Journal of Natural Products 最新文献

Betaxanthins are natural pigments responsible for the vivid yellow coloration and intrinsic fluorescence of flowering succulent plants within the order Caryophyllales. Though less extensively studied than other plant pigments classes, betaxanthins hold potential for application as safe food dyes, solar cell absorbers, antioxidants, and genetically encodable fluorophores. Herein, we report the absorption spectra, fluorescence properties, and hydrolysis rate constants of 24 distinct betaxanthins obtained by semisynthesis from betalamic acid and a variety of amino acids. The molecular library includes all known derivatives from amino acids present in plants and fungi, as well as cysteine-betaxanthin (which remains undetected in nature) and a selection of model non-natural analogues. Structure-property relationships were examined to contextualize the spectroscopic data. Medium effects on the spectral properties of both betaxanthins and their biosynthetic precursor, betalamic acid, are discussed in terms of light energy dissipation, supporting a proposed photoprotective role for these secondary metabolites in vivo. All spectral data have been made accessible in a PhotochemCAD absorption/fluorescence spectral database, enabling streamlined analysis and quantification.

Kudzu's invasive nature has contributed to its classification as a weed, as it frequently outcompetes native plant species, leading to extensive overgrowth. Efforts to control kudzu have proven challenging, with moderate success using physical or biological agents. In this study, we evaluated the effects of two such control agents, ultraviolet C radiation and Myrothecium verrucaria, to significantly increase the production of tuberosin, a phytoalexin isoflavone. Our findings demonstrate that estrogenic activity of tuberosin is cell-type-dependent, displaying antagonist or competitive inhibition when combined with 17-β-estradiol in the estrogen receptor (ER) positive cell lines MCF-7 and T-47D, while showing dose-dependent agonist activity in HEK293 cells transfected to express both ER receptors (α and β). Tuberosin was shown to modulate ER pathways, alter ER-mediated gene expression, and increase cell proliferation in a dose-dependent manner while maintaining expression of the ERα protein. Binding affinity and docking simulations confirmed tuberosin binding to the ERα pocket in a similar but weaker manner compared to synthetic estrogen. Tuberosin-treated endothelial cells suppressed vascular network assembly and maturation without affecting the cellular proliferative capacity. The presented studies leverage current kudzu management methods to naturally produce tuberosin, examine cell-type-specific effects, and support further investigation as an antiestrogen for breast cancer treatment.

A novel azaphilone dimer, humilone A (1), along with its related monomer, humilone B (2), was isolated from cultures of the marine-derived fungus Humicola sp. HK1-8 using a molecular networking-guided discovery approach. Further investigation of the molecular family of azaphilone dimers led to the putative identification of four analogues, humilones C-F (3-6), based on systematic analysis of their characteristic MS/MS fragmentation patterns. Detailed fragmentation studies of the dimers revealed that the predominant cleavage fragments originated from C-C bond scission at the dimeric methylene bridge. Compound 1 displayed antifungal activity against Rhizoctonia solani.

As part of our long-standing program evaluating the biosynthetic complexity and biomedical potential of natural products from marine microbes, our attention was drawn to culture extracts from a Verrucosispora sp. (strain TAA-831), which produced multiple compounds with unique UV absorbance signatures and HRMS data. Large-scale fermentation and targeted isolation afforded verrucosins A-E (1-5), a mixture of linear and macrocyclic polyketides whose structures were determined through a synergistic combination of experimental, computational, and genomic approaches. The conserved sequence of methyl malonate and malonate motifs across the verrucosins implied a shared biosynthetic origin despite structural divergence as linear and cyclic congeners. Targeted genome mining revealed a lone type I/type III hybrid polyketide synthase biosynthetic gene cluster, vrs, that is likely responsible for verrucosin production. This revelation demonstrates for the first time that linear 3,5-dihydroxybenzenic (1 and 2) and cyclic ansamycin (3-5) polyketides can be naturally produced by a single biosynthetic gene cluster. The identification of the vrs cluster and bioinformatic prediction of the stereoselectivity of the embedded reductive domains within the modular type I polyketide synthase reinforced the NMR and computational stereochemical assignments for the co-isolates, particularly the stereochemically complex linear verrucosins (1 and 2).

The connection between humans and Nature's chemistry is astonishing and built into the very fabric of our genetic code. In this Perspective, we focus on bioactive molecules from microbes, plants, and animals that transformed our health and society and continue to change the course of human history. In light of our changing planet and recent public distrust in science, our intimate connection with Nature and its solutions to our problems are in peril. It has never been more important to invest new effort into understanding the mysteries of life's molecules to preserve our own existence.

The biosynthetic mechanism underlying the formation of thiocarboxylic acid moieties in natural products remains largely unknown. Thioquinolobactin (TQB) is a Pseudomonas fluorescens derived siderophore that contains a thiocarboxylic acid moiety within its structure. Although the biosynthetic gene cluster and proposed pathway for TQB formation have been reported, the biosynthetic mechanism related to the thiocarboxylic acid formation are yet to be fully understood. In this study, we address this question by demonstrating that a unique dual-domain protein QbsL, which possesses both CoA ligase and methyltransferase activities, along with the sulfurtransferase QbsK, facilitates the assembly of the thiocarboxylic acid. Based on this mechanism, we develop a chemoenzymatic method to convert carboxylic acid into selenocarboxylic acid, thereby generating selenium-containing analogues of TQB. These findings resolve the long-standing mystery in TQB biosynthesis and expand the synthetic toolkit for carboxylic acid modification.

Three mutant strains of Streptomyces sp. NRRL 30471 were screened with eight different media based on "One Strain Many Compounds" (OSMAC) and precursor-feeding strategies. Five new muraymycins, D5-D9 (4-8), together with three known congeners were isolated and identified from Streptomyces sp. NRRL 30475 using an optimized BPM23A medium containing methionine, leucine, and arginine (each 1.5 g/L). Structures of new compounds were elucidated using HR-MS and NMR spectroscopic data. Muraymycin D6 (5) represents the first natural muraymycin with phosphorylation at the 3'-OH of the ribofuranoside moiety. Muraymycin D9 (8) features a unique dehydrocyclization of the carboxyl of a valine with the epicapreomycidine imide of the peptide moiety, forming an isopropyl hydantoin structure. Except for muraymycin D8 (7), which lacked the ribofuranose, all isolated muraymycins (1-6 and 8) displayed potent antimycobacterial activity against Mycolicibacterium smegmatis (MIC = 2-32 μg/mL). Specifically, the activities of 1-4 and 6 were even better than those of the positive control isoniazid (MIC = 16 μg/mL). Moreover, muraymycins D1, D2, D4, and D5 (1-4) had antimycobacterial effects against M. tuberculosis with MIC values in the range of 8-16 μg/mL. This finding highlights muraymycin nucleoside has potential for the development of antituberculosis antibiotics.

An antiviral screening of plant extracts from Rutaceae and Annonaceae families led to the isolation of a series of new cycloheptapeptides, comptonellins A-H (1-8), along with the known ternatin (9). These compounds were isolated from the ethyl acetate bark extract of Comptonella drupacea (Labill.) Guillaumin, an endemic Rutaceae species of New Caledonia. Following targeted isolation guided by multi-informative molecular networks, the structures of compounds 1-9 were elucidated through a comprehensive analysis of spectroscopic data. This revealed novel molecules featuring previously unreported and noncanonical amino acids. The absolute configuration of stereocenters was partially determined by advanced Marfey's method. Biological evaluation against Zika virus demonstrated the potent antiviral properties of comptonellin A and comptonellins C-G, with IC₅₀ values ranging from 7 to 240 nM. Further investigations revealed that comptonellin A displayed broad-spectrum antiviral activity, inhibiting Dengue virus, Ross River virus, and SARS-CoV-2. These findings highlight comptonellins as promising antiviral scaffolds, supporting further investigation into their therapeutic potential against emerging viral infections.

Mitochondrial dysfunction has been implicated in many neurodegenerative diseases, such as Parkinson's disease, and mitoprotective metabolites may hold the key to potentially effective treatments. In this study, comprehensive chemical investigation of an Australian marine sponge, Aaptos lobata, led to the isolation of three new aaptamine-type 1H-benzo[de][1,6]-naphthyridine alkaloids, namely 3,6'-diaaptamine (2), aaptanone A (3) and 8-demethylaaptamine (4), alongside four known compounds, 8,8',9,9'-tetramethoxy-1H,1'H-3,3'-bibenzo[de][1,6]naphthyridine (5), aaptanone (6), 9-methoxy-N-demethylaaptanone (7) and aaptamine (1). The structures of these compounds were determined using an analysis of spectroscopic data. Biological evaluation in SH-SY5Y using 6-OHDA as neurotoxin revealed that compounds 2, 3, 4, 5 and 7 displayed potent mitoprotective activity, effectively attenuating cell death with apparent EC₅₀ values ranging from 0.05 μM to 1.06 μM. These compounds also mitigated mitochondrial membrane depolarization with apparent EC₅₀ values between 0.021 μM and 0.78 μM. These findings highlight the therapeutic potential of A. lobata-derived alkaloids as promising candidates for mitochondria-targeted drug development.

Tandem mass spectrometry (MS/MS)-based molecular networking has emerged as a powerful tool for rapid dereplication of known compounds and discovery of novel structural analogues within the same metabolite class. In this study, the chemical diversity of indolo-sesquiterpene hybrids from the mangrove rhizosphere soil-derived fungus, Aspergillus terreus N4-9, was investigated by using molecular networking strategies. The known indolo-sesquiterpene hybrid terreuside B (1) along with three new analogues, terreusides C-E (2-4), were targeted isolation from the fungal cultures. Additionally, three putative new congeners, terreusides F-H (8-10), were tentatively identified through systematic analysis of their characteristic MS/MS fragmentation patterns. Detailed fragmentation studies revealed two predominant cleavage pathways for these hybrids related to fracture of the methylene bridge connecting Rings A and B (Type I) and furan opening in Ring C (Type II). Compound 2 demonstrated significant growth inhibitory activity against human gastric cancer SGC-7901 cells with an IC₅₀ value of 6.25 μM.