Journal of Natural Products 最新文献

Eight undescribed spiro-polycyclic polyprenylated acylphloroglucinols (PPAPs) with a 6/6/5 tricyclic architecture (1−8), together with eight known analogues (9−16), were isolated from Hypericum monogynum L. Their structures including absolute configurations were elucidated by spectroscopic analysis, single-crystal X-ray diffraction, and quantum chemical calculations. Biological evaluation revealed that compounds 4 and 16 showed potential as dual-target anti-Alzheimer’s disease (AD) lead compounds, as they not only exhibited potent acetylcholinesterase (AChE) inhibitory activities but also induced peroxisome proliferator-activated receptor-γ transactivation and upregulated ATP-binding cassette transporter A1 expression. The in vivo anti-AD effects of 4 and 16 were evaluated by the zebrafish behavioral experiments. Compound 16 exhibited anti-AD effects with no detectable toxicity or teratogenicity, whereas 4 exhibited toxicity to zebrafish at 10 μM. These findings not only expand the chemical diversity of spiro-PPAPs but also underscore their potential as dual-target agents for AD treatment.

A soil-derived Mycoarthris sp. isolate yielded a combination of eight new and known secondary metabolites consisting of four cyclic tetrapeptides, omnipolyphilins A−D (1−4), and four lipopeptides, mycoarpeptins A−D (5−8). The structures of natural products 1−8 were established based on analysis of the HRESIMS, MS/MS fragmentation, and 1D and 2D NMR data. Their absolute configurations were determined using Marfey’s analysis, chemical synthesis, and conformational analysis. Omnipolyphilins A−D (1−4) stand as a unique group of fungal cyclopeptides characterized by the presence of a hexahydropyrrolo[2,3-b]indole-2-carboxylic acid (HPIC) and 3-hydroxytyrosine (DOPA). Mycoarpeptins A−D (5−8) are acyclic lipopeptides featuring non-proteinogenic β-aminoisobutyric acid (BAIBA) residues. A survey of the metabolite profiles indicated the likelihood of regional and phylogenetic variation in the production of omnipolyphilins and mycoarpeptins.

Thirty-four chimeric pyridone alkaloids, including twenty-eight new compounds named aspernigrins F₁−F₈, G₁−G₅, H₁−H₇, and I−P (1−28), were isolated from the mangrove endophytic fungus Aspergillus niger H6a, together with six known ones (29−34). The structures of these compounds were elucidated by HRESIMS, NMR spectroscopic data, single-crystal X-ray diffraction analyses, TDDFT-ECD calculations, and chemical methods, including Marfey’s derivatization. The structure of 26 contains two units of 2-aminododecanoic acid, whereas those of 27 and 28 not only contain two moieties of 2-aminododecanoic acid but also possess an ester-linked neo-inositol group, featuring unprecedented chimeric pyridone alkaloids with amphiphilic properties. Compound 26 exhibited antibacterial activity against Enterococcus faecalis and Micrococcus luteus with minimum inhibitory concentration values of 8.0 and 16.0 μg/mL, respectively, whereas compound 27 displayed anti-tumor activity against the Hela cell line with an IC₅₀ value of 15.9 μM. Further studies disclosed that 27 exerted concentration-dependent anti-tumor activity against HeLa cells, including the inhibition of cell proliferation, invasion, and migration, along with the successful induction of mitochondrial-mediated cell apoptosis and the arrest of cell cycle in the G₀/G₁ phase. This work provides insight into the discovery of new pyridone alkaloids as lead compounds for the development of anti-bacterial and anti-tumor agents.

N-Acetylglucosamine (GlcNAc)-decorated natural products represent a structurally unique class of metabolites that possess diverse biological activities. Through the genome mining of Coccidioides sp. CMB-TN39F, we identified a GlcNAc transferase-encoding terpene synthase gene cluster brc. Heterologous expression of this cluster in Aspergillus nidulans enabled the characterization of seven GlcNAc-adorned brasilane-type sesquiterpene glycosides, including six previously undocumented compounds, brasilane G−L (1−6), and one known compound, brasilane A (7). Functional characterization revealed that the cytochrome P450 BrcC functions as an epoxidase, catalyzing a stereoselective epoxidation of 7 to form 1. Compound 1 can undergo non-enzymatic conversions to generate compounds 2−5 under mildly acidic conditions. Pharmacological evaluation demonstrated that compounds 1−6 effectively downregulate the expression of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) in LPS/IFN-γ-stimulated THP-1-derived macrophages. Notably, 1, which features an epoxide moiety, exhibits superior anti-inflammatory activity compared to its biosynthetic precursor 7, with an IC₅₀ value of 30.4 μM against IL-6. This study expands the chemical space of GlcNAc-conjugated terpenoids and showcases a biosynthetic logic in which enzymatic tailoring is coupled with nonenzymatic reactions to amplify both structural diversity and biological properties.

Two new 4-hydroxy-2-pyridone alkaloids, prebassianins F (5) and G (6), featuring a rare 1,4-cyclohexanediol moiety, were isolated from rice cultures of Akanthomyces araneicola GY29011. Genome mining and heterologous expression of the corresponding biosynthetic gene cluster (pre) in Aspergillus nidulans afforded six additional new analogues (3−4 and 7−10), along with two known compounds (1−2). Combinatorial expression and substrate feeding experiments enabled the elucidation of the biosynthetic pathway and functional assignment of the tailoring enzymes. Notably, PreC was identified as a rare bifunctional fusion enzyme comprising old yellow enzyme (OYE) and short-chain dehydrogenase (SDR) domains. Truncation of PreC led to the accumulation of a key intermediate (10), supporting its role in sequential reductions. cDNA analysis confirmed that PreC is encoded as a single open reading frame containing four introns, including a rare GC−AG intron. Compounds 3 and 4 exhibited antibacterial activity against Bacillus subtilis (MIC = 16 μg/mL). These findings expand the structural diversity of 4-hydroxy-2-pyridone alkaloids and provide new insights into the enzymatic logic and evolution of fungal biosynthetic pathways.

The MeOH extract of the newly described deadly mushroom Amanita vidua was dominated by an unknown peptide. Despite the limited fungal material available, the compound was isolated and characterized as a homodetic cyclic hexapeptide by NMR and MS/MS analyses, and its structure was confirmed by high-efficiency solid-phase peptide synthesis. Recently implemented genome mining further validated the structure and provided a broader insight into the cyclopeptide-producing capabilities of this rare mushroom. Named viduamanide, this compound is a non-canonical cycloamanide of the “prolineless” subtype and the first of its kind ever reported to not contain a proline residue.

Licorice (Glycyrrhiza) is a medicinal plant widely used in approximately 70% of traditional Japanese Kampo formulations and is known to produce a wide array of specialized metabolites with diverse pharmacological properties. Although hundreds of metabolites have been reported, the overall chemical diversity of Glycyrrhiza remains poorly characterized. Here, using mass spectrometry data obtained from fully ¹³C-labeled leaves and roots of Glycyrrhiza uralensis and Glycyrrhiza glabra, we determined the carbon number, followed by the molecular formula and substructure prediction in combination with MS/MS similarity-based molecular networking. After excluding redundant ions, including isotopic peaks, adducts, and in-source fragments, we extracted 3060 unique metabolite features with assigned carbon numbers. Among these, substructure information was assigned to 1015 features (33%) across the four plant tissues, revealing tissue-specific metabolome profiles. Furthermore, we discovered five previously unreported homopipecolic acid-conjugated flavonoids in the roots of G. uralensis and G. glabra and Glycine max, another member of the Fabaceae family. Two of these compounds were structurally characterized using nuclear magnetic resonance spectroscopy. We further proposed a biosynthetic route involving a spontaneous reaction between 1-piperideine and malonyl glycoside substrates and confirmed the formation of the conjugated product using authentic standards.

Current treatments for hepatitis B virus (HBV) infection are constrained by adverse effects, drug resistance, and the need for long-term administration. Therefore, the development of safer and more effective therapeutic agents remains an important priority. In this study, two new amphilectane-type diterpenoids, 7-isocyanatoneoamphilecta-11,15-diene (1) and 7-isothiocyanatoneoamphilecta-11,15-diene (2), together with three known analogues (3−5), were isolated as anti-HBV agents from the Okinawan marine sponge Stylissa sp. The structures of 1 and 2 were elucidated by spectroscopic analysis, single-crystal X-ray diffraction, microcrystal electron diffraction (microED), and chemical derivatization. The previously reported amphilectanes 6 and 7 from an Adociidae sponge were also evaluated to examine structure−activity relationships. Compounds 3 and 6 showed the most potent anti-HBV activity and significantly suppressed the formation of HBV covalently closed circular DNA (cccDNA) without affecting HBV binding, entry, or RNA transcription. These results suggest that the combination of an isocyanide group and an exomethylene moiety is critical for activity. This study expands the chemical diversity of amphilectane diterpenoids and highlights their potential as promising scaffolds for the development of anti-HBV therapeutics.

As part of our continuing search for antifungal natural products, we investigated the secondary metabolites of Streptomyces sp. SID10815, an actinomycete isolated from a ground-nesting bee-associated environment that exhibited notable antifungal activity in preliminary screenings. Herein, we report the discovery of four new N-acetylcysteine-modified ansamycins (1−4) and three new hydroxymycotrienin analogues (5−7), together with six known ansamycins (8−13), produced by this strain. These metabolites were detected and prioritized through a metabolomics-guided dereplication strategy integrating LC−MS profiling and bioactivity correlation. Their structures were elucidated by comprehensive spectroscopic analyses, including 1D and 2D nuclear magnetic resonance (¹H, ¹³C, COSY, HSQC, HMBC, and NOESY) in combination with high-resolution mass spectrometry. The newly identified metabolites expand the structural diversity of the ansamycin family and provide a basis for future structure−activity relationship studies of N-acetylcysteine-conjugated ansamycins. These findings define a distinctive ansamycin profile of Streptomyces sp. SID10815 that may serve as a useful chemical signature for future comparative studies of insect-associated actinomycetes.

Celastrol, a quinone methide triterpenoid present in plants of the genus Tripterygium, is a potent leptin sensitizer and a promising scaffold for anti-obesity drug development. Metabolite profiling of the stems of Tripterygium regelii using UPLC-qTOF-MS/MS, combined with building block-based molecular networking (BBMN) analysis, led to the isolation of ten previously undescribed triterpene−flavanol conjugates (1−10), including celastrol derivatives, as well as the annotation of 34 additional congeners sharing a similar core scaffold. The structures of compounds 1−10 were elucidated through comprehensive spectroscopic analyses, chemical derivatization, and quantum chemical calculations. All isolates exhibited configurationally stable sp³−sp² axial chirality at ambient temperature, and both P- and M-configured atropisomers were identified. In vitro evaluation of protein tyrosine phosphatase 1B (PTP1B) inhibition revealed that compound 10 exhibited potent activity, with an IC₅₀ value of 0.6 ± 0.1 μM, acting as a mixed-type inhibitor. These triterpene−flavanol conjugates represent a new structural class with potential as lead compounds for the development of anti-obesity agents.