5-Hydroxyindole-type alkaloids,as Candida albicans isocitrate lyase inhibitors,from the tropical sponge Hyrtios sp.

Chemical investigations of the tropical marine sponge Hyrtios sp. have resulted in the isolation of a new alkaloid, 1-carboxy-6-hydroxy-3,4-dihydro-β-carboline (1) together with the known metabolites, 6-hydroxy-3,4-dihydro-1-oxo-β-carboline (2), 5-hydroxy-1H-indole-3-carboxylic acid methyl ester (3), serotonin (4), hyrtiosin A (5), 5-hydroxyindole-3-carbaldehyde (6), and hyrtiosin B (7). Their structures were elucidated on the basis of mass spectrometry and detailed 2D NMR spectroscopic data. Hyrtiosin B (7) displayed a potent inhibitory activity against isocitrate lyase (ICL) of Candida albicans with an IC₅₀ value of 89.0 μM.     

N-Formyllapatin A,a new N-formylspiroquinazoline derivative from the marine-derived fungus Penicillium adametzioides AS-53

N-Formyllapatin A (1), a new spiroquinazoline derivative, and four known quinazoline metabolites, lapatins A (2) and B (3), prelapatin B (4), and glyantrypine (5), along with two known indolediketopiperazine derivatives, fumitremorgin B (6) and verruculogen (7), were characterized from Penicillium adametzioides AS-53, a fungus obtained from the fresh tissue of an unidentified marine sponge. The structure of compound 1 was established by detailed interpretation of NMR and MS data, and its absolute configuration was established by a single-crystal X-ray diffraction analysis. N-Formyllapatin A (1) represents the first N-formylspiroquinazoline secondary metabolite. Compounds 3 and 5–7 showed moderate inhibitory activity against aqua-pathogenic bacterial Vibrio harveyi.     

Three new sterigmatocystin analogues from marine-derived fungus Aspergillus versicolor MF359

During the systematic screening of active compounds from marine-derived fungi, the extract of a strain of Aspergillus versicolor MF359 isolated from a marine sponge of Hymeniacidon perleve was identified for detailed chemical investigation. Three new secondary metabolites, named hemiacetal sterigmatocystin (1), acyl-hemiacetal sterigmatocystin (2), and 5-methoxydihydrosterigmatocystin (3), together with a known compound, aversin (4), were characterized. 1 represents a first structure of sterigmatocystin hemiacetal from nature. The antibacterial activities of these identified compounds were evaluated against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Bacillus subtilis, and Pseudomonas aeruginosa. Compound 3 showed activity against S. aureus and B. subtilis with MIC values of 12.5 and 3.125 μg/mL, respectively.     

Isolation,structure determination and cytotoxicity studies of tryptophan alkaloids from an Australian marine sponge Hyrtios sp.

Mass-guided fractionation of the MeOH extract from a specimen of the Australian marine sponge Hyrtios sp. resulted in the isolation of two new tryptophan alkaloids, 6-oxofascaplysin (2), and secofascaplysic acid (3), in addition to the known metabolites fascaplysin (1) and reticulatate (4). The structures of all molecules were determined following NMR and MS data analysis. Structural ambiguities in 2 were addressed through comparison of experimental and DFT-generated theoretical NMR spectral values. Compounds 1–4 were evaluated for their cytotoxicity against a prostate cancer cell line (LNCaP) and were shown to display IC₅₀ values ranging from 0.54 to 44.9 μM.     

A tetramic acid derivative with protein tyrosine phosphatase 1B inhibitory activity and a new nortriterpene glycoside from the Indonesian marine sponge Petrosia sp.

During the search for protein tyrosine phosphatase 1B (PTP1B) inhibitors from marine organisms, the known tetramic acid derivative, melophlin C (1), was isolated as an active component together with the new nortriterpenoid saponin, sarasinoside S (2), and three homologues: sarasinosides A₁ (3), I₁ (4), and J (5), from the Indonesian marine sponge Petrosia sp. The structure of 2 was elucidated on the basis of its spectroscopic data. Compound 1 inhibited PTP1B activity with an IC₅₀ value of 14.6 μM, while compounds 2–5 were not active at 15.2–16.0 μM. This is the first study to report the inhibitory effects of a tetramic acid derivative on PTP1B activity.     

Australian marine sponge alkaloids as a new class of glycine-gated chloride channel receptor modulator

Chemical analysis of a specimen of the sponge Ianthella cf. flabelliformis returned two new sesquiterpene glycinyl lactams, ianthellalactams A (1) and B (2), the known sponge sesquiterpene dictyodendrillin (3) and its ethanolysis artifact ethyl dictyodendrillin (4), and five known sponge indole alkaloids, aplysinopsin (5), 8E-3′-deimino-3′-oxoaplysinopsin (6), 8Z-3′-deimino-3′-oxoaplysinopsin (7), dihydroaplysinopsin (8) and tubastrindole B (9). The equilibrated mixture 6/7 exhibited glycine-gated chloride channel receptor (GlyR) antagonist activity with a bias towards α3 over α1 GlyR, while tubastrindole B (9) exhibited a bias towards α1 over α3 GlyR. At low- to sub-micromolar concentrations, 9 was also a selective potentiator of α1 GlyR, with no effect on α3 GlyR—a pharmacology that could prove useful in the treatment of movement disorders such as spasticity and hyperekplexia. Our investigations into the GlyR modulatory properties of 1–9 were further supported by the synthesis of a number of structurally related indole alkaloids.     

Aureolic acids from a marine-derived Streptomyces sp. WBF16

A marine-derived actinomycete (Streptomyces sp. WBF16) exhibiting antitumor activities was investigated. The strain was identified using morphological, biochemical and genetic techniques. 16S rDNA sequence of the isolate indicated that it was most closely related to Streptomyces coelicolor A3 (2). Furthermore, a new aureolic acid (Chromomycin B, 1), along with Chromomycin A₂ (2) and Chromomycin A₃ (3) were isolated from its secondary metabolites. Their structures were determined by chemical and spectroscopic methods including 1D, 2D NMR and HRMS. Compounds 1–3 showed strong cytotoxicity against SGC7901, HepG2, A549, HCT116 and COC1 and HUVEC.     

Anti-mycobacterial alkaloids,cyclic 3-alkyl pyridinium dimers,from the Indonesian marine sponge Haliclona sp.

Three new dimeric 3-alkyl pyridinium alkaloids, named haliclocyclamines A–C (1–3), were isolated together with five known congeners, cyclostellettamines A (4), B (5), C (6), E (7), and F (8), from the Indonesian marine sponge Haliclona sp. The structures of 1–3 were assigned based on their spectroscopic data (1D and 2D NMR, HRFABMS, ESIMS/MS, UV, and IR). Compounds 1–8 exhibited antimicrobial activities against Mycobacterium smegmatis with inhibition zones of 17, 10, 13, 14, 8, 8, 12, and 12 mm, respectively, at 10 μg/disc. Compounds 3 and 8 also modestly inhibited the activity of vaccinia H-1-related phosphatase (VHR), a dual-specificity phosphatase, at 17–18 μM.     

ApoE secretion modulating bromotyrosine derivative from the Australian marine sponge Callyspongia sp.

High throughput screening of a pre-fractionated natural product library identified 11 active fractions showing ApoE modulation activity. Mass-directed fractionation of one active crude extract from the Australian marine sponge Callyspongia sp. resulted in the isolation of 13 metabolites, including three new bromotyrosine derivatives, callyspongic acid (1), 3,5-dibromo-4-methoxyphenylpyruvic acid (2), N-acetyl-3-bromo-4-hydroxylphenylethamine (3), and ten known compounds (4–13). The structure elucidation of compounds 1–3 was based on their 1D and 2D NMR and MS spectroscopic data. 3,5-Dibromo-4-methoxyphenylpyruvic acid (2) showed weak activity in increasing the apolipoprotein E secretion from human CCF-STTG1 cells at the concentration of 40 μM.     

Two new secondary metabolites,saccharochlorines A and B,from a marine bacterium Saccharomonospora sp. KCTC-19160

Two new chlorinated secondary metabolites, saccharochlorines A and B (1 and 2), were isolated from the saline cultivation of a marine-derived bacterium Saccharomonospora sp. (KCTC-19160). The chemical structures of the saccharochlorines were elucidated by 2D NMR and MS spectroscopic data. Saccharochlorines A and B (1 and 2) exhibit weak inhibition of β-secretase (BACE1) in biochemical inhibitory assay, but they induced the release of Aβ (1–40) and Aβ (1–42) in H4-APP neuroglial cells. This discrepancy might be derived from the differences between the cellular and sub-cellular environments or the epigenetic stimulation of BACE1 expression.     

Ehrenasterol and biemnic acid; new bioactive compounds from the Red Sea sponge Biemna ehrenbergi

In continuation of our efforts to identify bioactive compounds from the Red Sea marine sponges, we have recently investigated the organic extract of the sponge Biemna ehrenbergi. This study resulted in the isolation of eight compounds including a new sterol, ehrenasterol (1), a new C₂₄-acetylenic acid, biemnic acid (2), together with six known compounds including a hopanoid, three steroids and two nucleosides. The isolated compounds were identified as (22E)-ergosta-22-ene-8,14-epoxy-3,7-dione (1), (E)-tetracos-8-en-5-ynoic acid (2), (22E)-ergosta-5,8,22-trien-7-one-3β-ol (3), 32,35-anhydrobacteriohopanetetrol (4), (24R)-ergosta-6,22-diene-5,8-epidioxy-3-ol (5), melithasterol B (6), thymidine (7) and 2′-deoxyuridine (8). The structures of the isolated compounds were assigned by different spectral data including 1D and 2D NMR (COSY, HSQC, and HMBC) and high-resolution mass spectrometry. Compound 1 displayed inhibition zone of 20 mm at 100 μg/disc against Escherichia coli in the disc diffusion assay. Similarly, compounds 2 and 4 displayed inhibition zones of 20 and 18 mm respectively against Candida albicans at the same concentration. Compounds 1–3 displayed weak cytotoxic activity against human colon adenocarcinoma (HCT-116) cancer cell line.     

Ceratinadins A–C,new bromotyrosine alkaloids from an Okinawan marine sponge Pseudoceratina sp.

Three new bromotyrosine alkaloids, ceratinadins A–C (1–3), were isolated from an Okinawan marine sponge Pseudoceratina sp. and the structures of 1–3 were elucidated on the basis of spectroscopic data. Ceratinadin A (1) was a novel bromotyrosine alkaloid possessing an N-imidazolyl-quinolinone moiety. Ceratinadins A (1) and B (2) showed antifungal activity.     

Callyspongiamides A and B,sterol O-acyltransferase inhibitors,from the Indonesian marine sponge Callyspongia sp.

Callyspongiamides A (1) and B (2), two new sterol O-acyltransferase (SOAT) inhibitors, were isolated from the Indonesian marine sponge Callyspongia sp. together with a known congener, dysamide A (3). The structures of 1 and 2 were elucidated to be polychlorine-containing modified dipeptides based on their spectroscopic data. Compounds 1–3 inhibited both of the SOAT isozymes, SOAT1 and SOAT2, in cell-based and enzyme-based assays.     

Unusual C19-diterpenoid alkaloids from Aconitum vilmorinianum var. patentipilum

Three new C₁₉-diterpenoid alkaloids vilmotenitines A-C (1-3), together with seven known ones, vilmorine D (4), talatizidine (5), isotalatizidine (6), vilmorrianine B (7), vilmorrianine D (8), talatizamine (9), 8-deacetyl-yunaconitine (10), were isolated from Aconitum vilmorinianum var. patentipilum. Vilmotenitines A (1) and B (2) are the second natural occurrences of C₁₉-diterpenoid alkaloids with a unique rearranged six-membered B ring formed by the C₍₈₎–C₍₁₀₎ linkage.     

Protoilludane sesquiterpenes from the wood decomposing fungus Granulobasidium vellereum (Ellis & Cragin) Jülich

The secondary metabolites of the saprotrophic wood-decay basidiomycete fungus Granulobasidium vellereum were studied. Six sesquiterpenes were obtained; 2-hydroxycoprinolone (1), 8-deoxy-4a-hydroxytsugicoline (2), 8-deoxydihydrotsugicoline (3), which were previously not described, radulone A and B, and coprinolone ketodiol. Additionally, base-treatment of 1 yielded the diagnostic degradation products 1a and 1b, whereas radulone A was found to form 4 under mild acidic conditions. The structures were determined by NMR, MS, CD and polarimetry, along with biosynthetic considerations. Radulone A fully inhibited the spore germination of the potentially competing fungi Phlebiopsis gigantea, Coniophora puteana and Heterobasidion occidentale at 10 μM, 500 μM and 100 μM, respectively. None of the other substances tested gave rise to any growth inhibition.     

Caulerprenylols A and B,two rare antifungal prenylated para-xylenes from the green alga Caulerpa racemosa

Two new prenylated para-xylenes, named caulerprenylols A (1) and B (2), were isolated from the green alga Caulerpa racemosa, collected from the Zhanjiang coastline, China. The structures of the two metabolites were elucidated on the basis of detailed spectroscopic analysis. This is the first report of prenylated para-xylenes from marine algae and from marine organisms as well. Moreover, caulerprenylol B (2) is also characterized by an uncommon indane ring system. In in vitro bioassays, the new compounds exhibited a broad spectrum of antifungal activity against Candida glabrata (537), Trichophyton rubrum (Cmccftla), and Cryptococcus neoformans (32609) with MIC₈₀ values between 4 and 64 μg/mL when compared to amphotericin B (MIC₈₀ values of 2.0, 1.0, and 4.0 μg/mL, respectively) as a positive control and showed no growth inhibition activity against the tumor cells HL60 and A549.     

Tetradehydrohalicyclamine B,a new proteasome inhibitor from the marine sponge Acanthostrongylophora ingens

A new halicyclamine derivative, tetradehydrohalicyclamine B (1), was isolated from the marine sponge Acanthostrongylophora ingens, along with halicyclamine B (2) as proteasome inhibitors. Compound 1 is the second example found to have a pyridinium ring in the halicyclamine family. Although the relative configuration of 2 was previously determined by X-ray crystallographic analysis, here we determined the absolute configuration of 2 by ECD experiment. Compounds 1 and 2 inhibited the constitutive proteasome as well as the immunoproteasome. The inhibitory activities of 2 were 4- to 10-fold more potent than those of 1.     

Antioxidant metabolites from marine alga-derived fungus Aspergillus wentii EN-48

Eight secondary metabolites (1–8) including a new seco-anthraquinone (wentiquinone C, 1) and a new benzamide derivative (methyl 4-(3,4-dihydroxybenzamido)butanoate, 2), as well as three other derivatives (4, 7, and 8) that were isolated from natural source for the first time, were characterized from the EtOAc extracts of the marine alga-derived endophytic fungus Aspergillus wentii EN-48. The structures of the isolated compounds were elucidated on the basis of 1D and 2D NMR experiments. Each of the isolated compounds was evaluated for α,α-diphenyl-picrylhydrazyl (DPPH) radical scavenging activity, and some of them showed potent activities with IC₅₀ values ranging from 5.2 to 99.4 μg/mL, compared to the positive control, butylated hydroxytoluene (BHT), with an IC₅₀ of 36.9 μg/mL.     

Highly diverse cembranoids from the South China Sea soft coral Sinularia scabra as a new class of potential immunosuppressive agents

The first and in-depth chemical investigation of the South China Sea soft coral Sinularia scabra has resulted to the isolation of a library of diverse cembrane type diterpenoids, including six new compounds, namely xiguscabrates A and B (1 and 2), xiguscabral A (3), xiguscabrols A and B (4 and 5), and 8-epi-xiguscabrol B (6), and twenty-seven known analogs (7–33). Their structures were elucidated by extensive spectroscopic analysis and by the comparison with literature data. In bioassay, several isolates exhibited inhibitory effects on the ConA-induced T lymphocytes and/or LPS-induced B lymphocytes proliferation. Among them, compound 24 showed considerable specific inhibition on B cell proliferation, with IC₅₀ value of 4.4 μM and selectivity index (SI) of 10.9. The structure-activity relationship (SAR) of the tested metabolites was analyzed, and the further mechanism study of the specific B-cell targeted immunosuppressive compound 24 on purified CD19⁺ B cells was also performed to uncover the effects on the function and maturity of B cells, including cytokines production, abnormal activation, antigen presenting capacity and plasma cells formation.     

Indoloditerpenes from an algicolous isolate of Aspergillus oryzae

Two new indoloditerpene derivatives asporyzin A (1) and asporyzin B (2), one new indoloditerpene asporyzin C (3), and three known related indoloditerpenes JBIR-03 (4), emindole SB (5), and emeniveol (6) were isolated from an endophytic fungus Aspergillus oryzae, isolated from the marine red alga Heterosiphonia japonica. Their structures were unambiguously established by spectroscopic techniques. In addition, all the isolates were evaluated preliminarily for insecticidal and antimicrobial activities in order to probe into their chemical defensive function. Compound 4 was more active against brine shrimp than the others, and 3 possessed potent activity against Escherichia coli.