Acremosides A-G, Sugar Alcohol-Conjugated Acyclic Sesquiterpenes from a Sponge-Derived Acremonium Species.

Seven new sugar alcohol-conjugated acyclic sesquiterpenes, acremosides A-G (1-7), were isolated from the cultures of the sponge-associated fungus Acremonium sp. IMB18-086 cultivated with heat-killed Pseudomonas aeruginosa. The structures were determined by comprehensive analyses of 1D and 2D NMR spectroscopic data. The relative configurations were established by J-based configuration analysis and acetonide derivatization. The absolute configurations were elucidated by the Mosher ester method and ECD calculations. The structures of acremosides E-G (5-7) featured the linear sesquiterpene skeleton with a tetrahydrofuran moiety attached to a sugar alcohol. Acremosides A (1) and C-E (3-5) showed significant inhibitory activities against hepatitis C virus (EC50 values of 4.8-8.8 µM) with no cytotoxicity (CC50 of >200 µM).

Antimicrobial and Anti-inflammatory Cyclic Tetrapeptides from the Co-cultures of Two Marine-Derived Fungi.

Violaceotides B-E (1-4), four new cyclic tetrapeptides, along with seven known compounds, were identified from the sponge-associated Aspergillus insulicola IMB18-072 co-cultivated with the marine-derived Alternaria angustiovoidea IMB20-805. Their structures were elucidated by extensive analysis of spectroscopic data, including HRESIMS, 1D and 2D NMR, and MS/MS data. The absolute configurations were determined by the advanced Marfey's method. Compounds 2, 3, and violaceotide A (5) displayed selective antimicrobial activities against the aquatic pathogenic bacteria Edwardsiella tarda and E. ictaluri. In addition, compounds 1-5 showed inhibitory activities against the LPS-induced expression of the inflammatory mediator IL-6 in RAW264.7 cells at a concentration of 10 µM.

Chromomycins from soil-derived Streptomyces sp. inhibit the growth of human non-small cell lung cancer cells by targeting c-FLIP.

Three chromomycin derivatives, chromomycins A3 (1, CA3), A5 (2, CA5), and monodeacetylchromomycin A3 (3, MDA-CA3), were identified from the soil-derived Streptomyces sp. CGMCC 26516. A reinvestigation of the structure of CA5 is reported, of which the absolute configuration was unambiguously determined for the first time to be identical with that of CA3 based on nuclear magnetic resonance (NMR) data analysis as well as NMR and electronic circular dichroism calculations. Compounds 1-3 showed potent cytotoxicity against the non-small-cell lung cancer (NSCLC) cells (A549, H460, H157-c-FLIP, and H157-LacZ) and down-regulated the protein expression of c-FLIP in A549 cells. The IC50 values of chromomycins in H157-c-FLIP were higher than that in H157-LacZ. Furthermore, si-c-FLIP promoted anti-proliferation effect of chromomycins in NSCLC cells. In nude mice xenograft model, 1 and 2 both showed more potent inhibition on the growth of H157-lacZ xenografts than that of H157-c-FLIP xenografts. These results verify that c-FLIP mediates the anticancer effects of chromomycins in NSCLC.

Anti-Biofilm Activity of Cocultimycin A against Candida albicans.

Candida albicans (C. albicans), the most common fungal pathogen, has the ability to form a biofilm, leading to enhanced virulence and antibiotic resistance. Cocultimycin A, a novel antifungal antibiotic isolated from the co-culture of two marine fungi, exhibited a potent inhibitory effect on planktonic C. albicans cells. This study aimed to evaluate the anti-biofilm activity of cocultimycin A against C. albicans and explore its underlying mechanism. Crystal violet staining showed that cocultimycin A remarkably inhibited biofilm formation in a dose-dependent manner and disrupted mature biofilms at higher concentrations. However, the metabolic activity of mature biofilms treated with lower concentrations of cocultimycin A significantly decreased when using the XTT reduction method. Cocultimycin A could inhibit yeast-to-hypha transition and mycelium formation of C. albicans colonies, which was observed through the use of a light microscope. Scanning electron microscopy revealed that biofilms treated with cocultimycin A were disrupted, yeast cells increased, and hypha cells decreased and significantly shortened. The adhesive ability of C. albicans cells treated with cocultimycin A to the medium and HOEC cells significantly decreased. Through the use of a qRT-PCR assay, the expression of multiple genes related to adhesion, hyphal formation and cell membrane changes in relation to biofilm cells treated with cocultimycin A. All these results suggested that cocultimycin A may be considered a potential novel molecule for treating and preventing biofilm-related C. albicans infections.

Zelkovamycins F and G, Cyclopeptides with Cα-Methyl-threonine Residues, from an Endophytic Kitasatospora sp.

Zelkovamycins F and G (1 and 2), two new natural cyclic octapeptides possessing the unprecedented nonproteinogenic amino acid residues l-α-methyl-threonine and l-α-methyl-allo-threonine, respectively, along with four new analogues, zelkovamycins H-K (3-6), were identified from the endophytic Kitasatospora sp. CPCC 204717. Their structures were elucidated by detailed analysis of NMR and HRESIMS/MS spectroscopic data. The configurations of amino acid residues were determined by Marfey's analysis combined with NMR calculations. Compounds 1, 2, and 4 showed potent antibacterial activity against methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis. The structure-activity relationship study revealed that the 2-methyl-3-oxobutyrine and sarcosine residues played important roles in their antibacterial activities. Zelkovamycin (7) and zelkovamycin E (8) exhibited significant antiviral activity against the hepatitis C virus.

Antimicrobial alkaloids from the root bark of Dictamnus dasycarpus.

Two new furoquinoline alkaloids, named 1'-oxo-isoplatydesmine (1) and demethoxyacrophylline (2), as well as 11 known alkaloids (3-13) were isolated from the root bark of Dictamnus dasycarpus Turcz. The structures of 1 and 2 were established by detailed spectroscopic elucidation, such as 1 D & 2 D NMR and HRMS, etc. The unexpected autoracemization of 1 was discussed based on the stereochemistry of reported dihydrofuroquinolines. Compounds 3-5 exhibited moderate inhibitory activities against Bacillus subtilis, Candida albicans, and Pseudomonas aeruginosa with MICs 32-64 µg/ml, revealing the active principles of D. dasycarpus for treating skin diseases in its traditional usage.

Illihenin A: An Antiviral Sesquiterpenoid with a Cage-like Tricyclo[6.2.2.01,5]dodecane Skeleton from Illicium henryi.

Illihenin A (1), a novel sesquiterpenoid, was isolated from the roots of Illicium henryi. The structure was determined by spectroscopic analyses, ECD calculation, and single-crystal X-ray diffraction. Compound 1 represents a class of novel 5/7/6 tricyclic sesquiterpenoids featuring a rare cage-like tricyclo[6.2.2.01,5]dodecane core. A plausible biosynthetic pathway of 1 by rearrangement of allo-cedrane is proposed. Additionally, 1 showed potent antiviral activity against coxsackievirus B3 with an IC50 value of 2.87 µM.

Acremopeptaibols A-F, 16-Residue Peptaibols from the Sponge-Derived Acremonium sp. IMB18-086 Cultivated with Heat-Killed Pseudomonas aeruginosa.

Six new 16-residue peptaibols, acremopeptaibols A-F (1-6), along with five known compounds, were isolated from the cultures of the sponge-associated fungus Acremonium sp. IMB18-086 grown in the presence of the autoclaved bacterium Pseudomonas aeruginosa on solid rice medium. The peptaibol sequences were established based on comprehensive analysis of 1D and 2D NMR spectroscopic data in conjunction with HRESIMS/MS experiments. The configurations of the amino acid residues were determined by advanced Marfey's analysis. Compounds 1-6 feature the lack of the highly conserved Thr6 and Hyp10 residues in comparison with other members of the SF3 subfamily peptaibols. A plausible biosynthetic pathway of compounds 1-6 was proposed on the basis of genomic analysis. Compounds 1, 5, 7, and 10 exhibited significant antimicrobial activity against Staphylococcus aureus, methicillin-resistant S. aureus, Bacillus subtilis, and Candida albicans. Compounds 7-10 showed potent cytotoxicities against the A549 and/or HepG2 cancer cell lines.

Raistrickindole A, an Anti-HCV Oxazinoindole Alkaloid from Penicillium raistrickii IMB17-034.

Raistrickindole A (1), a new indole diketopiperazine alkaloid containing an unusual pyrazino[1',2':2,3][1,2]oxazino[6,5- b]indole tetraheterocyclic ring system, a new benzodiazepine derivative, raistrickin (2), and the known haenamindole (3) and sclerotigenin (4) were isolated from the marine-derived fungus Penicillium raistrickii IMB17-034. Their structures were elucidated by extensive spectroscopic analyses and TDDFT calculations of the NMR and ECD data. Compounds 1 and 2 showed inhibitory activities against the hepatitis C virus.

Tetracenomycin X Exerts Antitumour Activity in Lung Cancer Cells through the Downregulation of Cyclin D1.

Tetracenomycin X (Tcm X) has been reported to have antitumour activity in various cancers, but there have not been any studies on its activity with respect to lung cancer to date. Therefore, this study aims to investigate the anti-lung cancer activity of Tcm X. In this study, we found that tetracenomycin X showed antitumour activity in vivo and selectively inhibited the proliferation of lung cancer cells without influencing lung fibroblasts. In addition, apoptosis and autophagy did not contribute to the antitumour activity. Tetracenomycin X exerts antitumour activity through cell cycle arrest induced by the downregulation of cyclin D1. To explore the specific mechanism, we found that tetracenomycin X directly induced cyclin D1 proteasomal degradation and indirectly downregulated cyclin D1 via the activation of p38 and c-JUN proteins. All these findings were explored for the first time, which indicated that tetracenomycin X may be a powerful antimitotic class of anticancer drug candidates for the treatment of lung cancer in the future.

Broad-Spectrum Antiviral Natural Products from the Marine-Derived Penicillium sp. IMB17-046.

A new pyrazine derivative, trypilepyrazinol (1), a new α-pyrone polyketide, (+)-neocitreoviridin (2), and a new ergostane analogue, 3ß-hydroxyergosta-8,14,24(28)-trien-7-one (3), were isolated and characterized along with five known compounds from the marine-derived fungus Penicillium sp. IMB17-046. The structures of these new compounds were determined using spectroscopic data analyses (HRESIMS, 1D- and 2D-NMR), X-ray crystallography analysis, and TDDFT ECD calculation. Compounds 1 and 3 exhibited broad-spectrum antiviral activities against different types of viruses, including human immunodeficiency virus (HIV), hepatitis C virus (HCV), and influenza A virus (IAV), with IC50 values ranging from 0.5 to 7.7 µM. Compounds 1 and 2 showed antibacterial activities against Helicobacter pylori, a causative pathogen of various gastric diseases, with minimum inhibitory concentration (MIC) values of 1-16 µg/mL.

Identification and Proposed Relative and Absolute Configurations of Niphimycins C-E from the Marine-Derived Streptomyces sp. IMB7-145 by Genomic Analysis.

Analysis of the whole genome sequence of Streptomyces sp. IMB7-145 revealed the presence of seven type I polyketide synthase biosynthetic gene clusters, one of which was highly homologous to the biosynthetic gene cluster of azalomycin F. Detailed bioinformatic analysis of the modular organization of the PKS gene suggested that this gene is responsible for niphimycin biosynthesis. Guided by genomic analysis, a large-scale cultivation ultimately led to the discovery and characterization of four new niphimycin congeners, namely, niphimycins C-E (1-3) and 17-O-methylniphimycin (4). The configurations of most stereocenters of niphimycins have not been determined to date. In the present study, the relative configurations were elucidated by spectroscopic analysis, including J-based analysis and the CNMR database method. Further, the full absolute configurations of niphimycins were completely proposed for the first time based on biosynthetic gene cluster analysis of the ketoreductase and enoylreductase domains for hydroxy- and methyl-bearing stereocenters. Compounds 1, 3, 4, and niphimycin Iα (5) showed antimicrobial activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci (MIC: 8-64 µg/mL), as well as cytotoxicity against the human HeLa cancer cell line (IC50: 3.0-9.0 µM). In addition, compounds 1 and 5 displayed significant activity against several Mycobacterium tuberculosis clinical isolates (MIC: 4-32 µg/mL).

Seco-Tetracenomycins from the Marine-Derived Actinomycete Saccharothrix sp. 10-10.

Six new tetracenomycin congeners, saccharothrixones E⁻I (1⁻5) and 13-de-O-methyltetracenomycin X (6), were isolated from the rare marine-derived actinomycete Saccharothrix sp. 10-10. Their structures were elucidated by spectroscopic analysis and time-dependent density functional theory (TDDFT)-electronic circular dichroism (ECD) calculations. Saccharothrixones G (3) and H (4) are the first examples of tetracenomycins featuring a novel ring-A-cleaved chromophore. Saccharothrixone I (5) was determined to be a seco-tetracenomycin derivative with ring-B cleavage. The new structural characteristics, highlighted by different oxidations at C-5 and cleavages in rings A and B, enrich the structural diversity of tetracenomycins and provide evidence for tetracenomycin biosynthesis. Analysis of the structure⁻activity relationship of these compounds confirmed the importance of the planarity of the naphthacenequinone chromophore and the methylation of the polar carboxy groups for tetracenomycin cytotoxicity.

Saccharothrixones A-D, Tetracenomycin-Type Polyketides from the Marine-Derived Actinomycete Saccharothrix sp. 10-10.

Saccharothrixones A-C (1-3), three new aromatic polyketide seco-tetracenomycins, and saccharothrixone D (4), a new tetracenomycin analogue possessing opposite configurations at all of the stereogenic centers, were isolated from the marine-derived actinomycete Saccharothrix sp. 10-10. Compounds 1-3 represent the first examples of seco-tetracenomycins where the quinone ring B is cleaved and re-formed into a furanone ring. Their structures were elucidated by spectroscopic analyses and ECD calculations. The absolute configuration of 4 was confirmed by single-crystal X-ray diffraction analysis. Saccharothrixone D (4) showed in vitro cytotoxic activity against the HepG2 cancer cell line with an IC50 value of 7.5 µM.

Chemical constituents from branch of Fraxinus sieboldiana.

Using a combination of various chromatographic techniques including column chromatography over silica gel, Sephadex LH-20, macroporous adsorbent resin, and reversed-phase HPLC, 115 compounds including diterpenes, sesquiterpenes, treterpenes, coumarins, lignans, fatty acid derivatives, and simple aromatic derivatives were isolated from an ethanol extract of branch of Fraxinus sieboldiana (Oleaceaue), and their structures of the compounds were elucidated by spectroscopic methods including 1 D, 2D NMR and MS techniques. Among them, 41 compounds were new. In previous reports, we have been described the isolation, structure elucidation, and bioactivities of the 41 new compounds and 22 known orii including 8 coumarins, 4 phenolic and 12 phenylethanoidal glycosides. As a consequence, we herein reported the isolation and structure elucidation of the remaining 50 known compounds including 8- hydroxy-12-oxoabieta-9(11),13-dien-20-oic 8, 20-lactone(1), 6beta-hydroxyfcrruginol(2),(+)-pisiferic acid(3), (+)-pisiferal(4),(+)-7-dehydroabiet6none(5), 1-oxomiltirone(6), subdigitatone(7), linarionoside B(8), (9S)-linarionoside B(9), (3R,9R)-3-hydroxy-7,8-dihydro-beta-ionol 9-O-beta-D-apiofuranosyl-(1-->6)-beta-D-glucopyranoside(10), ursolic acid(11), betulinic acid(12), euscaphic acid(13), (+)-syringaresinol(14), (+)-fraxiresinol(15), (+)-1-hydroxysyringaresinol(16), pinoresinol(17), medioresinol(18), 8-acetoxypinoresinol(19), epipinoresinol(20), (-)-olivil(21), (+)-cyclo-olivil(22), 3,3'-dimethoxy-4,4',9-trihydroxy-7,9'-epoxylignan-7'-one(23),(+)-1-hydroxypinoresinol 4'-O-beta-D-glucopyranoside (24), (+)-1-hydroxypinoresinol 4"-O-beta-D-glucopyranoside(25),(+)-syringaresinol O-beta-D-glucopyranoside (26), liriodendrin (27), ehletianol D(28), icariside E5(29) (-)-(7R, 8R)-threo-1-C-syringylglycerol(30),(-)-(7R, 8S)-erythro-guaiacylglycerol (31),(-)-(7R, 8R)-threo-guaiacylglycerol(32), 3-(4-beta-D-glucopyranosyloxy-3-methoxy)-phenyl-2E-propenol(33),2,3-dihydroxy-l-(4-hydroxy-3,5-dimethoxyphenyl)-1-propanone(34), 2,3-dihydroxy-1-(4-hydroxy-3-methoxyphenyl)-1-propanone (35), 3-hydroxy-l-(4-hydroxy-3,5-dimethoxyphenyl)-1-propanone(36), omega-hydroxypropioguaiacone(37), sinapyladehyde(38), trans-p-hydroxycinnamaldehyde(39), syringic acid(40), vanilic acid(41), vanillin(42), 4-hydroxy-benzaldehyde (43), (24R)-24-ethyl-5alpha-cholestane-3beta,5,6beta-triol(44), beta-sitosterol(45), daucosterol(46), 2,6-dimethoxy-I,4-benzoquinone(47), 2,6-dimethoxy-pyran-4-one(48), 1-(beta-D-ribofuranosyl)uracil(49), and mannitol(50). Compouds 1-7,12,18,28-37,44 and 48 were obtained from the genus Fraxinus for the first time.

[Identification of tetracenomycin X from a marine-derived Saccharothrix sp. guided by genes sequence analysis].

The crude extracts of the fermentation broth from a marine sediment-derived actinomycete strain, Saccharothrix sp. 10-10, showed significant antibacterial activities against drug-resistant pathogens. A genome-mining PCR-based experiment targeting the genes encoding key enzymes involved in the biosynthesis of secondary metabolites indicated that the strain 10-10 showed the potential to produce tetracenomycin-like compounds. Further chemical investigation of the cultures of this strain led to the identification of two antibiotics, including a tetracenomycin (Tcm) analogs, Tcm X (1), and a tomaymycin derivative, oxotomaymycin (2). Their structures were identified by spectroscopic data analysis, including UV, 1D-NMR, 2D-NMR and MS spectra. Tcm X (1) showed moderate antibacterial activities against a number of drug-resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) pathogens, with the MIC values in the range of 32-64 microg x mL(-1). In addition, 1 also displayed significant cytotoxic activities against human cancer cell lines, including HL60 (leukemia), HepG2 (liver), and MCF-7 (breast) with the IC 50 values of 5.1, 9.7 and 18.0 micromol x L(-1), respectively. Guided by the PCR-based gene sequence analysis, Tcm X (1) and oxotomaymycin (2) were identified from the genus of Saccharothrix and their 13C NMR data were correctly assigned on the basis of 2D NMR spectroscopic data analysis for the first time.

Quinomycins with an unusual N-methyl-3-methylsulfinyl-alanine residue from a Streptomyces sp.

Four new echinomycin congeners, quinomycins M-P (1-4) were isolated from the cultures of the soil-derived Streptomyces sp. CPCC205575. The planar structures were determined by comprehensive analyses of NMR and HRESIMS/MS data. The absolute configurations were elucidated by the advanced Marfey's method combined with biosynthetic gene analysis. Compounds 1-4 represent the first examples of quinomycin-type natural products with the sulfur atom at the N,S-dimethylcysteine residue oxidized as a sulfoxide group forming the unusual N-methyl-3-methylsulfinyl-alanine residue. Bioassay results revealed that the oxidation of the sulfur atom at the Cys or Cys' residues led to dramatic decrease of cytotoxicity and antimicrobial activity.

Polyketides with New Delhi metallo-ß-lactamase 1 inhibitory activity from Penicillium sp.

Three new polyketide compounds (1-3), a new quinolone alkaloid (4), and seven known polyketide derivatives were identified from the cultures of Penicillium sp. I09F 484, a strain isolated from the rhizosphere soil of the plant Picea asperata from Kanas Lake, Xinjiang, China. Their structures were elucidated by extensive spectroscopic data analysis. The absolute configurations of 1 and 4 were established by quantum chemical time-dependent density functional theory electronic circular dichroism calculation and Marfey's method, respectively. Compounds 1 and 2 displayed inhibitory activity against New Delhi metallo-ß-lactamase 1 with IC50 values of 94.9 and 87.9 µM, respectively.

Identification of elaiophylin derivatives from the marine-derived actinomycete Streptomyces sp. 7-145 using PCR-based screening.

A PCR-based genetic screening experiment targeting the dTDP-glucose-4,6-dehydratase gene revealed that a marine sediment-derived strain, Streptomyces sp. 7-145, had the potential to produce glycosidic antibiotics. Chemical investigation of culture extracts of this strain yielded two new 6-deoxyhexose-containing antibiotics, 11',12'-dehydroelaiophylin (1) and 11,11'-O-dimethyl-14'-deethyl-14'-methylelaiophylin (2), together with four known elaiophylin analogues (3-6). Their structures were determined by extensive NMR, MS, and CD analyses. Compounds 1, 3, 4, and 6 showed good antibacterial activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci pathogens.

19-[(1'S,4'R)-4'-Hydroxy-1'-methoxy-2'-oxopentyl]geldanamycin, a natural geldanamycin analogue from Streptomyces hygroscopicus 17997.

A novel natural geldanamycin analogue was discovered in Streptomyces hygroscopicus 17997. Its 4,5-dihydro form was also identified in the gdmP gene disruption mutant of Streptomyces hygroscopicus 17997. The structures of the two compounds were determined to be 19-[(1'S,4'R)-4'-hydroxy-1'-methoxy-2'-oxopentyl]geldanamycin (1) and 19-[(1'S,4'R)-4'-hydroxy-1'-methoxy-2'-oxopentyl]-4,5-dihydrogeldanamycin (2), respectively, by extensive spectroscopic data analysis, including 2D NMR, modified Mosher's method, and electronic circular dichroism. Compared to geldanamycin, 1 and 2 showed increased water solubility and decreased cytotoxicity against HepG2 cells.