Two New Cytotoxic Compounds from a Deep-Sea Penicillum citreonigrum XT20-134.

Penicillum citreonigrum XT20-134 (MCCC 3A00956) is a fungus with cytotoxic activity, derived from deep-sea sediment. Five new compounds, adeninylpyrenocine (1), 2-hydroxyl-3-pyrenocine-thio propanoic acid (2), ozazino-cyclo-(2,3-dihydroxyl-trp-tyr) (3), 5,5-dichloro-1-(3,5-dimethoxyphenyl)-1,4-dihydroxypentan-2-one (4), and 2,3,4-trihydroxybutyl cinnamate (5), together with 19 known compounds (6-24), were isolated from an ethyl acetate (EtOAc) extract of its fermentation. The structures of the new compounds were comprehensively characterized by high-resolution electrospray ionization-mass spectrometry (HR-ESI-MS), 1D and 2D nuclear magnetic resonance (NMR). All isolates were evaluated for their cytotoxic activities. The heteroatom-containing new compounds 2 and 4 showed potent cytotoxicity to the human hepatoma tumor cell Bel7402 with IC50 values of 7.63 ± 1.46, 13.14 ± 1.41 µM and the human fibrosarcoma tumor cell HT1080 with IC50 values of 10.22 ± 1.32, 16.53 ± 1.67 µM, respectively.

Open-Ring Butenolides from a Marine-Derived Anti-Neuroinflammatory Fungus Aspergillus terreus Y10.

To investigate structurally novel and anti-neuroinflammatory natural compounds from marine-derived microorganisms, the secondary metabolites of Aspergillus terreus Y10, a fungus separated from the sediment of the coast in the South China Sea, were studied. Three new compounds (2⁻4), with novel open-ring butenolide skeletons, were isolated from the ethyl acetate extract of the culture medium. In addition, a typical new butenolide, asperteretal F (1), was found to dose-dependently inhibit tumor necrosis factor (TNF-α) generation with an IC50 of 7.6 µg/mL. The present study shows the existence of open-ring butenolides, and suggests that butenolides such as asperteretal F (1) are a promising new anti-neuroinflammatroy candidate for neurodegenerative diseases.

Biosynthetic Functional Gene Analysis of Bis-Indole Metabolites from 25D7, a Clone Derived from a Deep-Sea Sediment Metagenomic Library.

This work investigated the metabolites and their biosynthetic functional hydroxylase genes of the deep-sea sediment metagenomic clone 25D7. 5-Bromoindole was added to the 25D7 clone derived Escherichia coli fermentation broth. The new-generated metabolites and their biosynthetic byproducts were located through LC-MS, in which the isotope peaks of brominated products emerged. Two new brominated bis-indole metabolites, 5-bromometagenediindole B (1), and 5-bromometagenediindole C (2) were separated under the guidance of LC-MS. Their structures were elucidated on the basis of 1D and 2D NMR spectra (COSY, HSQC, and HMBC). The biosynthetic functional genes of the two new compounds were revealed through LC-MS and transposon mutagenesis analysis. 5-Bromometagenediindole B (1) also demonstrated moderately cytotoxic activity against MCF7, B16, CNE2, Bel7402, and HT1080 tumor cell lines in vitro.

Macrolactins from Marine-Derived Bacillus subtilis B5 Bacteria as Inhibitors of Inducible Nitric Oxide and Cytokines Expression.

In order to find new natural products with anti-inflammatory activity, chemical investigation of a 3000-meter deep-sea sediment derived bacteria Bacillus subtilis B5 was carried out. A new macrolactin derivative was isolated and identified as 7,13-epoxyl-macrolactin A (1). Owing to the existence of the epoxy ring, 1 exhibited a significant inhibitory effect on the expression of inducible nitric oxide and cytokines, compared with previously isolated known macrolactins (2-5). Real-time Polymerase Chain Reaction (PCR) analysis showed that the new compound significantly inhibited the mRNA expressions of inducible nitric oxide synthase (iNOS), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Reverse transcription-PCR analysis demonstrated that the new compound reduced the mRNA expression level of IL-1ß in a concentration-dependent manner.

Novel N-Substituted 2-(2-(Adamantan-1-yl)-1H-Indol-3-yl)-2-Oxoacetamide Derivatives: Synthesis and Biological Evaluation.

In this study, a series of novel N-substituted 2-(2-(adamantan-1-yl)-1H-indol-3-yl)-2-oxoacetamide derivatives were synthesized, and evaluated for their cytotoxicity in human cell lines including Hela (cervical cancer), MCF7 (breast cancer ) and HepG2 (liver cancer). Several compounds were found to have potent anti-proliferative activity against those human cancer cell lines and compound 5r showed the most potent biological activity against HepG2 cells with an IC50 value of 10.56 ± 1.14 µΜ. In addition, bioassays showed that compound 5r induced time-dependent and dose-dependent cleavage of poly ADP-ribose polymerase (PARP), and also induced a dose-dependent increase in caspase-3 and caspase-8 activity, but had little effect on caspase-9 protease activity in HepG2 cells. These results provide evidence that 5r-induced apoptosis in HepG2 cell is caspase-8-dependent.

Tracing the nitrogen metabolites of glycine using (15)N-glycine and mass spectrometry.

RATIONALE: Glycine is the smallest amino acid used in protein synthesis, but it is also a very important precursor for the biosynthesis of other nitrogen-containing metabolites, such as purine nucleosides and nucleotides for synthesis of RNA, DNA etc. Abnormalities in glycine metabolism therefore cause diseases such as cancer. A quick and unambiguous method to trace the metabolites arising from glycine is required for targeting defect points within metabolic networks. METHODS: This paper describes a method for using (15)N-glycine to culture A549 cancer cells for use with high-resolution mass spectrometry (HRMS) and tandem mass spectrometry (HRMS(2)) that can detect the (M+1)/M pair peaks appearing in the cell metabolites. The 1 Da difference in the pair peaks can be used to point out and identify the nitrogen metabolites of glycine. RESULTS: Thirteen nitrogen-containing metabolites derived from glycine were confirmed. Among them were metabolites containing purine, such as adenine, adenosine, AMP, ADP, ATP, S-adenosylmethionine and γ-glutathione; these were the most sensitive to the (15)N-glycine-enrichment technique. Therefore, they are promising biomarkers for monitoring the glycine metabolism network. CONCLUSIONS: The method developed here could be applied to investigations of metabolism of other amino acids, and for drug discovery studies targeting the enzymes related to amino acid metabolism.

Two new cytotoxic indole alkaloids from a deep-sea sediment derived metagenomic clone.

Two new indole alkaloids, metagenetriindole A (1) and metagenebiindole A (2), were identified from deep-sea sediment metagenomic clone derived Escherichia coli fermentation broth. The structures of new compounds were elucidated by spectroscopic methods. The two new indole alkaloids demonstrated moderately cytotoxic activity against CNE2, Bel7402 and HT1080 cancer cell lines in vitro.

(2Z,4E)-1-(5-Fluoro-2-hy-droxy-phen-yl)-5-(4-fluoro-phen-yl)-3-hy-droxy-penta-2,4-dien-1-one.

In the title mol-ecule, C17H12F2O3, the dihedral angle between the benzene rings is 8.6 (2)°. In the crystal, two pairs of O-H⋯O hydrogen bonds connect the mol-ecules into inversion dimers. In addition, weak C-H⋯F hydrogen bonds link the dimers into a two-dimensional network parallel to (10-4). The carbonyl O atom is an acceptor for two weak intra-molecular hydrogen bonds.

Diethyl [(4-nitrobenzamido)(phen-yl)meth-yl]phospho-nate.

In the title compound, C18H21N2O6P, the dihedral angle between the benzene and phenyl rings is 85.1 (2)°. In the crystal, mol-ecules are linked via pairs of N-H⋯O(=P) hydrogen bonds, forming inversion dimers with graph-set notation R 2 (2)(10). One of the ethyl groups is disordered over two sets of sites, with occupancies 0.746 (11) and 0.254 (11).

Global trends in colorectal cancer and metabolic syndrome research: a bibliometric and visualization analysis.

Numerous studies have demonstrated a robust correlation between metabolic syndrome (MetS) and colorectal cancer (CRC). Nonetheless, no systematic analysis or visualization of relevant publications has been conducted via bibliometrics. This research, centred on 616 publications obtainable through the Web of Science Core Collection (WoSCC), employed CiteSpace software and VOSviewer software for correlation analyses of authors, journals, institutions, countries, keywords, and citations. The findings indicate that the Public Library of Science had the highest number of publications, while the United States, China, and South Korea were the most contributory nations. Recent years have seen the mechanisms linking Metabolic Syndrome with Colorectal Cancer, including diet, obesity, insulin resistance, and intestinal flora, remain a burgeoning research area. Furthermore, bariatric surgery appears to be a promising new area of study. This paper presents the initial bibliometric and visualization analysis of research literature concerning CRC and MetS which examines research trends and hotspots.

Hinokione: an abietene diterpene with pancreatic ß cells regeneration and hypoglycemic activity, and other derivatives with novel structures from the woods of Agathis dammara.

In this study, 14 abietene and pimarene diterpenoids were isolated from the woods of Agathis dammara. Among them, 4 new compounds, dammarone A-C and dammaric acid A (1-4), were firstly reported, respectively. The structure of the new compounds was determined by HR ESI-MS and 1D/2D NMR spectroscopy, and their absolute configuration was determined by electronic circular dichroism (ECD) exciton chirality method. The hypoglycemic effect of all compounds was evaluated by transgenic zebrafish model, and the structure-activity relationship was discussed. Hinokione (7, HO) has low toxicity and significant hypoglycemic effects on zebrafish, the mechanism is mainly by promoting the differentiation of zebrafish pancreatic endocrine precursor cells (PEP cells) into ß cells, thereby promoting the regeneration of pancreatic ß cells.

A comprehensive study on solvent effect and establishment of n-hexane solvent system based normal-phase liquid chromatography × reversed-phase liquid chromatography for isolation of natural products.

Reversed-phase liquid chromatography (RPLC) represents an effective separation method, and is widely employed as the second dimension in most 2D-LC systems. Nevertheless, the solvent effect of the eluent from the first dimension on RPLC presents a challenge to the online coupling of RPLC with other separation modes, particularly normal phase liquid chromatography (NPLC). To address this issue, a comprehensive understanding of the solvent effect is essential. Following a comprehensive investigation into the influence of diverse solvents on RPLC separations, it was observed that alkane solvents, such as n-hexane, exhibited a pronounced tendency to be retained during RPLC separations. Such solvents do not affect the analysis of samples with weaker retention abilities than themselves, even when a large injection volume is used. The solvent effect was thus reduced by employing n-hexane-based solvent dilution. Leveraging the markedly enhanced solvent tolerance and extensive injection volume in RPLC, a versatile integration of the NPLC and RPLC was devised, necessitating merely a purge pump and a 10 port 2 position valve in conjunction with two sample loops. The novel 2D-LC system was then deployed for the analysis of propolis, a naturally occurring complex sample, and demonstrated remarkable separation efficiency.

Compounds from Agathis dammara exert hypoglycaemic activity by enhancing glucose uptake: lignans, terpenes and others.

In this study, two new kaurane diterpenes (16, 17), together with 12 lignans (1-12), a triterpene (15), and two other compounds (13, 14) were isolated from the woods of Agathis dammara. The structure of the new compound was determined by HR ESIMS and 1D/2D NMR spectroscopy, and its absolute configuration was determined by electronic circular dichroism (ECD) exciton chirality method. Compounds 5, 11, 14 exhibit significant hypoglycaemic activity in zebrafish, and their mechanism of action is to enhance glucose uptake in zebrafish.

New cyclopentenoneacrylic acid derivatives from a marine-derived fungus Trichoderma atroviride H548.

Three new cyclopentenoneacrylic acid derivatives, trichodermacid A (1), trichodermester A (2), and trichodermester B (3), together with thirteen known compounds, were isolated from an ethyl acetate extract of Trichoderma atroviride H548, a fungus derived from mangrove sediment. The structures of the new compounds were elucidated by spectroscopic methods including HR ESI-MS, 1H NMR, 13C NMR, and 2D-NMR techniques. The antifungal activity of the isolated compounds was evaluated against tea pathogenic fungus Pestalotiopsis theae. Trichodermester A (2) showed potent anti P. theae activity with MIC of 125 µg/disc, while the other compounds were inactive.

Benzyl N-(4-pyrid-yl)carbamate.

The title compound, C(13)H(12)N(2)O(2), was obtained by the reaction of 4-amino-pyridine and benzyl chloro-formate in tetra-hydro-furan. The crystal structure contains N-H⋯N hydrogen bonds between two unique mol-ecules within layers and anti-parallel C-O⋯O-C inter-actions [O⋯O = 3.06 (3) Å] between the two mol-ecules of the asymmetric unit.

A new compound, brefeldin A formylate, from Penicillium sp. strain HLKG-44.

A novel compound named as brefeldin A formylate (1), together with two known compounds, brefeldin A (2) and ergosterol (3), was isolated from the Penicillium sp. strain HLKG-44, which was isolated from polluted environment in Fujian Province. Their structures were identified based on the spectral and X-ray crystallographic analyses. The compound 1, brefeldin A formylate, exhibited moderate cytotoxic activity against the human lung cancer cell line A549 with IC(50) value of 18.9 microg/ml by the MTT assay protocol.

Diisopropyl [(benzoyl-amino)-(phen-yl)meth-yl]phospho-nate.

The title compound, C(20)H(26)NO(4)P, has been obtained by the reaction of benzoyl chloride and diisoprop-yl[amino-(phen-yl)meth-yl]phospho-nate. The dihedral angle between the planes of the benzoyl-amino group and the phenyl ring is 77.0 (2)°. The crystal structure is stabilized by strong inter-molecular N-H⋯O hydrogen bonds between the doubly bonded phosphoryl O atom and the amide N atom which link the mol-ecules into pairs about a center of symmetry.

New ß-Lactone with Tea Pathogenic Fungus Inhibitory Effect from Marine-Derived Fungus MCCC3A00957.

Fusarium solani H915 (MCCC3A00957), a fungus originating from mangrove sediment, showed potent inhibitory activity against tea pathogenic fungus Pestalotiopsis theae. Successive chromatographic separation on an ethyl acetate (EtOAc) extract of F. solani H915 resulted in the isolation of five new alkenoic diacid derivatives: fusarilactones A-C (1-3), and fusaridioic acids B (4) and C (5), in addition to seven known compounds (6-12). The chemical structures of these metabolites were elucidated on the basis of UV, IR, HR-ESI-MS, and NMR spectroscopic data. The antifungal activity of the isolated compounds was evaluated. Compounds with a ß-lactone ring (1, 2, and 7) exhibited potent inhibitory activities, while none of the other compounds show activity. The ED50 values of the compounds 1, 2, and 7 were 38.14 ± 1.67, 42.26 ± 1.96, and 18.35 ± 1.27 µg/mL, respectively. In addition, inhibitory activity of these compounds against 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase gene expression was also detected using real-time RT-PCR. Results indicated that compounds 1, 2, and 7 may inhibit the growth of P. theae by interfering with the biosynthesis of ergosterol by down-regulating the expression of HMG-CoA synthase.

Comprehensive two-dimensional normal-phase liquid chromatography × reversed-phase liquid chromatography for analysis of toad skin.

An analytical two-dimensional normal-phase liquid chromatography × reversed-phase liquid chromatography (2D NPLC × RPLC) system was constructed with a newly developed thermal evaporation assisted adsorption (TEAA) interface. This novel TEAA interface with heating temperature above solvent boiling point allowed fast removal of organic NPLC solvent and successfully solved the solvent incompatibility problem between NPLC and RPLC. The system achieved rapid on-line solvent exchange between the two dimensions within a short modulation time of 190 s and was applied in the analysis of an extract from the skin of Bufo bufo gargarizans. This is the first time to realize the on-line comprehensive analysis of a moderate polar natural product by coupling NPLC with reversed phase ultra-high performance liquid chromatography (UHPLC). To be highlighted, with the TEAA interface, the 2D NPLC × RPLC system provided excellent resolution and orthogonality (75.2%), when compared with that of 2D RPLC × RPLC.

Two new cytochalasan derivatives from Chaetomium globosum SNSHI-5, a fungus derived from extreme environment.

Two new cytochalasan derivatives, isochaetoglobosin Db (1) and cytoglobosin Ab (2), were isolated from an ethyl acetate extract of Chaetomium globosum SNSHI-5, a fungus derived from extreme environment. The structures of the new compounds were comprehensively characterized by HR-ESI-MS, 1H NMR, 13C NMR and 2D-NMR. Cytotoxic activity against H292 human lung cancer cell of the new compounds was tested. Isochaetoglobosin Db (1) showed potent cytotoxicity with IC50 of 3.5 µM, while cytoglobosin Ab was inactive (IC50 > 10 µM).