Journal of Natural Products 最新文献

In the search for novel natural products with hepatoprotective effects against acetaminophen-induced acute liver injury, the marine-derived fungus Aspergillus aculeatinus WHUF0198 was investigated. Seventeen undescribed pyranopyridone alkaloids, aculeapyridones A-Q (1-17), were isolated by bioactivity-guided fractionation of an extract obtained by coculture of the A. aculeatinus WHUF0198 with the mangrove-associated fungus Penicillium sp. DM27. Notably, compounds 12-15, which possessed a unique N-methoxy group, were identified as activation products of fungal coculture in liquid media. The structures and absolute configurations of these compounds were elucidated using a combination of universal spectroscopic techniques (NMR and HR-ESI-MS), ECD calculations, and single crystal X-ray diffraction analysis. All the isolated compounds, except 8 and 17, were evaluated for their hepatoprotective activity against acetaminophen-induced acute liver injury in vitro. Compounds 1-7, 9, 10 and 12-15 increased cell viability and reduced alanine aminotransferase (ALT) levels of acetaminophen-induced murine hepatocytes at either 5 or 10 μM.

Inspired by our previous efforts in the semisynthetic modification of naturally occurring pyranoacridones, we report the targeted design and semisynthesis of dual inhibitors of HDAC and topoisomerase II α (Topo II α) derived from Glycosmis pentaphylla des-N-methylacronycine (1) and noracronycine (8) pyranoacridone alkaloids. Designed from the clinically approved SAHA, the cytotoxic pyranoacridone nuclei from the alkaloids served as the capping group, while a hydroxamic acid moiety functioned as the zinc-binding group. Out of 16 compounds evaluated in an in vitro cytotoxicity assay, KT32 (10c) with noracronycine (8) as the capping group and five-carbon linker hydroxamic acid side chains showed good cytotoxic activity with IC₅₀ values of 1.0, 1.5, and 0.3 μM on MCF-7, CALU-3, and SCC-25 cell lines, respectively. KT32 (10c) showed potent HDAC inhibitory activity and partial Topo II α inhibitory activity in both enzyme assays. The SAR results strongly aligned with the predicted binding affinities from the molecular docking study. KT32 (10c) was further explored for a preliminary mechanistic understanding of SCC-25 cell lines. Flow cytometry analysis suggests that KT32 (10c) induces cell death through apoptosis, as evidenced by the substantial increase in the population of late apoptotic cells.

An activity-guided isolation study on the EtOH extract prepared from the bulbs of Prospero autumnale yielded four new phenolic compounds, including a new stilbenoid (1), a new homoisoflavonoid derivative (8), a new homoisoflavonoid dimer (9), and an unprecedented homoisoflavone-stilbene heterodimer (10), together with six known (2-7) analogs. Their chemical structures were elucidated by spectroscopic analysis and theoretical NMR and ECD calculations. Compounds 9 and 10 are unique in their scaffolds. The in vitro cytotoxic activity of purified compounds was evaluated against eight tumor cell lines (HCT116, LoVo, DU145, PC3, HEP3B, HEPG2, MCF7, and MDA-MB-231) and one nontumor cell line (L929) by the MTS assay. Compounds 1, 2, 4, and 10 exhibited inhibition with IC₅₀ values ranging from 8.2 to 37.6 μM. Cytotoxic cell death mechanisms were further investigated, indicating variability in apoptosis, necrosis, or cell cycle arrest.

In the pathogenesis of neurodegenerative diseases, particularly Alzheimer's disease, cholinergic neuron dysfunction and neuroinflammation are integral components. Against this backdrop, within the vast array of potential sources under exploration, Lethariella cladonioides, a remarkable lichen with profound ethnopharmacological significance among various Chinese ethnic minorities, has recently emerged as a promising candidate. Through our comprehensive phytochemical investigation, five undescribed diphenylmethanes (1-5), three unreported depsides (6-8), and one novel diphenylether (9), along with 16 known compounds, were successfully isolated and identified. Their structures were elucidated by spectroscopic analysis and X-ray crystallography. Specifically, compounds 3-7 and 9 exhibited acetylcholinesterase inhibitory activity, while compounds 1, 2, and 4 significantly inhibited NO production by LPS in RAW264.7 cells. Collectively, these findings suggest that L. cladonioides has potential value in preventing and treating neurodegenerative diseases. This potential lies in its ability to potentially retard disease progression or alleviate symptoms by enhancing cholinergic transmission and mitigating neuroinflammation.

A chemical examination of a root extract of Oxytropis trichophysa led to the isolation and identification of 23 compounds, including oxazole-type alkaloids and isoflavonoid derivatives. Notably, three oxazole-type alkaloids (1, 2, and 3) and two isoflavonoid derivatives (7 and 10) were obtained from a natural source for the first time. In addition, O. trichophysa derived 2,5-diphenyloxazoles and their derivatives were synthesized. Despite their potential activity, the antiplasmodial activities of naturally occurring 2,5-diphenyloxazoles and certain isoflavonoids remain unexplored. Therefore, the antiplasmodial activities of both the naturally occurring and synthesized compounds were evaluated against Plasmodium falciparum strain 3D7. Among the tested compounds, three naturally occurring oxazole-type alkaloids (1, 5, and 6), one synthesized alkaloid (34), and two isoflavonoid derivatives (13 and 15) demonstrated significant inhibitory effects, with half-maximal inhibitory concentration (IC₅₀) values ranging from 3.1 to 6.2 μM and selective indices between 0.9 and 18.8. Compound 1 showed the most potent inhibitory activity, with an IC₅₀ of 3.1 μM, while its cytotoxic concentration 50% value against human foreskin fibroblasts was found to be 8.5 μM. The oxazole-type alkaloids and isoflavonoids isolated from this plant provide valuable insights into its chemical composition and may help elucidate the antiplasmodial properties of O. trichophysa.

Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis (Mtb), is still a leading cause of mortality worldwide. Fifty-fungi from a marine-derived fungal library were screened for anti-Mtb activity, and an Aspergillus candidus strain with strong anti-Mtb activity was found. Three known flavones, chlorflavonin (1), dechlorflavonin (2), and bromoflavone (3), were isolated from this fungus. Chlorflavonin and bromoflavone showed inhibitory activity with MIC₉₀ values of 2.6 and 1.2 μM, respectively. In combination with molecular docking, a series of new chlorflavonin derivatives (4-41) were rationally designed and semisynthesized. Three new derivatives substituted with (2)-chlorocinnamate (14), (3)-chlorocinnamate (15), and benzoate (18) at position 2' showed MIC₉₀ values ranging from 0.7 to 1.0 μM, having the potential to be further explored as antitubercular agents.

The Zika virus (ZIKV), an emerging orthoflavivirus, presents a significant public health threat due to its rapid dissemination and association with severe neurological complications. The urgent need for effective antiviral agents has driven research into novel bioactive compounds derived from unique natural sources. Microorganisms inhabiting extreme environments are particularly promising for such discoveries due to their potential to produce unique metabolites. In this study, we explored microorganisms from the underexplored French Polynesian microbial mats known as "Kopara" to identify new bioactive natural products. Using a molecular networking-based dereplication strategy, we investigated various culture and extraction techniques of the strain Nocardia otitidiscaviarum 20-S13, leading to the discovery of two novel glycoglycerolipids, otitiglycomycins A and B (1 and 2). Structure elucidation of these compounds was achieved through NMR spectroscopy, X-ray crystallography, and TDDFT-specific rotation prediction. We found that otitiglycomycin A (1), but not otitiglycomycin B (2), suppresses ZIKV infection at non cytotoxic concentrations without effects on cell viability. Time-of-drug addition assays along with virus inactivation and binding assays demonstrated that 1 neutralizes ZIKV infectivity by preventing the virus from attaching to the host cell membrane.

As part of an ongoing search for new anti-inflammatory agents from medicinal plants, five new dimeric and trimeric flavonoids (1-5) were isolated from the roots of Pistacia weinmannifolia. The structures of pistachalcone A (1), pistachalcone B (2), pistaflavanone A (3), pistachalcone C (4), and pistachalcone D (5) were elucidated by the analysis of spectroscopic data. The known compounds rhuschalcone II (6), rhuschalcone VI (7), and pauferrol B (8) were also isolated and identified. Our in vitro analysis found that compounds isolated from P. weinmannifolia root extract exert anti-inflammatory effects in phorbol myristate acetate (PMA)-induced NCI-H292 airway epithelial cells by the suppression of expression levels such as interleukin-8 (IL-8) and mucin 5AC (MUC5AC), which are closely related to the pulmonary inflammatory response in the pathogenesis of COPD. Therefore, these dihydrochalcone derivatives may have value as new starting materials for the development of drug candidates against COPD.

Quantum chemical spectroscopic calculations have grown increasingly popular in natural products research for aiding the elucidation of chemical structures, especially their stereochemical configurations. These calculations have become faster with modern computational speeds, but subsequent data handling, inspection, and presentation remain key bottlenecks for many researchers. In this article, we introduce the SpectroIBIS computer program as a user-friendly tool to automate tedious tasks commonly encountered in this workflow. Through a simple graphical user interface, researchers can drag and drop Gaussian or ORCA output files to produce Boltzmann-averaged ECD, VCD, UV-vis and IR data, optical rotations, and/or ¹H and ¹³C NMR chemical shifts in seconds. Also produced are formatted, publication-quality supplementary data tables containing conformer energies and atomic coordinates, saved to a DOCX file compatible with Microsoft Word and LibreOffice. Importantly, SpectroIBIS can assist researchers in finding common calculation issues by automatically checking for redundant conformers and imaginary frequencies. Additional useful features include recognition of conformer energy recalculations at a higher theory level, and automated generation of input files for quantum chemistry programs with optional exclusion of high-energy conformers. Lastly, we demonstrate the applicability of SpectroIBIS with spectroscopic calculations for five natural products. SpectroIBIS is open-source software available as a free desktop application (https://github.com/bbulcock/SpectroIBIS).

A structurally novel metabolite, fatuamide A (1), was discovered from a laboratory cultured strain of the marine cyanobacterium Leptolyngbya sp., collected from Faga'itua Bay, American Samoa. A bioassay-guided approach using NCI-H460 human lung cancer cells directed the isolation of fatuamide A, which was obtained from the most cytotoxic fraction. The planar structure of fatuamide A was elucidated by integrated NMR and MS/MS analysis, and a combination of bioinformatic and computational approaches was used to deduce the absolute configuration at its eight stereocenters. A putative hybrid PKS/NRPS biosynthetic gene cluster responsible for fatuamide A production was identified from the sequenced genomic DNA of the cultured cyanobacterium. The biosynthetic gene cluster possessed elements that suggested fatuamide A binds metals, and this metallophore property was demonstrated by native metabolomics and indicated a preference for binding copper. The producing strain was found to be highly resistant to toxicity from elevated copper concentrations in culture media.