Journal of Natural Products 最新文献

Despite numerous advances in compound identification and purification, the extraction techniques for metabolites from Streptomyces biomass have remained relatively unchanged. Accelerated solvent extraction (ASE) has been widely used in plant natural product discovery for the past two decades. Yet, to our knowledge, it has not been applied to Streptomyces biomass despite purported benefits in increasing extract yields. In this study, different ASE parameters were compared against traditional microbial biomass extraction techniques using Streptomyces coelicolor A3(2). Extraction efficacy was evaluated by quantifying the intracellular metabolites ectoine and undecylprodigiosin. In contrast to previous work with botanical metabolites, this study's findings suggest that ASE does not provide a significant advantage in extraction yield compared to traditional extraction techniques for Streptomyces biomass. The lack of increased metabolite yield per unit of biomass, in tandem with the disadvantages inherent to ASE, such as reduced scalability and potential for thermal degradation, indicates that ASE may lack a distinct advantage over traditional extraction methods for enhanced targeted metabolite recovery from Streptomyces biomass.

Circadian rhythms are fundamental regulatory mechanisms for various biological and biochemical functions in diverse organisms. To identify new circadian rhythm modulators, secondary metabolites in the edible mushroom Cyclocybe erebia were examined. Six new diterpenoids, cyclocircadins C-H, were isolated from a mushroom culture. Their structures, including absolute configurations, were determined using HR-ESI-MS, NMR, and quantum chemical calculations. Cyclocircadins are prenylaromadendrane-type diterpenoids with unique fused ring systems consisting of 3-, 5-, and 7-membered rings. Cyclocircadins C-E possess a hydroxy or carbonyl group on the 7-membered ring, whereas cyclocircadins F-H lack these functional groups, and have the double bonds at a different position within the ring. The effects on the circadian rhythm were assessed in human osteosarcoma U2OS cells expressing Emerald Luciferase (ELuc) under the control of the Per2 promoter. Cyclocircadins A, C, D, and F-H delayed the phase of the circadian rhythm, and reduced the amplitude of bioluminescence oscillations. In addition, cyclocircadins A, C, F, and G tended to lengthen the circadian period, whereas cyclocircadin E tended to shorten it. Cyclocircadins A and F-H were more active at lower concentrations than cyclocircadins C-E, indicating that structural variations in the seven-membered ring are critical for their activity.

A new microbial secondary metabolite, paulobutalipin (1), was isolated and characterized from the culture of a mountain soil-derived Streptomyces strain. The structure of paulobutalipin (1) was elucidated through a combined analysis of spectroscopic data, single-crystal X-ray diffraction, chemical modifications including application of the modified Mosher's method, and electronic circular dichroism calculations. In an in vitro hepatocellular steatosis model induced by palmitic and oleic acids, paulobutalipin (1) reduced intracellular lipid accumulation in AML12 hepatocytes by approximately 30% compared to that of vehicle controls. Moreover, it enhanced mitochondrial abundance in a dose-dependent manner, suggesting stimulation of mitochondrial β-oxidation. Our data identify paulobutalipin as a unique microbial natural product that promotes energy metabolism possessing structural complexity and minimal toxicity.

Five new compounds with diverse skeletons, namely, lobophytumins G (1, prenylgermacrane-type), H (2, spatane-type), sclerophytumins A (3, kikainane-type), B (4, prenyloplopanone-type), and ent-obscuronatin (5, prenylgermacrane-type), were isolated from the soft coral Sclerophytum heterospiculatum collected from Kikai Island, Kagoshima Prefecture, Japan. Their chemical structures, including their relative configurations, were elucidated by detailed analysis of spectroscopic data such as NMR and direct analysis in real-time time-of-flight mass spectrometry (DART-TOF MS), as well as by comparison with related known compounds. The relative and absolute configurations of the cyclic skeletons in 1-5 were determined through extensive spectroscopic data analysis, DFT-based DP4 analysis, and electronic circular dichroism (ECD) calculations. Notably, the trans-11-oxabicyclo[4.4.1]undecane skeleton observed in 3 represents the first report of this framework from a marine organism. In addition, DP4 analysis distinguished the asymmetric center at C-11 in the acyclic portion, thereby revealing the stereochemistry of the linear side chain bearing a terminal C5 prenyl unit in 4. Based on the obtained relative and absolute configurations, biosynthetic pathways were also proposed. Furthermore, the cytotoxicities of isolated compounds 1-5 were evaluated against four human cancer cell lines.

Marine bacteria are integral components of planktonic communities, where they regulate algal growth, induce cell death, and contribute to bloom termination and species succession. They also play a key role in marine biogeochemical cycling by recycling algal-derived organic matter and releasing bioactive metabolites. Despite their ecological importance, bacterial-plankton interactions and their consequences for community structure and chemistry remain poorly understood. We investigated the impact of the algicidal marine bacterium Kordia algicida OT-1 on a natural plankton microbiome collected from a mesocosm experiment simulating present and future climate conditions. Plankton communities were exposed to ambient conditions or to a worst-case climate scenario, with a subset further subjected to a one-week heatwave. After 24 h of incubation, K. algicida significantly altered phytoplankton abundance and phylum-level community composition, independent of the applied abiotic conditions. Chemical changes induced by bacterial interactions were assessed by extracting filtrates from cocultures and analyzing them using ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS). Four natural products, i.e., adenosylhomocysteine, two indole alkaloid derivatives, and 5-bromotryptophan, were identified among metabolites released in response to bacterial exposure. Overall, shifts in the planktonic chemical landscape were primarily driven by bacterial activity, rather than abiotic conditions.

We reported the first enantioselective total synthesis of four naturally occurring angular dihydropyranocoumarins (1-4), each obtained in high enantiomeric excess (94-98% ee). The synthetic route featured Jacobsen epoxidation followed by anhydride-mediated angeloylation as key transformations. The anti-inflammatory properties of compounds 1-4 were evaluated using a panel of in vitro assays. Notably, compound 4 exhibited significant anti-inflammatory activity by reducing the secretion of proinflammatory cytokines. Results from Western blotting, in conjunction with molecular dynamics analysis, indicated that inhibition of the NF-κB signaling pathway may partially explain the anti-inflammatory activity of compound 4.

Seven novel abietane-type diterpenoid dimers (ADDs), bistaxascendins A-G (1-7), and two known analogues (8 and 9) were isolated from the cones of Taxodium ascendens. Their structures were assigned through analysis of detailed spectroscopic data, X-ray crystallography, and quantum chemical calculations. Particularly, compound 1 is an unprecedented 6-O-8' and 7-O-7' angularly fused dioxygen-bridged ADD, while compound 6 represents the first example of an ADD connected by a 7-O-6' ether bond. The isolated compounds were systematically evaluated for cytotoxicity against human colorectal cancer cell lines via the MTT assay. Compounds 4 and 8 demonstrated dose-dependent antiproliferative efficacy against HCT116, SW480, and RKO cells, with IC₅₀ of 4.6-17.3 μM. Compound 8 displayed the most potent antiproliferative activity, with IC₅₀ values of 4.6 ± 0.2 μM, 5.1 ± 0.2 μM, and 5.6 ± 0.2 μM. Mechanistic studies revealed that compound 8 activated PINK1/Parkin-mediated mitophagy, as evidenced by upregulated autophagosomal markers and enhanced autophagic and mitophagic flux, indicating compound 8 as a promising lead compound for mitophagy-targeted colorectal cancer therapy.

Cyanobacteria have been a promising source for natural product drug discovery for decades using mainly activity-guided approaches. More recently, genome mining and bioinformatics-guided approaches have become increasingly utilized in bacterial drug discovery and have proven to be successful in revealing novel metabolites predicted by biosynthetic gene clusters. However, detection and identification of these predicted metabolites can be difficult. Connecting nitrogen-containing natural products with the corresponding gene clusters encoding them in cyanobacteria can be aided by cyanobacteria's ability to incorporate inorganic nitrogen into their secondary metabolites. Feeding cyanobacteria with ¹⁵N-labeled and ¹⁴N nitrate and comparing the resulting metabolic profiles via mass spectrometry allows for the identification of nitrogen-containing metabolites, which can then be connected to biosynthetic gene clusters. Investigation of Nostoc sp. UIC 10890 using this workflow identified 28 total gene clusters and five groups of masses incorporating ¹⁵N-labeled nitrogen. Two of these groups contained new compounds, and the structures were elucidated by NMR and MS/MS. Three new compounds suomilide F, cyanopeptolin UIC949, and cyanopeptolin UIC999 were shown to have inhibitory activity against different serine proteases.

Quality control systems such as Good Agricultural and Collection Practices, current Good Manufacturing Practices, and regulations emphasize the importance of botanical identity verification for assuring safety and purported benefits. The inherent biological variability and chemical complexity of botanical raw materials, extracts, and fractions demand fit-for-purpose methods for the accurate identification and discrimination from confounding materials and adulterants. Compendial botanical identity testing comprises orthogonal procedures for morphological and chemical characterization; specifications and acceptance criteria versus reference standards; consistent nomenclature; and labeling. Pharmacopeial general chapters provide guidance on the system suitability and method validation tests needed for each matrix to demonstrate specificity and sensitivity.