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.     

Four New Chloro-Eremophilane Sesquiterpenes from an Antarctic Deep-Sea Derived Fungus,Penicillium sp. PR19N-1

A new chloro-trinoreremophilane sesquiterpene 1, three new chlorinated eremophilane sesquiterpenes 2–4, together with a known compound, eremofortine C (5), were isolated from an Antarctic deep-sea derived fungus, Penicillium sp. PR19N-1. Structures were established using IR, HRMS, 1D and 2D NMR techniques. In addition, the plausible metabolic network of these isolated products is proposed. Compound 1 showed moderate cytotoxic activity against HL-60 and A549 cancer cell lines.     

Three New Resveratrol Derivatives from the Mangrove Endophytic Fungus Alternaria sp.

Three new resveratrol derivatives, namely, resveratrodehydes A–C (1–3), were isolated from the mangrove endophytic fungus Alternaria sp. R6. The structures of these compounds were elucidated by analysis of their MS, 1D and 2D NMR spectroscopic data. All compounds showed broad-spectrum inhibitory activities against three human cancer cell lines including human breast MDA-MB-435, human liver HepG2, and human colon HCT-116 by MTT assay (IC₅₀ < 50 μM). Among them, compounds 1 and 2 both exhibited marked cytotoxic activities against MDA-MB-435 and HCT-116 cell lines (IC₅₀ < 10 μM). Additionally, compounds 1 and 3 showed moderate antioxidant activity by DPPH radical scavenging assay.     

Hemimycalins C–E; Cytotoxic and Antimicrobial Alkaloids with Hydantoin and 2-Iminoimidazolidin-4-one Backbones from the Red Sea Marine Sponge Hemimycale sp.

In the course of our continuing efforts to identify bioactive secondary metabolites from Red Sea marine sponges, we have investigated the sponge Hemimycale sp. The cytotoxic fraction of the organic extract of the sponge afforded three new compounds, hemimycalins C–E (1–3). Their structural assignments were obtained via analyses of their one- and two-dimensional NMR spectra and HRESI mass spectrometry. Hemimycalin C was found to differ from the reported hydantoin compounds in the configuration of the olefinic moiety at C-5–C-6, while hemimycalins D and E were found to contain an 2-iminoimidazolidin-4-one moiety instead of the hydantoin moiety in previously reported compounds from the sponge. Hemimycalins C–E showed significant antimicrobial activity against Escherichia coli and Candida albicans and cytotoxic effects against colorectal carcinoma (HCT 116) and the triple-negative breast cancer (MDA-MB-231) cells.     

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.     

Novel Adociaquinone Derivatives from the Indonesian Sponge Xestospongia sp.

Seven new adociaquinone derivatives, xestoadociaquinones A (1a), B (1b), 14-carboxy-xestoquinol sulfate (2) and xestoadociaminals A–D (3a, 3c, 4a, 4c), together with seven known compounds (5–11) were isolated from an Indonesian marine sponge Xestospongia sp. Their structures were elucidated by extensive 1D and 2D NMR and mass spectrometric data. All the compounds were evaluated for their potential inhibitory activity against eight different protein kinases involved in cell proliferation, cancer, diabetes and neurodegenerative disorders as well as for their antioxidant and antibacterial activities.     

Isolation of Scalarane-Type Sesterterpenoids from the Marine Sponge Dysidea sp. and Stereochemical Reassignment of 12-epi-Phyllactone D/E

The chemical investigation of the marine sponge Dysidea sp., which was collected from Bohol province in the Philippines, resulted in the identification of 15 new scalarane-type sesterterpenoids (1–14, 16), together with 15 known compounds. The chemical structures of the new compounds were elucidated based on NMR spectroscopy and HRMS. The structure of 12-epi-phyllactone D/E (15) isolated during this study was originally identified in 2007. However, careful inspection of our experimental ¹³C NMR spectrum revealed considerable discrepancies with the reported data at C-9, C-12, C-14, and C-23, leading to the correction of the reported compound to the C-12 epimer of 15, phyllactone D/E. The biological properties of compounds 1–16 were evaluated using the MDA-MB-231 cancer cell line. Compound 7, which bears a pentenone E-ring, exhibits significant cytotoxicity with a GI₅₀ value of 4.21 μM.     

Bioactive Chaetoglobosins from the Mangrove Endophytic Fungus Penicillium chrysogenum

A novel chaetoglobosin named penochalasin I (1) with a unprecedented six-cyclic 6/5/6/5/6/13 fused ring system, and another new chaetoglobosin named penochalasin J (2), along with chaetoglobosins G, F, C, A, E, armochaetoglobosin I, and cytoglobosin C (3–9) were isolated from the culture of Penicillium chrysogenum V11. Their structures were elucidated by 1D, 2D NMR spectroscopic analysis and high resolution mass spectroscopic data. The absolute configuration of compounds 1 and 2 were determined by comparing the theoretical electronic circular dichroism (ECD) calculation with the experimental CD. Compound 1 was the first example, with a six-cyclic fused ring system formed by the connection of C-5 and C-2′ of the chaetoglobosin class. Compounds 5–8 remarkably inhibited the plant pathogenic fungus R. solani (minimum inhibitory concentrations (MICs) = 11.79–23.66 μM), and compounds 2, 6, and 7 greatly inhibited C. gloeosporioides (MICs = 23.58–47.35 μM), showing an antifungal activity higher than that of carbendazim. Compound 1 exhibited marked cytotoxicity against MDA-MB-435 and SGC-7901 cells (IC₅₀ < 10 μM), and compounds 6 and 9 showed potent cytotoxicity against SGC-7901 and A549 cells (IC₅₀ < 10 μM).     

Three bianthraquinone derivatives from the mangrove endophytic fungus Alternaria sp. ZJ9-6B from the South China Sea

Three new bianthraquinone derivatives, alterporriol K (1), L (2) and M (3), along with six known compounds were obtained from extracts of the endophytic fungus Alternaria sp. ZJ9-6B, isolated from the mangrove Aegiceras corniculatum collected in the South China Sea. Their structures were elucidated by one- and two-dimensional NMR spectroscopy, MS data analysis and circular dichroism measurements. Compounds 1, 2 and 3 were first isolated alterporriols with a C-2–C-2′ linkage. The crystallographic data of tetrahydroaltersolanol B (7) was reported for the first time. In the primary bioassays, alterporriol K and L exhibited moderate cytotoxic activity towards MDA-MB-435 and MCF-7 cells with IC₅₀ values ranging from 13.1 to 29.1 μM.     

New Dimeric Members of the Phomoxanthone Family: Phomolactonexanthones A,B and Deacetylphomoxanthone C Isolated from the Fungus Phomopsis sp.

Three new phomoxanthone compounds, phomolactonexanthones A (1), B (2) and deacetylphomoxanthone C (3), along with five known phomoxanthones, including dicerandrol A (4), dicerandrol B (5), dicerandrol (6), deacetylphomoxanthone B (7) and penexanthone A (8), were isolated in the metabolites of the fungus Phomopsis sp. HNY29-2B, which was isolated from the mangrove plants. The structures of compounds 1–3 were established on the basis of spectroscopic analysis. All compounds were evaluated against four human cancer cell lines including human breast MDA-MB-435, human colon HCT-116, human lung Calu-3 and human liver Huh7 by MTT assay. The compounds 4, 5, 7 and 8 showed cyctotoxic activities against tested cancer cell lines (IC₅₀ < 10 μM).     

Neuroprotective Metabolites from Vietnamese Marine Derived Fungi of Aspergillus and Penicillium Genera

Low molecular weight secondary metabolites of marine fungi Aspergillus flocculosus, Aspergillus terreus and Penicillium sp. from Van Phong and Nha Trang Bays (Vietnam) were studied and a number of polyketides, bis-indole quinones and terpenoids were isolated. The structures of the isolated compounds were determined by 1D and 2D NMR and HR-ESI-MS techniques. Stereochemistry of some compounds was established based on ECD data. A chemical structure of asterriquinone F (6) was thoroughly described for the first time. Anthraquinone (13) was firstly obtained from a natural source. Neuroprotective influences of the isolated compounds against 6-OHDA, paraquat and rotenone toxicity were investigated. 4-Hydroxyscytalone (1), 4-hydroxy-6-dehydroxyscytalone (2) and demethylcitreoviranol (3) have shown significant increasing of paraquat- and rotenone-treated Neuro-2a cell viability and anti-ROS activity.     

Didemnaketals F and G,New Bioactive Spiroketals from a Red Sea Ascidian Didemnum Species

In continuation of our ongoing efforts to identify bioactive compounds from Red Sea marine organisms, a new collection of the ascidian Didemnum species was investigated. Chromatographic fractionation and HPLC purification of the CH₂Cl₂ fraction of an organic extract of the ascidian resulted in the identification of two new spiroketals, didemnaketals F (1) and G (2). The structure determination of the compounds was completed by extensive study of 1D (¹H, ¹³C, and DEPT) and 2D (COSY, HSQC, and HMBC) NMR experiments in addition to high-resolution mass spectral data. Didemnaketal F (1) and G (2) differ from the previously reported compounds of this class by the lack the terminal methyl ester at C-1 and the methyl functionality at C-2. Instead, 1 and 2 possess a methyl ketone moiety instead of the terminal ester. Furthermore, didemnaketal F possesses a disubstituted double bond between C-2 and C-3, while the double bond was replaced by a secondary alcohol at C-3 in didemnaketal G. In addition, they possess the unique spiroketal/hemiketal functionality which was previously reported in didemnaketal E. Didemnaketals F (1) and G (2) displayed moderate activity against HeLa cells with of IC_50s of 49.9 and 14.0 µM, respectively. In addition, didemnaketal F (1) displayed potent antimicrobial activity against E. coli and C. albicans. These findings provide further insight into the biosynthetic capabilities of this ascidian and the chemical diversity as well as the biological activity of this class of compounds.     

Bioactive Hydantoin Alkaloids from the Red Sea Marine Sponge Hemimycale arabica

In the course of our continuing efforts to identify bioactive secondary metabolites from Red Sea marine invertebrates, we have investigated the sponge Hemimycale arabica. The antimicrobial fraction of an organic extract of the sponge afforded two new hydantoin alkaloids, hemimycalins A and B (2 and 3), together with the previously reported compound (Z)-5-(4-hydroxybenzylidene)imidazolidine-2,4-dione (1). The structures of the compounds were determined by extensive 1D and 2D NMR (COSY, HSQC and HMBC) studies and high-resolution mass spectral determinations. Hemimycalins A (2) and B (3) represent the first examples of the natural N-alkylated hydantoins from the sponge Hemimycale arabica. Compounds 1–3 displayed variable antimicrobial activities against E. coli, S. aureus, and C. albicans. In addition, compound 1 displayed moderate antiproliferative activity against the human cervical carcinoma (HeLa) cell line. These findings provide further insight into the chemical diversity as well as the biological activity of this class of compounds.     

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).     

An Unusual Conformational Isomer of Verrucosidin Backbone from a Hydrothermal Vent Fungus,Penicillium sp. Y-50-10

A new verrucosidin derivative, methyl isoverrucosidinol (1), was isolated from the marine fungus Penicillium sp. Y-50-10, dwelling in sulfur rich sediment in the Kueishantao hydrothermal vents off Taiwan. The structure was established by spectroscopic means including HRMS and 2D-NMR spectroscopic analysis. The absolute configuration was defined mainly by comparison of quantum chemical TDDFT calculated and experimental ECD spectra. Among hitherto known compounds with a verrucosidine backbone isolated from natural resource, compound 1 represents the first example of a new conformational isomer of its skeleton, exhibiting antibiotic activity against Bacillus subtilis with MIC value 32 μg/mL.     

Four eremophilane sesquiterpenes from the mangrove endophytic fungus Xylaria sp. BL321

Three new eremophilane sesquiterpenes (1–3) were isolated from the mangrove endophytic fungus Xylaria sp. BL321 together with 07H239-A (4), a known analogue of the new compounds. The structures of these compounds were elucidated by analysis of their MS, 1D and 2D NMR spectroscopic data. Compound 4 showed activation activity on α-glucosidase at 0.15 μM (146%), and then, 4 gradually produced inhibitory activity on α-glucosidase with increasing concentration, and the IC₅₀ value is 6.54 μM.     

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.     

Cytotoxic and Antibacterial Angucycline- and Prodigiosin- Analogues from the Deep-Sea Derived Streptomyces sp. SCSIO 11594

Two new C-glycoside angucyclines, marangucycline A (1) and marangucycline B (2), along with three known compounds, dehydroxyaquayamycin (3), undecylprodigiosin (4) and metacycloprodigiosin (5), have been identified as products of the deep-sea sediment strain Streptomyces sp. SCSIO 11594. New structures were elucidated on the basis of HRESIMS, 1D and 2D NMR analyses and comparisons to previously reported datasets. Compounds 2 and 4 displayed in vitro cytotoxicity against four cancer cell lines A594, CNE2, HepG2, MCF-7 superior to those obtained with cisplatin, the positive control. Notably, compound 2 bearing a keto-sugar displayed significant cytotoxicity against cancer cell lines with IC₅₀ values ranging from 0.24 to 0.56 μM; An IC₅₀ value of 3.67 μM was found when using non-cancerous hepatic cell line HL7702, demonstrating the cancer cell selectivity of 2. Compounds 1–3 were proved to have weak antibacterial activities against Enterococcus faecalis ATCC29212 with an MIC value of 64.0 μg/mL. Moreover, 3 displayed selective antibacterial activity against methicillin-resistant Staphylococcus epidermidis shhs-E1 with an MIC value of 16.0 μg/mL.     

Anti-Mycobacterial Nucleoside Antibiotics from a Marine-Derived Streptomyces sp. TPU1236A

Five new nucleoside antibiotics, named streptcytosines A–E (1–5), and six known compounds, de-amosaminyl-cytosamine (6), plicacetin (7), bamicetin (8), amicetin (9), collismycin B (10), and SF2738 C (11), were isolated from a culture broth of Streptomyces sp. TPU1236A collected in Okinawa, Japan. The structures of new compounds were elucidated on the basis of their spectroscopic data (HRFABMS, IR, UV, and 2D NMR experiments including ¹H-¹H COSY, HMQC, HMBC, and NOESY spectra). Streptcytosine A (1) belonged to the amicetin group antibiotics, and streptcytosines B–E (2–5) were derivatives of de-amosaminyl-cytosamine (6), 2,3,6-trideoxyglucopyranosyl cytosine. Compound 1 inhibited the growth of Mycobacterium smegmatis (MIC = 32 µg/mL), while compounds 2–5 were not active at 50 µg/disc. Bamicetin (8) and amicetin (9) showed the MICs of 16 and 8 µg/mL, respectively.     

New Drimane Sesquiterpenes and Polyketides from Marine-Derived Fungus Penicillium sp. TW58-16 and Their Anti-Inflammatory and α-Glucosidase Inhibitory Effects

Marine fungi-derived natural products represent an excellent reservoir for the discovery of novel lead compounds with biological activities. Here, we report the identification of two new drimane sesquiterpenes (1 and 2) and six new polyketides (3–8), together with 10 known compounds (9–18), from a marine-derived fungus Penicillium sp. TW58-16. The planar structures of these compounds were elucidated by extensive 1D and 2D NMR, which was supported by HR-ESI-MS data. The absolute configurations of these compounds were determined by experimental and calculated electronic circular dichroism (ECD), and their optical rotations compared with those reported. Evaluation of the anti-inflammatory activity of compounds 1–18 revealed that compound 5 significantly inhibited the release of nitric oxide (NO) induced by lipopolysaccharide (LPS) in RAW264.7 cells, correlating with the inhibition of expression of inducible nitric oxide synthase (iNOS). In addition, we revealed that compounds 1, 3–6, 14, 16, and 18 showed strong α-glucosidase inhibitory effects with inhibition rates of 35.4%, 73.2%, 55.6%, 74.4%, 32.0%, 36.9%, 88.0%, and 91.1%, respectively, which were comparable with or even better than that of the positive control, acarbose. Together, our results illustrate the potential of discovering new marine-based therapeutic agents against inflammation and diabetes mellitus.