Journal of Natural Products 最新文献

Kidney fibrosis represents a hallmark pathological outcome in the progression of chronic kidney diseases. The clinical approval of therapeutics specifically for kidney fibrosis remains lacking to date. Toward the discovery of novel marine-derived drugs leads against kidney fibrosis, a fibronectin (FN)-based assay was used to screen various fractions of the crude extract from the growth medium of sponge-associated fungus Aspergillus clavatonanicus SCSIO 41444. A bioassay-guided fractionation process yielded six active compounds (1-6), including a new indole-quinazoline alkaloid (1) and an undescribed pyripyropene-type alkaloid (2). The structures and absolute configurations of 1 and 2 were determined by analysis of spectroscopic data and electron circular dichroism calculations. Compounds 1-6 (10 μM) were all active in the TGF-β1-stimulated HK-2 cell model of kidney fibrosis. The alkaloid 1 demonstrated potent activity, significantly suppressing the protein levels of FN and α-SMA at a concentration as low as 2.5 μM. Based on comprehensive proteomic analysis, 1 was found to decrease thyroid adenoma-associated protein levels, thereby modulating endoplasmic reticulum calcium homeostasis and influencing the progression of kidney fibrosis. These findings suggested that 1 is a promising anti-kidney fibrosis agent with a new mechanism for drug development.

Four new pyrazine derivatives, namely (S,E)-1-((5-(3-hydroxy-2-(hydroxymethyl)styryl)-3,6-dimethylpyrazin-2-yl)methyl)-1,3-dihydroisobenzofuran-4-ol (1), (S,E)-1-((5-(3-hydroxy-2-(methoxymethyl)styryl)-3,6-dimethylpyrazin-2-yl)methyl)-1,3-dihydroisobenzofuran-4-ol (2), (S,Z)-1-((5-(3-hydroxy-2-(methoxymethyl)styryl)-3,6-dimethylpyrazin-2-yl)methyl)-1,3-dihydroisobenzofuran-4-ol (3), and (S)-1-((5-(3-hydroxy-2-(methoxymethyl)phenethyl)-3,6-dimethylpyrazin-2-yl)methyl)-1,3-dihydroisobenzofuran-4-ol (4), together with one new 1,3-dihydroisobenzofuran derivative, (S)-2-(4-hydroxy-1,3-dihydroisobenzofuran-1-yl)acetamide (5), were isolated from the endophytic fungus Alternaria sp. HJT-Y7 collected from the leaves of Rhodiola tibetica. Their structures were determined based on extensive spectroscopic analysis and comparison of experimental and calculated electronic circular dichroism (ECD) curves. 1, 4, and 5 significantly inhibited osteoclast differentiation in RANKL-induced RAW264.7 cells and markedly restored bone mineralization in a dexamethasone-induced zebrafish osteoporosis model. These results highlight the potential of 1, 4, and 5 as promising candidates for osteoporosis therapy.

The ascidiacea-derived strain Streptomyces sp. GXX01-02 initially yielded the antifungal polyketide-nucleoside hybrid jawsamycin. To explore further metabolic diversity, the OSMAC strategy was employed, with the rice medium extract notably exhibiting a unique UV signature that suggested the presence of distinct secondary metabolites. This led to the identification of three filipin-type polyene macrolides, pemacromycins A–C (1–3), featuring oxygen bridges between C-13 and C-16 (1, 2) or C-13 and C-17 (3). Their structures were defined by a combination of comprehensive spectroscopic analysis, Kishi’s universal NMR database, Newman projections, DP4+ probability analyses, modified Mosher’s method, and Mo₂(AcO)₄-induced circular dichroism. Bioassays revealed that derivatives 1a and 2a exhibited antibacterial activity against Bacillus subtilis with an MIC value of 16 μg/mL, while 1b and 1c showed antifungal effects against Ceratocystis paradoxa and Corynespora cassiicola with MIC values ranging from 16 to 32 μg/mL.

The first total syntheses of dibenzylbutane-type lignan shibitubin G, and of its enantiomer, were achieved from commercially available vanillin. A key catalytic asymmetric Michael addition reaction was used to introduce the C8′ chiral center of this natural product. The absolute configuration of natural schibitubin G was revised to 8′S based on the X-ray crystallographic analysis of 14, and by comparing optical rotations of both synthetic samples with that of natural schibitubin G.

A high-throughput screening campaign designed to discover natural product inhibitors of rhabdomyosarcoma oncogene PAX3–FOXO1 gene expression identified partially purified fractions from an organic extract of the plant Gonystylus borneensis to have potent activity in the assay. Bioassay-guided isolation yielded five new 5,6-dihydro-α-pyrone natural products, namely, gonystylones A–E (1–5). Their structures were elucidated using 1D and 2D NMR experiments and their absolute configurations determined using semisynthetic and electronic circular dichroism methods. The gonystylones were found to be cytotoxic to rhabdomyosarcoma cells at low micromolar concentrations (3–19 μM).

Molecular networking-driven investigation of the root, stem bark, and fruit extracts of the medicinal plant Carapa macrantha led to the targeted isolation of seven previously undescribed limonoids (1–7), one new pregnane-type steroid (8), and 17 known compounds (9–25). Structural elucidation was achieved using spectroscopic methods, single-crystal X-ray analyses, and comparison with literature data. Extracts and isolated compounds were assessed in vitro for antiplasmodial activity against the chloroquine-sensitive 3D7 and the multidrug-resistant Dd2 strains of Plasmodium falciparum (Pf3D7 and PfDd2). The dichloromethane (CH₂Cl₂)/methanol (MeOH) (1:1) root extract showed significant activity against PfDd2, with an IC₅₀ value of 10 ± 2 μg/mL and good selectivity over Vero cells (SI > 10). Compounds, 6, 7, 9, 10, and 17 exhibited the best activity, with IC₅₀ values ranging from 5.7 to 22.9 μM against both strains. Compound 17 was the most active one on both strains, with IC₅₀ values of 5.7 ± 0.4 and 9.4 ± 0.4 μM against Pf3D7 and PfDd2 with SI > 7, respectively. These findings highlight C. macrantha as a potential source of antiplasmodial agents.

Roseocin, a novel two-peptide lantibiotic from Streptomyces roseosporus discovered in our lab, carries extensive lanthionine (Lan) and methyllanthionine (MeLan) thioether cross-links in both peptides. The two peptides, containing 33 and 35 residues, display synergistic antibacterial activity against Gram-positive pathogens. We used a systematic approach to assign the ring pattern of the alpha component of roseocin, whereby six individual ring variants were created. Four Ser/Thr residues that are dehydrated during biosynthesis and two Cys involved in cyclization were substituted individually with Ala. The data with these variants suggest that Cys10 partners with Ser2 to form Lan ring A, Cys11 partners with Thr7 to form MeLan ring B, Ser18 partners with Cys23 to generate Lan ring C, and Thr21 partners with Cys27 to form MeLan ring D. The stereochemistry of all lanthionine and methyllanthionine residues was shown to be DL by Marfey's analysis. Disruption of Lan rings of Rosα impacted both the structure and bioactivity while the MeLan rings were expendable but important for roseocin's bioactivity as their disruption led to a substantial increase in MIC. The installation of its two Lan rings is proposed to be decisive to attain the native ring pattern, essential for its synergistic antibacterial activity with Rosβ.

The medicinal plant Uncaria rhynchophylla is valued for producing tetracyclic oxindole alkaloids, including the neuro- and cardioprotective alkaloids rhynchophylline (RIN) and isorhynchophylline (IRN). However, the genomic and genetic basis of alkaloid biosynthesis remains poorly elucidated. Here, we report a chromosome-level genome assembly (653.3 Mb, contig N50 = 24.61 Mb) for U. rhynchophylla, revealing high repetitive content (63.71%) and 30,200 annotated genes. Evolutionary analysis uncovered an ancient whole-genome duplication event and species-specific gene families that could be potentially linked to metabolic diversification. Full-length transcriptome sequencing highlighted tissue-specific expression patterns with hooks showing strong enrichment of alkaloid-biosynthetic genes. A CYP71 family member, UrCYP13, was identified and exhibited high hook-specific expression. Heterologous expression in Nicotiana benthamiana confirmed that UrCYP13 catalyzes the conversion of hirsutine (1) to RIN (2) and IRN (3). The high-quality genome and transcriptome provide a platform for RIN/IRN discovery and establish that UrCYP13 is a key enzyme in the helical oxyindole pathway with hook-specific expression and post-transcriptional regulation underlying metabolite accumulation. These genomic resources will facilitate functional genomics, evolutionary studies, and the sustainable biotechnological production of these valuable alkaloids.

Two-component lantibiotics comprise two post-translationally modified peptides that synergistically exert antimicrobial activity. Most known two-component lantibiotics are made up of a structurally conserved α-lanthipeptide that binds to the peptidoglycan precursor lipid II and a β-lanthipeptide that interacts with the α-peptide-lipid II complex to form pores in the membranes of susceptible bacteria. A few two-component lantibiotics, including roseocin, do not appear to follow this general scheme and act by currently unresolved mechanisms. An important first step in studying these lanthipeptides is the determination of their chemical structure. Roseocin’s β-peptide (Rosβ) is formed by the RosM lanthipeptide synthetase from the RosA1 precursor peptide. RosM carries out nine dehydrations of Ser and Thr residues to the corresponding dehydroamino acids followed by six Michael-type additions of the thiols of Cys residues to a subset of the dehydroamino acids forming six thioether cross-links. Sequence alignment with structurally characterized lanthipeptides does not allow prediction of the ring pattern of Rosβ. In this study, Rosβ was produced in Escherichia coli and its ring pattern was established by multidimensional NMR spectroscopy. The stereochemistry of the lanthionine and methyllanthionine residues was determined by Marfey’s analysis with authentic standards. Rosβ is shown to have a unique ring pattern among previously characterized lanthipeptides.