield as well as the composition and thus also the bioactivity of their SP.
PMCID: PMC4306926  PMID: 25548975
Saccharina latissima; brown alga; fucoidan; sulfated polysaccharides; galactofucan; habitat; harvest time; salinity; tidal amplitude
7.  Chemical Profiling (HPLC-NMR & HPLC-MS), Isolation, and Identification of Bioactive Meroditerpenoids from the Southern Australian Marine Brown Alga Sargassum paradoxum 
Marine Drugs  2014;13(1):102-127.
A phytochemical investigation of a southern Australian marine brown alga, Sargassum paradoxum, resulted in the isolation and identification of four new (5, 9, 10, and 15) and nine previously reported (1, 2, 6–8, and 11–14) bioactive meroditerpenoids. HPLC-NMR and HPLC-MS were central to the identification of a new unstable compound, sargahydroquinal (9), and pivotal in the deconvolution of eight (1, 2, 5–7, and 10–12) other meroditerpenoids. In particular, the complete characterization and identification of the two main constituents (1 and 2) in the crude dichloromethane extract was achieved using stop-flow HPLC-NMR and HPLC-MS. This study resulted in the first acquisition of gHMBCAD NMR spectra in the stop-flow HPLC-NMR mode for a system solely equipped with a 60 μL HPLC-NMR flow cell without the use of a cold probe, microcoil, or any pre-concentration.
PMCID: PMC4306927  PMID: 25551779
Sargassum; profiling; dereplication; HPLC-NMR; HPLC-MS; bioassay-guided; biological activity; meroditerpenoid
8.  New Ikarugamycin Derivatives with Antifungal and Antibacterial Properties from Streptomyces zhaozhouensis 
Marine Drugs  2014;13(1):128-140.
A bioassay guided fractionation of the ethyl acetate extract from culture broths of the strain Streptomyces zhaozhouensis CA-185989 led to the isolation of three new polycyclic tetramic acid macrolactams (1–3) and four known compounds. All the new compounds were structurally related to the known Streptomyces metabolite ikarugamycin (4). Their structural elucidation was accomplished using a combination of electrospray-time of flight mass spectrometry (ESI-TOF MS) and 1D and 2D NMR analyses. Compounds 1–3 showed antifungal activity against Aspergillus fumigatus, Candida albicans and antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA).
PMCID: PMC4306928  PMID: 25551780
Streptomyces zhaozhouensis; ikarugamycin; polycyclic tetramate macrolactams; antifungal; antibacterial
9.  Does the Use of Chitosan Contribute to Oxalate Kidney Stone Formation? 
Marine Drugs  2014;13(1):141-158.
Chitosan is widely used in the biomedical field due its chemical and pharmacological properties. However, intake of chitosan results in renal tissue accumulation of chitosan and promotes an increase in calcium excretion. On the other hand, the effect of chitosan on the formation of calcium oxalate crystals (CaOx) has not been described. In this work, we evaluated the antioxidant capacity of chitosan and its interference in the formation of CaOx crystals in vitro. Here, the chitosan obtained commercially had its identity confirmed by nuclear magnetic resonance and infrared spectroscopy. In several tests, this chitosan showed low or no antioxidant activity. However, it also showed excellent copper-chelating activity. In vitro, chitosan acted as an inducer mainly of monohydrate CaOx crystal formation, which is more prevalent in patients with urolithiasis. We also observed that chitosan modifies the morphology and size of these crystals, as well as changes the surface charge of the crystals, making them even more positive, which can facilitate the interaction of these crystals with renal cells. Chitosan greatly influences the formation of crystals in vitro, and in vivo analyses should be conducted to assess the risk of using chitosan.
PMCID: PMC4306929  PMID: 25551781
urolithiasis; antioxidant activity; calcium oxalate monohydrate crystals; copper chelation
10.  Total Synthesis of Gobiusxanthin Stereoisomers and Their Application to Determination of Absolute Configurations of Natural Products: Revision of Reported Absolute Configuration of Epigobiusxanthin 
Marine Drugs  2014;13(1):159-172.
(3R)-Gobiusxanthin stereoisomers (1a–d) were synthesized by stereoselective Wittig reaction of the (3R)-C15-acetylenic tri-n-butylphosphonium salt 7 with C25-apocarotenal stereoisomers 5a,b and 14a,b bearing four kinds of 3,6-dihydroxy-ε-end groups. The validity of the reported stereochemistry of gobiusxanthin was demonstrated by the fact that the reported spectral data of natural gobiusxanthin were in agreement with those of synthetic (3R,3'S,6'R)-gobiusxanthin (1a). On the other hand, the reported CD spectral data of natural epigobiusxanthin, which has been assigned as (3R,3'R,6'R)-isomer (3'-epigobiusxanthin), were identical with those of synthetic (3R,3'S,6'S)-isomer 1d (6'-epigobiusxanthin) rather than those of the corresponding synthetic 3'-epi-isomer 1b. It was found that the stereochemistry at C3-position has little effect on the shape of their CD spectra. Thus, in order to reinforce the validity of the absolute configurations at C3-position of natural specimens, (3S,3'S,6'R)- and (3S,3'S,6'S)-stereoisomers 1e and 1f were also synthesized and a HPLC analytical method for four stereoisomers was established by using a column carrying a chiral stationary phase. The HPLC analysis has proven that the stereochemistry of the natural epigobiusxanthin is 3R,3'S,6'S.
PMCID: PMC4306930  PMID: 25561412
carotenoid; gobiusxanthin; epigobiusxanthin; total synthesis; chiral HPLC separation; absolute configuration
11.  Synthesis of Enantiopure Reversed Structured Ether Lipids of the 1-O-Alkyl-sn-2,3-diacylglycerol Type 
Marine Drugs  2015;13(1):173-201.
This report describes the synthesis of reversed structured 1-O-alkyl-2,3-diacyl-sn-glycerols (DAGEs) possessing a pure saturated even number fatty acid (C6:0–C16:0) at the sn-2 position along with a pure EPA or DHA located at the terminal sn-3 position of the glycerol backbone of chimyl, batyl and selachyl alcohols. These adducts were synthesized by a highly efficient two-step chemoenzymatic process involving an immobilized Candida antarctica lipase to introduce pure EPA and DHA activated as oxime esters exclusively to the sn-3 terminal position of enantiopure chimyl, batyl and selachyl alcohols in excellent yields. The saturated fatty acids were subsequently incorporated to the remaining sn-2 position of the resulting 3-monoacylglyceryl ethers (3-MAGEs) using EDAC coupling agent in the presence of DMAP in very high to excellent yields (85%–98%). No losses of enantiomeric composition were observed during these processes. The multiple utilities of the resulting focused library of reversed structured DAGEs are discussed including how such compounds may possibly be utilized within the pharmaceutical area.
PMCID: PMC4306931  PMID: 25574735
diacylglyceryl ethers (DAGE); ether lipids; structured lipids; n-3 PUFA; EPA; DHA; n-3 PUFA oxime esters; lipase; chemoenzymatic synthesis; focused lipid library
12.  Statistical Research on the Bioactivity of New Marine Natural Products Discovered during the 28 Years from 1985 to 2012 
Marine Drugs  2015;13(1):202-221.
Every year, hundreds of new compounds are discovered from the metabolites of marine organisms. Finding new and useful compounds is one of the crucial drivers for this field of research. Here we describe the statistics of bioactive compounds discovered from marine organisms from 1985 to 2012. This work is based on our database, which contains information on more than 15,000 chemical substances including 4196 bioactive marine natural products. We performed a comprehensive statistical analysis to understand the characteristics of the novel bioactive compounds and detail temporal trends, chemical structures, species distribution, and research progress. We hope this meta-analysis will provide useful information for research into the bioactivity of marine natural products and drug development.
PMCID: PMC4306932  PMID: 25574736
bioactivity; marine natural products; quantitative analysis; novel compounds
13.  Chitosan in Mucoadhesive Drug Delivery: Focus on Local Vaginal Therapy 
Marine Drugs  2015;13(1):222-236.
Mucoadhesive drug therapy destined for localized drug treatment is gaining increasing importance in today’s drug development. Chitosan, due to its known biodegradability, bioadhesiveness and excellent safety profile offers means to improve mucosal drug therapy. We have used chitosan as mucoadhesive polymer to develop liposomes able to ensure prolonged residence time at vaginal site. Two types of mucoadhesive liposomes, namely the chitosan-coated liposomes and chitosan-containing liposomes, where chitosan is both embedded and surface-available, were made of soy phosphatidylcholine with entrapped fluorescence markers of two molecular weights, FITC-dextran 4000 and 20,000, respectively. Both liposomal types were characterized for their size distribution, zeta potential, entrapment efficiency and the in vitro release profile, and compared to plain liposomes. The proof of chitosan being both surface-available as well as embedded into the liposomes in the chitosan-containing liposomes was found. The capability of the surface-available chitosan to interact with the model porcine mucin was confirmed for both chitosan-containing and chitosan-coated liposomes implying potential mucoadhesive behavior. Chitosan-containing liposomes were shown to be superior in respect to the simplicity of preparation, FITC-dextran load, mucoadhesiveness and in vitro release and are expected to ensure prolonged residence time on the vaginal mucosa providing localized sustained release of entrapped model substances.
PMCID: PMC4306933  PMID: 25574737
chitosan; drug delivery; mucoadhesion; vaginal therapy; FITC-dextran
14.  LC-MS-Based Metabolomics Study of Marine Bacterial Secondary Metabolite and Antibiotic Production in Salinispora arenicola 
Marine Drugs  2015;13(1):249-266.
An LC-MS-based metabolomics approach was used to characterise the variation in secondary metabolite production due to changes in the salt content of the growth media as well as across different growth periods (incubation times). We used metabolomics as a tool to investigate the production of rifamycins (antibiotics) and other secondary metabolites in the obligate marine actinobacterial species Salinispora arenicola, isolated from Great Barrier Reef (GBR) sponges, at two defined salt concentrations and over three different incubation periods. The results indicated that a 14 day incubation period is optimal for the maximum production of rifamycin B, whereas rifamycin S and W achieve their maximum concentration at 29 days. A “chemical profile” link between the days of incubation and the salt concentration of the growth medium was shown to exist and reliably represents a critical point for selection of growth medium and harvest time.
PMCID: PMC4306935  PMID: 25574739
Salinispora arenicola; salt concentration; antibiotic; metabolomics; secondary metabolites; liquid chromatography; mass spectrometry; multivariate analysis
15.  Acknowledgement to Reviewers of Marine Drugs in 2014 
Marine Drugs  2015;13(1):267-275.
PMCID: PMC4306936
16.  Penicibrocazines A–E, Five New Sulfide Diketopiperazines from the Marine-Derived Endophytic Fungus Penicillium brocae 
Marine Drugs  2015;13(1):276-287.
Five new sulfide diketopiperazine derivatives, namely, penicibrocazines A–E (1–5), along with a known congener (6), were isolated and identified from the culture extract of Penicillium brocae MA-231, an endophytic fungus obtained from the fresh tissue of the marine mangrove plant Avicennia marina. The structures of these compounds were elucidated by detailed interpretation of NMR and mass spectroscopic data and the structures of compounds 1 and 3 were confirmed by single-crystal X-ray diffraction analysis. All these compounds were examined for cytotoxic and antimicrobial activities. Compounds 2–6 exhibited antimicrobial activity against some of the tested strains with MIC values ranging from 0.25 to 64 μg/mL.
PMCID: PMC4306937  PMID: 25574740
mangrove plant; endophytic fungus; Pencillium brocae; secondary metabolites; antimicrobial activity
17.  Araguspongine C Induces Autophagic Death in Breast Cancer Cells through Suppression of c-Met and HER2 Receptor Tyrosine Kinase Signaling 
Marine Drugs  2015;13(1):288-311.
Receptor tyrosine kinases are key regulators of cellular growth and proliferation. Dysregulations of receptor tyrosine kinases in cancer cells may promote tumorigenesis by multiple mechanisms including enhanced cell survival and inhibition of cell death. Araguspongines represent a group of macrocyclic oxaquinolizidine alkaloids isolated from the marine sponge Xestospongia species. This study evaluated the anticancer activity of the known oxaquinolizidine alkaloids araguspongines A, C, K and L, and xestospongin B against breast cancer cells. Araguspongine C inhibited the proliferation of multiple breast cancer cell lines in vitro in a dose-dependent manner. Interestingly, araguspongine C-induced autophagic cell death in HER2-overexpressing BT-474 breast cancer cells was characterized by vacuole formation and upregulation of autophagy markers including LC3A/B, Atg3, Atg7, and Atg16L. Araguspongine C-induced autophagy was associated with suppression of c-Met and HER2 receptor tyrosine kinase activation. Further in-silico docking studies and cell-free Z-LYTE assays indicated the potential of direct interaction between araguspongine C and the receptor tyrosine kinases c-Met and HER2 at their kinase domains. Remarkably, araguspongine C treatment resulted in the suppression of PI3K/Akt/mTOR signaling cascade in breast cancer cells undergoing autophagy. Induction of autophagic death in BT-474 cells was also associated with decreased levels of inositol 1,4,5-trisphosphate receptor upon treatment with effective concentration of araguspongine C. In conclusion, results of this study are the first to reveal the potential of araguspongine C as an inhibitor to receptor tyrosine kinases resulting in the induction of autophagic cell death in breast cancer cells.
PMCID: PMC4306938  PMID: 25580621
araguspongine C; autophagy; breast cancer; c-Met; HER2
18.  Recent Modifications of Chitosan for Adsorption Applications: A Critical and Systematic Review 
Marine Drugs  2015;13(1):312-337.
Chitosan is considered to be one of the most promising and applicable materials in adsorption applications. The existence of amino and hydroxyl groups in its molecules contributes to many possible adsorption interactions between chitosan and pollutants (dyes, metals, ions, phenols, pharmaceuticals/drugs, pesticides, herbicides, etc.). These functional groups can help in establishing positions for modification. Based on the learning from previously published works in literature, researchers have achieved a modification of chitosan with a number of different functional groups. This work summarizes the published works of the last three years (2012–2014) regarding the modification reactions of chitosans (grafting, cross-linking, etc.) and their application to adsorption of different environmental pollutants (in liquid-phase).
PMCID: PMC4306939  PMID: 25584681
chitosan; modification; grafting; cross-linking; adsorption; pollutants; dyes; metals; pharmaceuticals; capacity
19.  Preparation of Photocrosslinked Fish Elastin Polypeptide/Microfibrillated Cellulose Composite Gels with Elastic Properties for Biomaterial Applications 
Marine Drugs  2015;13(1):338-353.
Photocrosslinked hydrogels reinforced by microfibrillated cellulose (MFC) were prepared from a methacrylate-functionalized fish elastin polypeptide and MFC dispersed in dimethylsulfoxide (DMSO). First, a water-soluble elastin peptide with a molecular weight of ca. 500 g/mol from the fish bulbus arteriosus was polymerized by N,N′-dicyclohexylcarbodiimide (DCC), a condensation reagent, and then modified with 2-isocyanatoethyl methacrylate (MOI) to yield a photocrosslinkable fish elastin polypeptide. The product was dissolved in DMSO and irradiated with UV light in the presence of a radical photoinitiator. We obtained hydrogels successfully by substitution of DMSO with water. The composite gel with MFC was prepared by UV irradiation of the photocrosslinkable elastin polypeptide mixed with dispersed MFC in DMSO, followed by substitution of DMSO with water. The tensile test of the composite gels revealed that the addition of MFC improved the tensile properties, and the shape of the stress–strain curve of the composite gel became more similar to the typical shape of an elastic material with an increase of MFC content. The rheology measurement showed that the elastic modulus of the composite gel increased with an increase of MFC content. The cell proliferation test on the composite gel showed no toxicity.
PMCID: PMC4306940  PMID: 25584682
elastin; fish peptide; microfibrillated cellulose; hydrogel; photocrosslinking; composite gel
20.  Preparative Separation of Sulfur-Containing Diketopiperazines from Marine Fungus Cladosporium sp. Using High-Speed Counter-Current Chromatography in Stepwise Elution Mode 
Marine Drugs  2015;13(1):354-365.
High-speed counter-current chromatography (HSCCC) was successively applied to the separation of three sulfur-containing diketopiperazines (DKPs) (including two new compounds cladosporin A (1) and cladosporin B (3), and a known compound haematocin (2)) from a marine fungus Cladosporium sp. The two-phase solvent system composed of n-hexane-ethyl acetate-methanol-water at (1:1:1:1, v/v) and (2:1:2:1, v/v), in stepwise elution mode, was used for HSCCC. The preparative HSCCC separation was performed on 300 mg of crude sample yielding 26.7 mg of compound 3 at a purity of over 95%, 53.6 mg of a mixture of compounds 1 and 2, which was further separated by preparative-HPLC yielding 14.3 mg of compound 1 and 25.4 mg of compound 2 each at a purity of over 95%. Their structures were established by spectroscopic methods. The sulfur-containing DKPs suppressed the proliferation of hepatocellular carcinoma cell line HepG2. The present work represents the first application of HSCCC in the efficient preparation of marine fungal natural products.
PMCID: PMC4306941  PMID: 25584683
Cladosporium; high-speed counter-current chromatography; marine fungus; sulfur-containing diketopiperazines
21.  Asperlones A and B, Dinaphthalenone Derivatives from a Mangrove Endophytic Fungus Aspergillus sp. 16-5C 
Marine Drugs  2015;13(1):366-378.
Racemic dinaphthalenone derivatives, (±)-asperlone A (1) and (±)-asperlone B (2), and two new azaphilones, 6″-hydroxy-(R)-mitorubrinic acid (3) and purpurquinone D (4), along with four known compounds, (−)-mitorubrinic acid (5), (−)-mitorubrin (6), purpurquinone A (7) and orsellinic acid (8), were isolated from the cultures of Aspergillus sp. 16-5C. The structures were elucidated using comprehensive spectroscopic methods, including 1D and 2D NMR spectra and the structures of 1 further confirmed by single-crystal X-ray diffraction analysis, while the absolute configuration of 3 and 4 were determined by comparing their optical rotation and CD with those of the literature, respectively. Compounds 1, 2 and 6 exhibited potent inhibitory effects against Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB) with IC50 values of 4.24 ± 0.41, 4.32 ± 0.60 and 3.99 ± 0.34 μM, respectively.
PMCID: PMC4306942  PMID: 25591039
marine fungi; Aspergillus sp.; asperlones; azaphilones; MptpB inhibitor
22.  Combination of Trabectedin and Gemcitabine for Advanced Soft Tissue Sarcomas: Results of a Phase I Dose Escalating Trial of the German Interdisciplinary Sarcoma Group (GISG) 
Marine Drugs  2015;13(1):379-388.
Background: Evaluation of the potential efficacy and safety of combination therapies for advanced soft tissue sarcomas (STS) has increased substantially after approval of trabectedin and pazopanib. Trabectedin’s introduction in Europe in 2007 depended mainly on its activity in so-called L-sarcomas (liposarcoma and leiomyosarcoma); combination of trabectedin with other chemotherapies used in STS seems of particular interest. Methods: We initiated within the German Interdisciplinary Sarcoma Group (GISG) a phase I dose escalating trial evaluating the combination of trabectedin and gemcitabine in patients with advanced and/or metastatic L-sarcomas (GISG-02; NCT01426633). Patients were treated with increasing doses of trabectedin and gemcitabine. The primary endpoint was to determine the maximum tolerated dose. Results: Five patients were included in the study. Two patients were treated on dose level 1 comprising trabectedin 0.9 mg/m2 on day 1 and gemcitabine 700 mg/m2 on days 1 + 8, every 3 weeks. Due to dose-limiting toxicity (DLT) in both patients (elevated transaminases and thrombocytopenia), an additional three patients were treated on dose level −1 with trabectedin 0.7 mg/m2 plus gemcitabine 700 mg/m2. Of these three patients, two demonstrated another DLT; therefore, the trial was stopped and none of the dose levels could be recommended for phase II testing. Conclusion: The GISG-02 phase I study was stopped with the conclusion that the combination of gemcitabine and trabectedin is generally not recommended for the treatment of patients with advanced and/or metastatic leiomyosarcoma or liposarcoma. Also, this phase I study strongly supports the necessity for careful evaluation of combination therapies.
PMCID: PMC4306943  PMID: 25591040
gemcitabine; pazopanib; phase I; safety; soft tissue sarcoma; trabectedin
23.  Magnetotactic Bacteria as Potential Sources of Bioproducts 
Marine Drugs  2015;13(1):389-430.
Magnetotactic bacteria (MTB) produce intracellular organelles called magnetosomes which are magnetic nanoparticles composed of magnetite (Fe3O4) or greigite (Fe3S4) enveloped by a lipid bilayer. The synthesis of a magnetosome is through a genetically controlled process in which the bacterium has control over the composition, direction of crystal growth, and the size and shape of the mineral crystal. As a result of this control, magnetosomes have narrow and uniform size ranges, relatively specific magnetic and crystalline properties, and an enveloping biological membrane. These features are not observed in magnetic particles produced abiotically and thus magnetosomes are of great interest in biotechnology. Most currently described MTB have been isolated from saline or brackish environments and the availability of their genomes has contributed to a better understanding and culturing of these fastidious microorganisms. Moreover, genome sequences have allowed researchers to study genes related to magnetosome production for the synthesis of magnetic particles for use in future commercial and medical applications. Here, we review the current information on the biology of MTB and apply, for the first time, a genome mining strategy on these microorganisms to search for secondary metabolite synthesis genes. More specifically, we discovered that the genome of the cultured MTB Magnetovibrio blakemorei, among other MTB, contains several metabolic pathways for the synthesis of secondary metabolites and other compounds, thereby raising the possibility of the co-production of new bioactive molecules along with magnetosomes by this species.
PMCID: PMC4306944  PMID: 25603340
biomineralization; bioproducts; genome mining; greigite; magnetite; magnetosomes; magnetotactic bacteria; Magnetovibrio blakemorei; nonribosomal peptide synthetase; polyketide synthase
24.  Ophiobolin O Isolated from Aspergillus ustus Induces G1 Arrest of MCF-7 Cells through Interaction with AKT/GSK3β/Cyclin D1 Signaling 
Marine Drugs  2015;13(1):431-443.
Ophiobolin O is a member of ophiobolin family, which has been proved to be a potent anti-tumor drug candidate for human breast cancer. However, the anti-tumor effect and the mechanism of ophiobolin O remain unclear. In this study, we further verified ophiobolin O-induced G1 phase arrest in human breast cancer MCF-7 cells, and found that ophiobolin O reduced the phosphorylation level of AKT and GSK3β, and induced down-regulation of cyclin D1. The inverse docking (INVDOCK) analysis indicated that ophiobolin O could bind to GSK3β, and GSK3β knockdown abolished cyclin D1 degradation and G1 phase arrest. Pre-treatment with phosphatase inhibitor sodium or thovanadate halted dephosphorylation of AKT and GSK3β, and blocked ophiobolin O-induced G1 phase arrest. These data suggest that ophiobolin O may induce G1 arrest in MCF-7 cells through interaction with AKT/GSK3β/cyclin D1 signaling. In vivo, ophiobolin O suppressed tumor growth and showed little toxicity in mouse xenograft models. Overall, these findings provide theoretical basis for the therapeutic use of ophiobolin O.
PMCID: PMC4306945  PMID: 25603341
ophiobolin O; G1 arrest; AKT/GSK3β/cyclin D1 signaling
25.  Isolation and Assessment of the in Vitro Anti-Tumor Activity of Smenothiazole A and B, Chlorinated Thiazole-Containing Peptide/Polyketides from the Caribbean Sponge, Smenospongia aurea 
Marine Drugs  2015;13(1):444-459.
The study of the secondary metabolites contained in the organic extract of Caribbean sponge Smenospongia aurea led to the isolation of smenothiazole A (3) and B (4), hybrid peptide/polyketide compounds. Assays performed using four solid tumor cell lines showed that smenothiazoles exert a potent cytotoxic activity at nanomolar levels, with selectivity over ovarian cancer cells and a pro-apoptotic mechanism.
PMCID: PMC4306946  PMID: 25603342
Smenospongia aurea; marine natural products; thiazole; structure elucidation; anti-tumor lead molecules; smenamides; solid tumor cell lines; apoptosis; MTT assays

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