Smenamides A and B,Chlorinated Peptide/Polyketide Hybrids Containing a Dolapyrrolidinone Unit from the Caribbean Sponge Smenospongia aurea. Evaluation of Their Role as Leads in Antitumor Drug Research

An in-depth study of the secondary metabolites contained in the Caribbean sponge Smenospongia aurea led to the isolation of smenamide A (1) and B (2), hybrid peptide/polyketide compounds containing a dolapyrrolidinone unit. Their structures were elucidated using high-resolution ESI-MS/MS and homo- and heteronuclear 2D NMR experiments. Structures of smenamides suggested that they are products of the cyanobacterial metabolism, and 16S rRNA metagenomic analysis detected Synechococcus spongiarum as the only cyanobacterium present in S. aurea. Smenamides showed potent cytotoxic activity at nanomolar levels on lung cancer Calu-1 cells, which for compound 1 is exerted through a clear pro-apoptotic mechanism. This makes smenamides promising leads for antitumor drug design.     

Phallusiasterols A and B: Two New Sulfated Sterols from the Mediterranean Tunicate Phallusia fumigata and Their Effects as Modulators of the PXR Receptor

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.     

Oxygenated Polyketides from Plakinastrella mamillaris as a New Chemotype of PXR Agonists

Further purification of the apolar extracts of the sponge Plakinastrella mamillaris, afforded a new oxygenated polyketide named gracilioether K, together with the previously isolated gracilioethers E–G and gracilioethers I and J. The structure of the new compound has been elucidated by extensive NMR (¹H and ¹³C, COSY, HSQC, HMBC, and ROESY) and ESI-MS analysis. With the exception of gracilioether F, all compounds are endowed with potent pregnane-X-receptor (PXR) agonistic activity and therefore represent a new chemotype of potential anti-inflammatory leads. Docking calculations suggested theoretical binding modes of the identified compounds, compatible with an agonistic activity on hPXR, and clarified the molecular basis of their biological activities.     

MDN-0170, a New Napyradiomycin from Streptomyces sp. Strain CA-271078

A new napyradiomycin, MDN-0170 (1), was isolated from the culture broth of the marine-derived actinomycete strain CA-271078, together with three known related compounds identified as 4-dehydro-4a-dechloronapyradiomycin A1 (2), napyradiomycin A1 (3) and 3-chloro-6,8-dihydroxy-8-α-lapachone (4). The structure of the new compound was determined using a combination of spectroscopic techniques, including 1D and 2D NMR and electrospray-time of flight mass spectrometry (ESI-TOF MS). The relative configuration of compound 1, which contains two independent stereoclusters, has been established by molecular modelling in combination with nOe and coupling constant analyses. Biosynthetic arguments also allowed us to propose its absolute stereochemistry. The antimicrobial properties of the compounds isolated were evaluated against methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, Aspergillus fumigatus, and Candida albicans. The potent bioactivity previously reported for compounds 2 and 3 against methicillin-sensitive S. aureus has been extended to methicillin-resistant strains in this report.     

Swinholide J, a potent cytotoxin from the marine sponge Theonella swinhoei

In our ongoing search for new pharmacologically active leads from Solomon organisms, we have examined the sponge Theonella swinhoei. Herein we report the isolation and structure elucidation of swinholide A (1) and one new macrolide, swinholide J (2). Swinholide J is an unprecedented asymmetric 44-membered dilactone with an epoxide functionality in half of the molecule. The structural determination was based on extensive interpretation of high-field NMR spectra and HRESIMS data. Swinholide J displayed potent in vitro cytotoxicity against KB cells (human nasopharynx cancer) with an IC(50) value of 6 nM.     

Isolation and Structure Elucidation of Three New Dolastanes from the Brown Alga Dilophus spiralis

Three new dolastane diterpenes (1–3) and five previously reported perhydroazulenes were isolated from the organic extracts of the brown alga Dilophus spiralis. The structure elucidation and the assignment of the relative configurations of the isolated natural products were based on extensive analyses of their spectroscopic data, whereas the absolute configuration of metabolite 2 was determined through its chemical conversion to a previously isolated compound of known configuration.     

Identification of Four New agr Quorum Sensing-Interfering Cyclodepsipeptides from a Marine Photobacterium

During our search for new natural products from the marine environment, we discovered a wide range of cyclic peptides from a marine Photobacterium, closely related to P. halotolerans. The chemical fingerprint of the bacterium showed primarily non-ribosomal peptide synthetase (NRPS)-like compounds, including the known pyrrothine antibiotic holomycin and a wide range of peptides, from diketopiperazines to cyclodepsipeptides of 500–900 Da. Purification of components from the pellet fraction led to the isolation and structure elucidation of four new cyclodepsipeptides, ngercheumicin F, G, H, and I. The ngercheumicins interfered with expression of virulence genes known to be controlled by the agr quorum sensing system of Staphylococcus aureus, although to a lesser extent than the previously described solonamides from the same strain of Photobacterium.     

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

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.     

A sterol and spiroditerpenoids from a Penicillium sp. isolated from a deep sea sediment sample

A new polyoxygenated sterol, sterolic acid (1), three new breviane spiroditerpenoids, breviones I-K (2-4), and the known breviones (5-8), were isolated from the crude extract of a Penicillium sp. obtained from a deep sea sediment sample that was collected at a depth of 5115 m. The structures of 1-4 were elucidated primarily by NMR experiments, and 1 was further confirmed by X-ray crystallography. The absolute configurations of 2 and 3 were deduced by comparison of their CD spectra with those of the model compounds. Compounds 2 and 5 showed significant cytotoxicity against MCF-7 cells, which is comparable to the positive control cisplatin.     

Pullularins E and F, two new peptides from the endophytic fungus Bionectria ochroleuca isolated from the mangrove plant Sonneratia caseolaris

Chemical investigation of the EtOAc extract of the endophytic fungus Bionectria ochroleuca, isolated from the inner leaf tissues of the plant Sonneratia caseolaris (Sonneratiaceae) from Hainan island (China), yielded two new peptides, pullularins E and F (1 and 2) together with three known compounds (3–5). The structures of the new compounds were unambiguously determined on the basis of one- and two-dimensional NMR spectroscopy as well as by high-resolution mass spectrometry. The absolute configurations of amino acids were determined by HPLC analysis of acid hydrolysates using Marfey’s method. The isolated compounds exhibited pronounced to moderate cytotoxic activity against the mouse lymphoma cells (L5178Y) with EC₅₀ values ranging between 0.1 and 6.7 µg/mL.     

Identification of Plakortide E from the Caribbean Sponge Plakortis halichondroides as a Trypanocidal Protease Inhibitor using Bioactivity-Guided Fractionation

In this paper, we report new protease inhibitory activity of plakortide E towards cathepsins and cathepsin-like parasitic proteases. We further report on its anti-parasitic activity against Trypanosoma brucei with an IC₅₀ value of 5 μM and without cytotoxic effects against J774.1 macrophages at 100 μM concentration. Plakortide E was isolated from the sponge Plakortis halichondroides using enzyme assay-guided fractionation and identified by NMR spectroscopy and mass spectrometry. Furthermore, enzyme kinetic studies confirmed plakortide E as a non-competitive, slowly-binding, reversible inhibitor of rhodesain.     

Aurantoside K, a new antifungal tetramic acid glycoside from a Fijian marine sponge of the genus Melophlus

A new tetramic acid glycoside, aurantoside K, was isolated from a marine sponge belonging to the genus Melophlus. The structure of the compound was elucidated on the basis of spectroscopic analysis (1H NMR, 1H-1H COSY, HSQC, and HMBC, as well as high-resolution ESILCMS). Aurantoside K did not show any significant activity in antimalarial, antibacterial, or HCT-116 cytotoxicity assays, but exhibited a wide spectrum of antifungal activity against wild type Candida albicans, amphotericin-resistant C. albicans, Cryptococcus neoformans, Aspergillus niger, Penicillium sp., Rhizopus sporangia and Sordaria sp.     

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.     

Woodylides A-C, new cytotoxic linear polyketides from the South China Sea sponge Plakortis simplex

Three new polyketides, woodylides A–C (1–3), were isolated from the ethanol extract of the South China Sea sponge Plakortis simplex. The structures were elucidated by spectroscopic data (IR, 1D and 2D NMR, and HRESIMS). The absolute configurations at C-3 of 1 and 3 were determined by the modified Mosher’s method. Antifungal, cytotoxic, and PTP1B inhibitory activities of these polyketides were evaluated. Compounds 1 and 3 showed antifungal activity against fungi Cryptococcus neoformans with IC₅₀ values of 3.67 and 10.85 µg/mL, respectively. In the cytotoxicity test, compound 1 exhibited a moderate effect against the HeLa cell line with an IC₅₀ value of 11.2 µg/mL, and compound 3 showed cytotoxic activity against the HCT-116 human colon tumor cell line and PTP1B inhibitory activity with IC₅₀ values of 9.4 and 4.7 µg/mL, respectively.     

Lobophytones O-T, new biscembranoids and cembranoid from soft coral Lobophytum pauciflorum

Chemical examination of a Chinese soft coral Lobophytum pauciflorum resulted in the isolation of five new biscembranoids named lobophytones O-S (1-5) and a new "monomeric" cembrane lobophytone T (6). The structures of the new compounds were elucidated by interpretation of 1D and 2D NMR (COSY, HSQC, HMBC, and NOESY) spectroscopic data in association with MS and IR data. Lobophytone Q showed significant inhibition against lipopolysaccharide (LPS)-induced nitric oxide (NO) release in mouse peritoneal macrophages, while lobophytones Q and T showed inhibitory activities against the bacteria S. aureus and S. pneumoniae.     

Briarane Diterpenoids from the Gorgonian Dichotella gemmacea

Seven new briarane diterpenoids, gemmacolides AS-AY (1–7), were isolated together with ten known analogues (8–17) from the South China Sea gorgonian Dichotella gemmacea. The structures of the new compounds were elucidated by the detailed analysis of spectroscopic data and comparison with reported data. The absolute configuration of compounds was determined based on electronic circular dichroism (ECD) experiments and genetic correlations as well. Compounds 15 and 16 were reported for the first time for the gorgonian. In the preliminary in vitro bioassays, compound 5 showed potential growth inhibitory activity against MG63 cells.     

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.     

A new diketopiperazine, cyclo-(4-S-hydroxy-R-proline-R-isoleucine), from an Australian specimen of the sponge Stelletta sp

While investigating the cytotoxic activity of the methanol extract of an Australian marine sponge Stelletta sp. (Demospongiae), a new diketopiperazine, cyclo-(4-S-hydroxy-R-proline-R-isoleucine) (1), was isolated together with the known bengamides; A (2), F (3), N (4), Y (5), and bengazoles; Z (6), C(4) (7) and C(6) (8). The isolation and structure elucidation of the diketopiperazine (1), together with the activity of 1-8 against a panel of human and mammalian cell lines are discussed.     

Isolation and Structural Characterization of a Novel Antioxidant Mannoglucan from a Marine Bubble Snail,Bullacta exarata (Philippi)

Bullacta exarata is one of the most economically important aquatic species in China, noted for not only its delicious taste and nutritional value, but also for its pharmacological activities. In order to explore its potential in medical applications, a mannoglucan designated as BEPS-IB was isolated and purified from the foot muscle of B. exarata after papain digestion. Chemical composition analysis indicated BEPS-IB contained mainly d-glucose and d-mannose in a molar ratio of 1:0.52, with an average molecular weight of about 94 kDa. The linkage information was determined by methylation analysis, and the anomeric configuration and chain linkage were confirmed by IR and 2D NMR. The results indicated BEPS-IB was composed of Glcp₆Manp heptasaccharide repeating unit in the backbone, with occasional branch chains of mannose residues (14%) occurring in the backbone mannose. Further antioxidant assay indicated BEPS-IB exhibited positive antioxidant activity in scavenging superoxide radicals and reducing power. This is the first report on the structure and bioactivity of the mannoglucan from the B. exarata.     

Capgermacrenes A and B,Bioactive Secondary Metabolites from a Bornean Soft Coral,Capnella sp.

Two new bicyclogermacrenes, capgermacrenes A (1) and B (2), were isolated with two known compounds, palustrol (3) and litseagermacrane (4), from a population of Bornean soft coral Capnella sp. The structures of these metabolites were elucidated based on spectroscopic data. Compound 1 was found to inhibit the accumulation of the LPS-induced pro-inflammatory IL-1β and NO production by down-regulating the expression of iNOS protein in RAW 264.7 macrophages.