Cytotoxic and Antibacterial Cembranoids from a South China Sea Soft Coral,Lobophytum sp

Chemical examination of a South China Sea soft coral Lobophytum sp. led to the isolation of three new α-methylene-γ-lactone-containing cembranoids, (1R*,3R*,4R*,14R*,7E,11E)-3,4-epoxycembra-7,11,15(17)-trien-16,14-olide (1), (1R*,7S*,14S*,3E,11E)-7-hydroperoxycembra-3,8(19),11,15(17)-tetraen-16,14-olide (2), and (1R*,7S*,14S*,3E,11E)-18-acetoxy-7-hydroperoxycembra-3,8(19),11,15(17)-tetraen-16,14-olide (3), along with eleven known analogues 4–14. The structures of the new compounds were elucidated through extensive spectroscopic analysis, including 1D and 2D NMR data. Compounds 1–3 exhibited moderate cytotoxic activity against the selected tumor cell lines. Moreover, 2 and 3 were found to be moderate inhibitors against the bacteria S. aureus and S. pneumoniae.     

Bioactive (3Z,5E)-11,20-epoxybriara-3,5-dien-7,18-olide diterpenoids from the South China Sea gorgonian Dichotella gemmacea

Six new (3Z,5E)-11,20-epoxybriara-3,5-dien-7,18-olide diterpenoids, gemmacolides N-S (1-6), were isolated together with four known analogues, juncenolide D, and juncins R, S and U (7-10), from the South China Sea gorgonian Dichotella gemmacea. The structures of the new compounds were elucidated by the detailed analysis of spectroscopic data in combination with the comparison with reported data. The absolute configuration of 1 was determined by a TDDFT calculation of its solution ECD spectrum, affording the determination of absolute configuration of other analogues by simply comparing their ECD spectra with that of 1. The cytotoxic and antimicrobial activities of these compounds were evaluated. In preliminary in vitro bioassays, compounds 4, 5, 6, 8 and 9 showed cytotoxicity against A549 and MG63, while compounds 1, 2, 4, 7-10 showed antimicrobial activity against the fungus Septoria tritici and the bacterium Escherichia coli.     

Exploring the Chemodiversity and Biological Activities of the Secondary Metabolites from the Marine Fungus Neosartorya pseudofischeri

The production of fungal metabolites can be remarkably influenced by various cultivation parameters. To explore the biosynthetic potentials of the marine fungus, Neosartorya pseudofischeri, which was isolated from the inner tissue of starfish Acanthaster planci, glycerol-peptone-yeast extract (GlyPY) and glucose-peptone-yeast extract (GluPY) media were used to culture this fungus. When cultured in GlyPY medium, this fungus produced two novel diketopiperazines, neosartins A and B (1 and 2), together with six biogenetically-related known diketopiperazines,1,2,3,4-tetrahydro-2,3-dimethyl-1,4-dioxopyrazino[1,2-a]indole (3), 1,2,3,4-tetrahydro-2-methyl-3-methylene-1,4-dioxopyrazino[1,2-a]indole (4), 1,2,3,4-tetrahydro-2-methyl-1,3,4-trioxopyrazino[1,2-a] indole (5), 6-acetylbis(methylthio)gliotoxin (10), bisdethiobis(methylthio)gliotoxin (11), didehydrobisdethiobis(methylthio)gliotoxin (12) and N-methyl-1H-indole-2-carboxamide (6). However, a novel tetracyclic-fused alkaloid, neosartin C (14), a meroterpenoid, pyripyropene A (15), gliotoxin (7) and five known gliotoxin analogues, acetylgliotoxin (8), reduced gliotoxin (9), 6-acetylbis(methylthio)gliotoxin (10), bisdethiobis(methylthio) gliotoxin (11) and bis-N-norgliovictin (13), were obtained when grown in glucose-containing medium (GluPY medium). This is the first report of compounds 3, 4, 6, 9, 10 and 12 as naturally occurring. Their structures were determined mainly by MS, 1D and 2D NMR data. The possible biosynthetic pathways of gliotoxin-related analogues and neosartin C were proposed. The antibacterial activity of compounds 2–14 and the cytotoxic activity of compounds 4, 5 and 7–13 were evaluated. Their structure-activity relationships are also preliminarily discussed.     

Identification and Bioactivity of Compounds from the Fungus Penicillium sp. CYE-87 Isolated from a Marine Tunicate

In the course of our continuous interest in identifying bioactive compounds from marine microbes, we have investigated a tunicate-derived fungus, Penicillium sp. CYE-87. A new compound with the 1,4-diazepane skeleton, terretrione D (2), together with the known compounds, methyl-2-([2-(1H-indol-3-yl)ethyl]carbamoyl)acetate (1), tryptamine (3), indole-3-carbaldehyde (4), 3,6-diisobutylpyrazin-2(1H)-one (5) and terretrione C (6), were isolated from Penicillium sp. CYE-87. The structures of the isolated compounds were established by spectral analysis, including 1D (¹H, ¹³C) and 2D (COSY, multiplicity edited-HSQC and HMBC) NMR and HRESIMS, as well as comparison of their NMR data with those in the literature. The compounds were evaluated for their antimigratory activity against the human breast cancer cell line (MDA-MB-231) and their antiproliferation activity against HeLa cells. Compounds 2 and 6 showed significant antimigratory activity against MDA-MB-231, as well as antifungal activity against C. albicans.     

Five New Cytotoxic Metabolites from the Marine Fungus Neosartorya pseudofischeri

The marine fungus Neosartorya pseudofischeri was isolated from Acanthaster planci from the South China Sea. In a preliminary bioactivity screening, the crude methanol extract of the fungal mycelia showed significant inhibitory activity against the Sf9 cell line from the fall armyworm Spodoptera frugiperda. Five novel compounds, including 5-olefin phenylpyropene A (1), 13-dehydroxylpyripyropene A (4), deacetylsesquiterpene (7), 5-formyl-6-hydroxy-8-isopropyl-2- naphthoic acid (9) and 6,8-dihydroxy-3-((1E,3E)-penta-1,3-dien-1-yl)isochroman-1-one (10), together with eleven known compounds, phenylpyropene A (2) and C (3), pyripyropene A (5), 7-deacetylpyripyropene A (6), (1S,2R,4aR,5R,8R,8aR)-1,8a-dihydroxy-2-acetoxy-3,8-dimethyl-5- (prop-1-en-2-yl)-1,2,4a, 5,6,7,8,8a-octahydronaphthalene (8), isochaetominine C (11), trichodermamide A (12), indolyl-3-acetic acid methyl ester (13), 1-acetyl-β-carboline (14), 1,2,3,4-tetrahydro-6-hydroxyl-2-methyl-l,3,4-trioxopyrazino[l,2-a]-indole (15) and fumiquinazoline F (16), were obtained. The structures of these compounds were determined mainly by MS and NMR data. The absolute configuration of 9 was assigned by the single-crystal X-ray diffraction studies. Compounds 1–11 and 15 showed significant cytotoxicity against the Sf9 cells from S. frugiperda.     

Formamido-Diterpenes from the South China Sea Sponge Acanthella cavernosa

Seven new formamido-diterpenes, cavernenes A-D (1-4), kalihinenes E and F (5-6), and kalihipyran C (7), together with five known compounds (8-12), were isolated from the South China Sea sponge Acanthella cavernosa. Structures were established using IR, HRESIMS, 1D and 2D NMR, and single X-ray diffraction techniques. The isolated compounds were assessed for their cytotoxicity against a small panel of human cancer cell lines (HCT-116, A549, HeLa, QGY-7701, and MDA-MB-231) with IC(50) values in the range of 6-18 μM. In addition, compound 9 showed weak antifungal activity against Trichophyton rubrum and Microsporum gypseum with MIC values of 8 and 32 μg/mL, respectively, compound 10 displayed weak antifungal activity against fungi Candida albicans, Cryptococcus neoformans, T. rubrum, and M. gypseum with MIC values of 8, 8, 4, and 8 μg/mL, respectively.     

Synthesis of 1-substituted carbazolyl-1,2,3,4-tetrahydro- and carbazolyl-3,4-dihydro-β-carboline analogs as potential antitumor agents

A series of 1-substituted carbazolyl-1,2,3,4-tetrahydro- and carbazolyl-3,4-dihydro-β-carboline analogs have been synthesized and evaluated for antitumor activity against human tumor cells including KB, DLD, NCI-H661, Hepa, and HepG2/A2 cell lines. Among these, compounds 2, 6, 7, and 9 exhibited the most potent and selective activity against the tested tumor cells. As for inhibition of topoisomerase II, compounds 1-14 and 18 showed better activity than etoposide. Among them, compounds 3, 4, 7, 9, and 10 exhibited potent activity. The structure and activity relationship (SAR) study revealed correlation between carbon numbers of the side chain and biological activities. The molecular complex with DNA for compound 2 was proposed.     

Bioactive Secondary Metabolites from the Red Sea Marine Verongid Sponge Suberea Species

In a continuation of our efforts to identify bioactive compounds from Red Sea Verongid sponges, the organic extract of the sponge Suberea species afforded seven compounds including two new dibrominated alkaloids, subereamollines C and D (1 and 2), together with the known compounds aerothionin (3), homoaerothionin (4), aeroplysinin-1 (5), aeroplysinin-2 (6) and a revised subereaphenol C (7) as ethyl 2-(2,4-dibromo-3,6-dihydroxyphenyl)acetate. The structures of the isolated compounds were assigned by different spectral data including optical rotations, 1D (¹H and ¹³C) and 2D (COSY, multiplicity-edited HSQC, and HMBC) NMR and high-resolution mass spectroscopy. Aerothionin (3) and subereaphenol C (7) displayed potent cytotoxic activity against HeLa cell line with IC₅₀ values of 29 and 13.3 µM, respectively. In addition, aeroplysinin-2 (6) showed potent antimigratory activity against the human breast cancer cell line MDA-MB-231 with IC₅₀ of 18 µM. Subereamollines C and D are new congeners of the previously reported compounds subereamollines A and B with methyl ester functionalities on the side chain. These findings provide further insight into the biosynthetic capabilities of members of the genus Suberea and the chemical diversity as well as the biological activity of these compounds.     

Sinularones A-I, new cyclopentenone and butenolide derivatives from a marine soft coral Sinularia sp. and their antifouling activity

Nine new compounds, namely sinularones A-I (1-9), characterized as cyclopentenone and butenolide-type analogues, were isolated from a soft coral Sinularia sp., together with a known butenolide (10). Their structures were elucidated by means of spectroscopic (IR, MS, 1D and 2D NMR, CD) analysis. The absolute configurations were determined on the basis of CD and specific rotation data in association with the computed electronic circular dichroism (ECD) by time dependent density functional theory (TD DFT) at 6-31+G(d,p)//DFT B3LYP/6-31+G(d,p) level. Compounds 1-2 and 7-10 showed potent antifouling activities against the barnacle Balanus amphitrite.     

New Isocoumarin Derivatives and Meroterpenoids from the Marine Sponge-Associated Fungus Aspergillus similanensis sp. nov. KUFA 0013

Two new isocoumarin derivatives, including a new 5-hydroxy-8-methyl-2H, 6H-pyrano[3,4-g]chromen-2,6-dione (1) and 6,8-dihydroxy-3,7-dimethylisocoumarin (2b), a new chevalone derivative, named chevalone E (3), and a new natural product pyripyropene S (6) were isolated together with 6, 8-dihydroxy-3-methylisocoumarin (2a), reticulol (2c), p-hydroxybenzaldehyde, chevalone B, chevalone C, S14-95 (4), and pyripyropene E (5) from the ethyl acetate extract of the undescribed marine sponge-associated fungus Aspergillus similanensis KUFA 0013. The structures of the new compounds were established based on 1D and 2D NMR spectral analysis, and in the case of compound 3, X-ray analysis was used to confirm its structure and the absolute configuration of its stereogenic carbons. Compounds 1, 2a–c and 3–6 were evaluated for their antimicrobial activity against Gram-positive and Gram-negative bacteria, Candida albicans ATCC 10231, and multidrug-resistant isolates from the environment. Chevalone E (3) was found to show synergism with the antibiotic oxacillin against methicillin-resistant Staphylococcus aureus (MRSA).     

Isolation,Characterization, and Bioactivity Evaluation of 3-((6-Methylpyrazin-2-yl)methyl)-1H-indole,a New Alkaloid from a Deep-Sea-Derived Actinomycete Serinicoccus profundi sp. nov

One new alkaloid, 3-((6-methylpyrazin-2-yl)methyl)-1H-indole (1) was obtained from the deep-sea actinomycete Serinicoccus profundi sp. nov., along with five known compounds (2–6). Their structures were determined on the basis of detailed analysis of the 1D and 2D NMR as well as MS data. The new indole alkaloid displayed weak antimicrobial activity against Staphylococcus aureus ATCC 25923 with an MIC value of 96 μg/mL. It showed no cytotoxicity on a normal human liver cell line (BEL7402) and a human liver tumor cell line (HL-7702).     

Six New Tetraprenylated Alkaloids from the South China Sea Gorgonian Echinogorgia pseudossapo

Six new tetraprenylated alkaloids, designated as malonganenones L–Q (1–6), were isolated from the gorgonian Echinogorgia pseudossapo, collected in Daya Bay of Guangdong Province, China. The structures of 1–6 featuring a methyl group at N-3 and a tetraprenyl chain at N-7 in the hypoxanthine core were established by extensive spectroscopic analyses. Compounds 1–6 were tested for their inhibitory activity against the phosphodiesterases (PDEs)-4D, 5A, and 9A, and compounds 1 and 6 exhibited moderate inhibitory activity against PDE4D with IC₅₀ values of 8.5 and 20.3 µM, respectively.     

New cytotoxic oxygenated sterols from the marine bryozoan Cryptosula pallasiana

Six new sterols (1-6), together with seven known sterols (7-13), were isolated from the CCl(4) extract of the marine bryozoan Cryptosula pallasiana, four (3-6) of which have already been reported as synthetic sterols. This is the first time that these compounds (3-6) are reported as natural sterols. The structures of the new compounds were determined on the basis of the extensive spectroscopic analysis, including two-dimensional (2D) NMR and HR-ESI-MS data. Compounds 1-4, 7 and 10-13 were evaluated for their cytotoxicity against HL-60 human myeloid leukemia cell line, and all of the evaluated compounds exhibited moderate cytotoxicity to HL-60 cells with a range of IC(50) values from 14.73 to 22.11 μg/mL except for compounds 12 and 13.     

Polyoxygenated Sterols from the South China Sea Soft Coral Sinularia sp

Chemical investigation of the ethanol extract of soft coral Sinularia sp. collected from the South China Sea led to the isolation of three new polyoxygenated sterols, (3S,23R,24S)-ergost-5-ene-3β,23α,25-triol (1), (24S)-ergostane-6-acetate-3β,5α,6β,25-tetraol (2), (24S)-ergostane-6-acetate-3β,6β,12β,25-tetraol (3) together with three known ones (4-6). The structures, including relative configurations of the new compounds (1-3), were elucidated by detailed analysis of spectroscopic data (IR, UV, NMR, MS) and by comparison with related reported compounds. The absolute configuration of 1 was further determined by modified Mosher's method. Compound 5 exhibited moderate cytotoxicity against K562 cell line with an IC(50) value of 3.18 μM, but also displayed strong lethality toward the brine shrimp Artemia salina with a LC(50) value of 0.96 μM.     

New α-Glucosidase Inhibitory Triterpenic Acid from Marine Macro Green Alga Codium dwarkense Boergs

The marine ecosystem has been a key resource for secondary metabolites with promising biological roles. In the current study, bioassay-guided phytochemical investigations were carried out to assess the presence of enzyme inhibitory chemical constituents from the methanolic extract of marine green alga—Codium dwarkense. The bioactive fractions were further subjected to chromatographic separations, which resulted in the isolation of a new triterpenic acid; dwarkenoic acid (1) and the known sterols; androst-5-en-3β-ol (2), stigmasta-5,25-dien-3β,7α-diol (3), ergosta-5,25-dien-3β-ol (4), 7-hydroxystigmasta-4,25-dien-3-one-7-O-β-d-fucopyranoside (5), 7-hydroxystigmasta-4,25-dien-3-one (6), and stigmasta-5,25-dien-3β-ol (7). The structure elucidation of the new compound was carried out by combined mass spectrometry and 1D (¹H and ¹³C) and 2D (HSQC, HMBC, COSY, and NOESY) NMR spectroscopic data. The sub-fractions and pure constituents were assayed for enzymatic inhibition of alpha-glucosidase. Compound 1 showed significant inhibition at all concentrations. Compounds 2, 3, 5, and 7 exhibited a dose-dependent response, whereas compounds 4–6 showed moderate inhibition. Utilizing such marine-derived biological resources could lead to drug discoveries related to anti-diabetics.     

Purpurogemutantin and purpurogemutantidin, new drimenyl cyclohexenone derivatives produced by a mutant obtained by diethyl sulfate mutagenesis of a marine-derived Penicillium purpurogenum G59

Two new drimenyl cyclohexenone derivatives, named purpurogemutantin (1) and purpurogemutantidin (2), and the known macrophorin A (3) were isolated from a bioactive mutant BD-1-6 obtained by random diethyl sulfate (DES) mutagenesis of a marine-derived Penicillium purpurogenum G59. Structures and absolute configurations of 1 and 2 were determined by extensive spectroscopic methods, especially 2D NMR and electronic circular dichroism (ECD) analysis. Possible biosynthetic pathways for 1-3 were also proposed and discussed. Compounds 1 and 2 significantly inhibited human cancer K562, HL-60, HeLa, BGC-823 and MCF-7 cells, and compound 3 also inhibited the K562 and HL-60 cells. Both bioassay and chemical analysis (HPLC, LC-ESIMS) demonstrated that the parent strain G59 did not produce 1-3, and that DES-induced mutation(s) in the mutant BD-1-6 activated some silent biosynthetic pathways in the parent strain G59, including one set for 1-3 production.     

Diketopiperazine Derivatives from the Marine-Derived Actinomycete Streptomyces sp. FXJ7.328

Five new diketopiperazine derivatives, (3Z,6E)-1-N-methyl-3-benzylidene-6-(2S-methyl-3-hydroxypropylidene)piperazine-2,5-dione (1), (3Z,6E)-1-N-methyl-3-benzylidene-6-(2R-methyl-3-hydroxypropylidene)piperazine-2,5-dione (2), (3Z,6Z)-3-(4-hydroxybenzylidene)-6-isobutylidenepiperazine-2,5-dione (3), (3Z,6Z)-3-((1H-imidazol-5-yl)-methylene)-6-isobutylidenepiperazine-2,5-dione (4), and (3Z,6S)-3-benzylidene-6-(2S-but-2-yl)piperazine-2,5-dione (5), were isolated from the marine-derived actinomycete Streptomyces sp. FXJ7.328. The structures of 1–5 were determined by spectroscopic analysis, CD exciton chirality, the modified Mosher’s, Marfey’s and the C₃ Marfey’s methods. Compound 3 showed modest antivirus activity against influenza A (H1N1) virus with an IC₅₀ value of 41.5 ± 4.5 μM. In addition, compound 6 and 7 displayed potent anti-H1N1 activity with IC₅₀ value of 28.9 ± 2.2 and 6.8 ± 1.5 μM, respectively. Due to the lack of corresponding data in the literature, the ¹³C NMR data of (3Z,6S)-3-benzylidene-6-isobutylpiperazine-2,5-dione (6) were also reported here for the first time.     

Frajunolides L-O, four new 8-Hydroxybriarane diterpenoids from the Gorgonian Junceella fragilis

Four new 8-hydroxybriarane diterpenoids, frajunolides L-O (1-4), were isolated from the Taiwanese gorgonian Junceella fragilis. The structures of compounds 1-4 were elucidated based on spectroscopic analysis, especially 2D NMR ((1)H-(1)H COSY, HSQC, HMBC and NOESY) and HRMS. Compounds 1 and 4 showed weak anti-inflammatory activity as tested by superoxide anion generation and elastase release by human neutrophil in response to fMLP/CB. Compound 3 showed selective inhibition on elastase release in vitro.     

Pseudaboydins A and B: Novel Isobenzofuranone Derivatives from Marine Fungus Pseudallescheria boydii Associated with Starfish Acanthaster planci

Two novel isobenzofuranone derivatives, pseudaboydins A (1) and B (2), along with five known compounds, including (R)-2-(2-hydroxypropan-2-yl)-2,3-dihydro-5-hydroxybenzofuran (3), (R)-2-(2-hydroxypropan-2-yl)-2,3-dihydro-5-methoxybenzofuran (4), 3,3′-dihydroxy-5,5′-dimethyldiphenyl ether (5), 3-(3-methoxy-5-methylphenoxy)-5-methylphenol (6) and (−)-regiolone (7), were isolated from the culture broth of the marine fungus, Pseudallescheria boydii, associated with the starfish, Acanthaster planci. Their structures were elucidated primarily based on NMR and MS data. The absolute configurations of 1–4 were determined by CD spectroscopy and single-crystal X-ray diffraction studies. The cytotoxic and antibacterial activities of 1–4 were evaluated. Pseudaboydin A (1) showed moderate cytotoxic activity against human nasopharyngeal carcinoma cell line HONE1, human nasopharyngeal carcinoma cell line SUNE1 and human glandular lung cancer cell line GLC82 with IC₅₀ values of 37.1, 46.5 and 87.2 μM, respectively.     

Effects of high salt stress on secondary metabolite production in the marine-derived fungus Spicaria elegans

To obtain structurally novel and bioactive natural compounds from marine-derived microorganisms, the effect of high salt stress on secondary metabolite production in the marine-derived fungal strain, Spicaria elegans KLA-03, was investigated. The organism, which was isolated from marine sediment, produced different secondary metabolites when cultured in 3% and 10% saline conditions. Four characteristic metabolites, only produced in the 10% salinity culture, were isolated, and their structures were identified as (2E,2'Z)-3,3'-(6,6'-dihydroxybiphenyl-3,3'-diyl)diacrylic acid (1), aspulvinone E (2), aspochalasin E (3) and trichodermamide B (6), according to their 1D and 2D NMR spectra. Compound 1 is a new compound. High salt stress may therefore be a promising means to induce the production of new and chlorinated compounds in halotolerant fungi. Compound 1 showed moderate antibacterial activity against Pseudomonas aeruginosa and Escherichia coli with minimum inhibitory concentration (MIC) values of 0.038 and 0.767 mM, respectively.