Journal of Natural Products 最新文献

The first synthesis of the proposed structure of a neuroprotective natural product, syzysamalactone, was accomplished starting from 4-ethylcyclohexane-1,3-dione. The synthesis features a one-pot Michael addition annulation cascade to 2-pyrone in water as a solvent. The spectral data of the synthetic product did not match the reported data, indicating the need for structural revision. A significant difference in the chemical shift of the carbonyl carbon suggested a 4-pyrone skeleton, which was subsequently confirmed by synthesis. The racemic mixture was resolved by chiral HPLC, and the natural product was assigned the (S, S) configuration by XRD analysis of its 4-nitrobenzoate ester.

Terpenoids are among the most chemically diverse natural product classes in the plant kingdom and are a source of numerous nature-inspired human medicines. One specific subclass, diterpenoids, defined by a C20 skeleton, includes attractive compounds such as the anticancer drug Taxol, the sweetener steviol, and the plant hormone gibberellin. One specialized group of ent-labdane (bicyclic) diterpenoids, primarily reported from the genus Andrographis (Acanthaceae), is the source of andrographolides, a diverse array of bioactive scaffolds with anti-inflammatory, antioxidant, anticancer, antimicrobial, and antihyperglycemic properties. Using high-throughput metabolomics, we set out to examine the molecular diversity within the Acanthaceae family, alongside other taxonomic lineages reported to accumulate diterpenoids. In a combined metabolomic investigation of 31 genera spanning Acanthaceae, Lamiaceae, and Poaceae, we annotated several reported andrographolide-type labdane diterpenoids and characteristic compounds unique to Acanthaceae. Integration of chemical, geographic, and taxonomic metadata with literature-driven assessments helped paint a chemotaxonomic and phylogeographic distribution map of andrographolide-type labdane diterpenoids across 163 countries. We found several species accumulate at least seven andrographolide-type compounds and another 17 labdane diterpenoids in our analysis. We conclude that labdane diterpenoid accumulation is more widespread, with multicontinental and shared evolutionary origins, than previously recognized.

Guided by the feature-based molecular networking approach, twenty-five previously undescribed sesquiterpenoid dimers (SDs) designated Inulaenoids A−Y (1−4, 8−25, and 27−29) along with four known analogues were isolated from the roots of Inula helenium L. and Inula racemosa Hook. f. Their structures and absolute configuration were unambiguously elucidated by spectroscopic data, X-ray diffraction, and theoretical calculations. Structurally, compounds 1−19 are rare SDs featuring two eudesmane units directly constructed through C−C bonds, including C-13−C-13′, C-13−C-11′, C-11−C-13′, and through a previously undescribed C-13−C-8′ connection. Fifteen compounds (3, 4, 10, 15−18, 20−23 and 25−28) showed potent cytotoxic activity to Huh-7 and HepG2 cells with the IC₅₀ values ranging from 1.9 ± 0.1 to 20.2 ± 0.3 μM. Among them, four compounds (3, 4, 10 and 17) displayed binding to proto-oncogenic c-Fos. Notably, compound 17 exhibited the highest binding affinity to recombinant human c-Fos, thereby activating TP53 transcription and subsequently driving BAX/Bcl2-mediated apoptosis in liver cancer cells. Taken together, this study expands the structural diversity of sesquiterpenoid dimers from genus Inula as novel c-Fos-targeting lead compounds, providing new insights for the development of natural product-based anti-hepatocellular carcinoma agents.

Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant threat to global public health. Marine natural products provide a rich source of novel chemical entities for tackling MRSA infections. In this study, a series of halogenated 2-benzoylquinazolin-4(3H)-one derivatives (1−48) was designed and synthesized by innovatively integrating halogen pharmacophores with the biologically validated marine alkaloid penipanoid C. Anti-MRSA assays revealed that the introduction of iodine atoms significantly enhanced the activity of this class of compounds. Compound 48 (CHNQD-01748), bearing three iodine atoms, exhibited the most significant and selective antibacterial effect against the MRSA strain with an MIC value of 4 μg/mL against the reference MRSA strain (ATCC 43300) and 8−16 μg/mL against three clinical isolates. Further investigations revealed that 48 possessed a sustained antibacterial effect, potent biofilm-disrupting and biofilm-inhibitory activity, a long half-life, and a favorable preliminary safety profile in the models tested. An in vivo antibacterial assay demonstrated that 48 had vancomycin-comparable efficacy against localized MRSA skin infections yet provided superior suppression of systemic dissemination, inhibiting bacterial loads by >95% in the spleen, lung, and kidney. These findings showed the promising potential of 48 as a potent agent for the treatment of MRSA infections.

Two spirosteroids, epoformsterols A and B (1 and 2), featuring a highly fused 6/6/6/5/6/6 hexacyclic framework, were isolated from the marine-derived fungus Galactomyces pseudocandidus. The structures of 1 and 2 were elucidated by NMR, HRMS, and single-crystal X-ray diffraction. The absolute configuration of 1 was established by comparison of calculated and experimental ECD spectra, and that of 2 was assigned by ECD comparison with 1. Compounds 1 and 2 exhibited inhibitory activity against Candida auris and C. albicans with MIC values of 3.12−12.5 μg/mL, and MFC/MIC ratios suggested a fungistatic mode of action. Both compounds also inhibited C. rugosa lipase (CRL) in a model enzyme assay, with IC₅₀ values of 5.7 and 8.9 μM, respectively. These results identify a distinctive class of fungal steroids with antifungal activity.

Two new lyngbyabellin analogs, Q (1) and R (2), were isolated from a marine cyanobacterial biomat dominated by Moorena sp. Their structures were established primarily by a combination of spectroscopic analyses and degradation reactions. Lyngbyabellin Q (1) inhibited the growth of HeLa cells and disrupted actin dynamics. In addition, lyngbyabellin Q (1) exhibited potent antimalarial activity with an IC₅₀ value of 22 nM, and a new structure−activity relationship enhancing selectivity for the growth inhibition of Plasmodium falciparum over mammalian cells was identified.

Marine cyanobacteria are a rich source of diverse bioactivenaturalproducts, targeting proteins involved in many diseases. Here, we combinedmetagenomic analysis to enhance the structure elucidation processof two new cyclodepsipeptides named dapalides D (1) andE (2) from a collection of a cyanobacterial mat containingmultiple Dapis species from Guam. Dapalides D/E arecomposed of 11 amino acids, including multiple identical units withdifferent configurations. Enantioselective amino acid identificationof the acid hydrolyzate established the identity of amino acids, includingthe configuration of α/β-stereogenic centers. Identificationand analysis of the dapalides D/E biosynthetic gene cluster from ametagenome-assembled genome aided the elucidation of α-configurationand establishment of the order of individual building blocks, collectivelyrevealing the total structure. Phylogenomic analysis indicates thatthe dapalides D/E producer belongs to Dapis sp. (Dapis sp. VPG23–80 MAG-2), which shares a 95.2% averagenucleotide identity with Dapis sp. VPG23–80MAG-1, the producer of dapalides A–C that cooccurs in the sameassemblage. Dapalide D (1) showed moderate growth inhibitoryactivity against various cancer cell lines. This work expands thedapalide structure class and further highlights the use of combinedchemical and metagenomic analyses for natural product structure elucidation.

Chemicalinvestigation of the fungus Penicillium sp. KYS-21 resulted in the isolation of 16 new curvulinic acid–gregatinhybrids (CAGHs), penicurgretides A–P (1–16), together with the only known analogue (17) of this rare class of natural products. Their structures were unambiguouslydetermined by comprehensive spectroscopic analyses, ECD calculations,single-crystal X-ray diffraction, and the modified Mosher’smethod. These hybrids exhibit remarkable diversity, featuring a conserved R-configuration at C-5 but variable stereochemistry at otherchiral centers. The α,β,γ,δ-unsaturated ketonein the C-5 side chain was established as a critical pharmacophore,as penicurgretides A (1) and G (7), bearingthis moiety, exhibited moderate anti-inflammatory activity with IC₅₀ values of 2.94 ± 0.54 and 3.50 ± 0.52 μM,respectively. Mechanistic studies revealed that penicurgretide A (1) suppresses inflammation through inhibition of the NF-κBand mitogen-activated protein kinase signaling pathways, with in vivoefficacy confirmed by reducing nitric oxide and ROS production inan LPS-induced zebrafish model. These findings expand the structuraldiversity of CAGHs and highlight penicurgretide A (1)as a promising lead for anti-inflammatory drug development.

An investigation into Australian pasture soil-derivedmicrobesled to the prioritization of Streptomyces sp. S4S-00182A09due to the media extract ability to inhibit the motility of dog heartworm Dirofilaria immitis microfilariae (Mf), and as asource of natural products with molecular formula unprecedented inthe scientific literature. Fractionation of a scaled-up cultivationextract of S4S-00182A09 yielded the new terpenyl-p-aminobenzoic acids, craterstatins A–D (1–4), together with the known fatty acid, 2-hydroxy-12-methylmyristicacid (5). Structures were assigned to 1–5 on the basis of spectroscopic, ECD, and Marfey’s analyses,as well as biosynthetic considerations and chemical transformation.Of note, craterstatin A (1) proved unstable to storageand handling, especially under acidic conditions, undergoing facileconversion to the stereoisomeric dehydration products craterstatinsB (2) and C (3) that feature an unprecedentedcarbo-heterocyclic framework, with 3 undergoing quantitativeconversion to 2 on storage. While the craterstatins 1–4 did not exhibit anthelmintic activity against D. immitis (EC₅₀ > 100 μM), weakactivity displayed by the hydroxylated fatty acid 5 promptedscreening of a library of synthetic hydroxy fatty acids 6–11, which revealed modest inhibitory activity for (±)-3-hydroxyundecanoicacid (6), (±)-3-hydroxytetradecanoic acid (7), and (±)-3-hydroxypentadecanoic acid (8) (EC₅₀ 16.3, 28.2, and 19.0 μM, respectively).

Ansamycins with diverse ring systems play an indispensablerolein the pharmaceutical industry. A novel 20-membered ester-incorporatingbenzenoid ansamycin, phenolmacrolide A (1), and a newnaphthalenoid ansamycin, olimycin I (2), were obtainedfrom the marine-derived Streptomyces olivaceus NBUA17 using a strategy of combining genome mining, SNAP-MS, andHSQC NMR interpretation tools. Furthermore, investigation of the putativeansamycin biosynthetic gene cluster suggested that the novel benzenoidansamycin scaffold of compound 1 could be formed in partby a hydroxylase and luciferase-like monooxygenase. Compound 1 exhibited moderate activity inhibiting proliferation, migration,and invasion against PANC-1 cells in vitro by inducingcell apoptosis and promoting cancer cell entry into G2/M phase, andinhibiting epithelial-mesenchymal transition. Further drug affinity-responsivetarget stability assay, molecular docking, cell thermal shift assay,and siRNA transfection identified EEF1A2 as a molecular target ofcompound 1 in PANC-1 cells. This study identifies anunprecedented subtype within the benzenoid ansamycin family, broadensthe structural and bioactive diversity of macrocyclic ansamycins,and underscores the potential of marine-derived actinomycetes as aprolific source of pharmacologically promising lead molecules.