A series of new C(11) cyclopentenones 1-7 was isolated, together with four known metabolites 9/10, 12 and 13, from the extract of the didemnid ascidian Lissoclinum sp. The other didemnid ascidian Diplosoma sp. contained didemnenones 1, 2 and 5, and five known metabolites 8-12. The structures of 1-7 were elucidated by spectroscopic analyses. Cytotoxicity of the isolated compounds was evaluated against three human cancer cell lines (HCT116, A431 and A549).

Plants are sources of diversified allelopathic substances that can be investigated for use in eco-friendly and efficient herbicides. An aqueous methanol extract from the leaves of Garcinia xanthochymus exhibited strong inhibitory activity against barnyard grass (Echinochloa crus-galli (L.) P. Beauv.), foxtail fescue (Vulpia myuros (L.) C.C.), alfalfa (Medicago sativa L.), and cress (Lepidium sativum L.), and appears to be a promising source of allelopathic substances. Hence, bio-activity guided purification of the extract through a series of column chromatography steps yielded a novel compound assigned as garcienone ((R, E)-5-hydroxy-5-((6S, 9S)-6-methyl-9-(prop-13-en-10-yl) tetrahydrofuran-6-yl) pent-3-en-2-one). Garcienone significantly inhibited the growth of cress at a concentration of 10 μM. The concentrations resulting in 50% growth inhibition (I50) of cress roots and shoots were 120.5 and 156.3 μM, respectively. This report is the first to isolate and identify garcienone and to determine its allelopathic potential.

Metabolomics can be used to study complex mixtures of natural products, or secondary metabolites, for many different purposes. One productive application of metabolomics that has emerged in recent years is the guiding direction for isolating molecules with structural novelty through analysis of untargeted LC-MS/MS data. The metabolomics-driven investigation and bioassay-guided fractionation of a biomass assemblage from the South China Sea dominated by a marine filamentous cyanobacteria, cf. Neolyngbya sp., has led to the discovery of a natural product in this study, wenchangamide A (1). Wenchangamide A was found to concentration-dependently cause fast-onset apoptosis in HCT116 human colon cancer cells in vitro (24 h IC50 = 38 μM). Untargeted metabolomics, by way of MS/MS molecular networking, was used further to generate a structural proposal for a new natural product analogue of 1, here coined wenchangamide B, which was present in the organic extract and bioactive sub-fractions of the biomass examined. The wenchangamides are of interest for anticancer drug discovery, and the characterization of these molecules will facilitate the future discovery of related natural products and development of synthetic analogues.

Advanced renal cell carcinoma (RCC) remains an incurable disease, and newer anticancer drugs are needed. Bisebromoamide, a novel cytotoxic peptide, was isolated from the marine cyanobacterium Lyngbya species at our laboratory in 2009. This compound specifically inhibited the phosphorylation of ERK in platelet-derived growth factor-activated normal rat kidney cells. The aim of this study was to evaluate the effect and elucidate the potential mechanism of Bisebromoamide actions on human RCC cells. Two renal cancer cell lines, 769-P and 786-O, were used. The effects of Bisebromoamide were analyzed employing assays for water-soluble Tetrazolium-1 salts. Apoptosis was determined by flow cytometric TUNEL analysis. Cell-cycle distributions were analyzed by flow cytometry using BrdU/propidium iodide (PI) staining. Kinases of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of Rapamycin (mTOR) pathway and Raf/MEK/ERK pathway were analyzed by Western blotting. After Bisebromoamide treatment for 48 and 72 h, cell viability was significantly decreased in both cell lines at 1 and 10 μmol/L. After treatment with 1 μmol/L Bisebromoamide for 72 h, apoptosis and the increased percentage of cells in the sub-G1 phase were observed in both cell lines. Bisebromoamide inhibited the phosphorylation of ERK and Akt in both cell lines tested. Similar effects were demonstrated for phosphorylation of mTOR and p70 S6. Bisebromoamide is a promising potential agent against RCC due to its ability to inhibit both the Raf/MEK/ERK and PI3K/Akt/mTOR pathways.

The phytotoxic potential of plants and their constituents against other plants is being increasingly investigated as a possible alternative to synthetic herbicides to control weeds in crop fields. In this study, we explored the phytotoxicity and phytotoxic substances of Schumannianthus dichotomus, a perennial wetland shrub native to Bangladesh, India, and Myanmar. Leaf extracts of S. dichotomus exerted strong phytotoxicity against two dicot species, alfalfa and cress, and two monocot species, barnyard grass and Italian ryegrass. A bioassay-driven purification process yielded two phenolic derivatives, syringic acid and methyl syringate. Both constituents significantly inhibited the growth of cress and Italian ryegrass in a concentration-dependent manner. The concentrations required for 50% growth inhibition (I50 value) of the shoot and root growth of cress were 75.8 and 61.3 μM, respectively, for syringic acid, compared with 43.2 and 31.5 μM, respectively, for methyl syringate. Similarly, to suppress the shoot and root growth of Italian rye grass, a greater amount of syringic acid (I50 = 213.7 and 175.9 μM) was needed than methyl syringate (I50 = 140.4 to 130.8 μM). Methyl syringate showed higher phytotoxic potential than syringic acid, and cress showed higher sensitivity to both substances. This study is the first to report on the phytotoxic potential of S. dichotomus and to identify phytotoxic substances from this plant material.

Plant parts and extracts that are rich in bioactive substances with allelopathic potential can be explored as a possible alternative to herbicides for natural weed control in sustainable agriculture. In the present study, we investigated the allelopathic potential of Marsdenia tenacissima leaves and its active substances. Aqueous methanol extracts of M. tenacissima showed significant inhibitory activities against the growth of lettuce (Lactuca sativa L.), alfalfa (Medicago sativa L.), timothy (Phleum pratense L.), and barnyard grass (Echinochloa crusgalli (L.) Beauv.). The extracts were purified through various chromatography steps, and one active substance was isolated and determined by spectral data to be a novel compound, assigned as steroidal glycoside 3 (8-dehydroxy-11β-O-acetyl-12β-O-tigloyl-17β-marsdenin). Steroidal glycoside 3 significantly inhibited the seedling growth of cress at a concentration of 0.03 mM. The concentrations needed for 50% growth inhibition of the cress shoots and roots were 0.25 and 0.03 mM, respectively. These results suggest that steroidal glycoside 3 may be responsible for the allelopathy of M. tenacissima leaves.

Wedelia chinensis (Asteraceae) is a wetland herb native to India, China, and Japan. It is a valuable medicinal plant recorded to have pharmaceutical properties. However, the phytotoxic potential of Wedelia chinensis has not yet been examined. Thus, we carried out this study to establish the allelopathic effects of Wedelia chinensis and to identify its phytotoxic substances. Extracts of Wedelia chinensis exhibited high inhibitory activity against the root and shoot growth of cress, alfalfa, rapeseed, lettuce, foxtail fescue, Italian ryegrass, timothy, and barnyard grass. The inhibition was varied with species and was dependent on concentrations. The extracts were separated through several purification steps, and the two effective substances were isolated and characterized as vanillic acid and gallic acid using spectral analysis. Vanillic acid and gallic acid significantly arrested the growth of cress and Italian ryegrass seedlings. The concentrations of vanillic acid and gallic acid needed for 50% inhibition (I50 values) of the seedling growth of the cress and Italian ryegrass were 0.04-15.4 and 0.45-6.6 mM, respectively. The findings suggest that vanillic acid and gallic acid may be required for the growth inhibitory activities of Wedelia chinensis.

Amebiasis is an important cause of morbidity and mortality worldwide, and caused by infection with the protozoan parasite Entamoeba histolytica. Metronidazole is currently the first-line drug despite adverse effects and concerns on the emergence of drug resistance. Fumagillin, a fungal metabolite from Aspergillus fumigatus, and its structurally related natural and synthetic compounds have been previously explored as potential anti-angiogenesis inhibitors for cancers, anti-microbial, and anti-obese compounds. Although fumagillin was used for human amebiasis in clinical trials in 1950s, the mode of action of fumagillin remains elusive until now. In this report, we showed that fumagillin covalently binds to methionine aminopeptidase 2 (MetAP2) and non-covalently but abundantly binds to patatin family phospholipase A (PLA). Susceptibility against fumagillin of the amebic strains in which expression of E. histolytica MetAP2 (EhMetAP2) gene was silenced increased compared to control strain. Conversely, overexpression of EhMetAP2 mutants that harbors amino acid substitutions responsible for resistance to ovalicin, a fumagillin analog, in human MetAP2, also resulted in decrease in fumagillin susceptibility. In contrast, neither gene silencing nor overexpression of E. histolytica PLA (EhPLA) affected fumagillin susceptibility. These data suggest that EhPLA is not essential and not the target of fumagillin for its amebicidal activity. Taken together, our data have demonstrated that EhMetAP2 is the primary target for amebicidal activity of fumagillin, and EhMetAP2 represents a rational explorable target for the development of alternative therapeutic agents against amebiasis.

Biselyngbyasides (BLSs), macrolides from a marine cyanobacterium, are cytotoxic natural products whose target molecule is unknown. Here we report that BLSs are high affinity (Ki∼10 nM) inhibitors of Ca(2+)-pumps with a unique binding mode. The crystal structures of the Ca(2+)-pump in complex with BLSs at 3.2-3.5 Å-resolution show that BLSs bind to the pump near the cytoplasmic surface of the transmembrane region. The crystal structures and activity measurement of BLS analogs allow us to identify the structural features that confer high potency to BLSs as inhibitors of the pump.

Three new compounds of the malyngamide series, 6,8-di-O-acetylmalyngamide 2 (1), 6-O-acetylmalyngamide 2 (2), and N-demethyl-isomalyngamide I (3), were isolated from the marine cyanobacterium Moorea producens. Their structures were determined by spectroscopic analysis and chemical derivatization and degradation. These compounds stimulated glucose uptake in cultured L6 myotubes. In particular, 6,8-di-O-acetylmalyngamide 2 (1) showed potent activity and activated adenosine monophosphate-activated protein kinase (AMPK).

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