Brachycybe is a genus of the millipede subterclass Colobognatha, a group that exhibits rare social characteristics, including species aggregations and male brood care. Although it has been hypothesized that alkaloid-based defensive secretions may also function as pheromones, no studies have examined these traits. Here, we evaluated the chemical secretions of six species, two of which had not been previously studied, and conducted Y-tube pheromone assays. Chemical investigations elucidated the structures of three new metabolites: hydrogosodesmine acid (6), homo-hydrogosodesmine acid (7), and buzonamine acid (8). Y-tube pheromone assays revealed that Brachycybe producta is significantly attracted to conspecifics (p = 0.0428) and is deterred by a different species of alkaloid-producing millipede (p = 0.0161). The former assay was repeated using a mixture of the crude (p = 0.0428) and purified (p = 0.0433) chemical defense secretion fromB. producta. This study provides the first evidence that colobognath millipede chemical secretions serve both defensive and pheromone roles.

Six new nor-terpene endoperoxides, diacarnusins A-F (1-6), along with five known ones (7-11), were isolated from the extract of the Red Sea sponge Diacarnus erythraeanus, which presented cytotoxic activity against the colon carcinoma cell line. The structure elucidation was performed by analysis of mass spectrometric and 1D and 2D NMR data. The relative and absolute configurations of the stereocenters of the compounds were deduced based on the Capon and Macleod empirical rule and comparison of the sign of their specific rotations with those of endoperoxides with proven absolute configurations. The cytotoxicity of the pure compounds was evaluated against a panel of cancer cell lines. The structure elucidation and biological activity of the compounds are discussed.

Bafilomycin and concanamycin analogs (1-3) are microbial natural products with potent V-ATPase inhibitory activity. Despite their promising therapeutic potential, limited access to these plecomacrolide scaffolds has constrained their broader bioactivity evaluation. Here, we report an integrative approach combining genome mining, strain engineering, and molecular networking to expand the chemical diversity of natural concanamycin analogs. Genome analysis identified a concanamycin-like biosynthetic gene cluster in Streptomyces humidus with a unique genetic architecture, suggesting that it may encode previously uncharacterized analogs. Coupling strain engineering, untargeted metabolomics, and feature-based molecular networking of the engineered S. humidus strain expedited dereplication and visualization of an underexplored subnetwork of concanamycin-like metabolites. This prioritization strategy enabled the isolation of five known analogs (4-7, 9) and three new analogs that we termed tanamycin E, X, and F (10-12). Optimization of cultivation conditions for the engineered S. humidus strain facilitated the isolation of 93.0 mg of TAN-1323 D (9) and 24.7 mg of the newly identified compound 10, per liter of culture. Collectively, this work provides scalable strategies for accessing and prioritizing new derivatives, overcoming traditional limitations in the production and discovery of bioactive natural products.

Coccidioidomycosis, or Valley fever, is a fungal respiratory disease caused by Coccidioides immitis or Coccidioides posadasii. Clinical manifestations range from asymptomatic infection to chronic pulmonary disease. Despite the increasing endemic range and affected population, therapeutic strategies display moderate efficacy and adverse side effects. This study explores California's rich botanical diversity as a source for agents that inhibit the early stages of Coccidioides development. We established a screening protocol containing a colorimetric metabolism assay and microscopic imaging. We then applied this protocol to extracts derived from local plants in San Diego, California, and discovered a potent inhibitor, persenone A, from avocados.

Factor inhibiting HIF-1α (FIH) is a 2-oxoglutarate-dependent oxygenase that controls hypoxia signaling and metabolic homeostasis by hydroxylating HIF-1α. Although selective pharmacological inhibition of FIH represents an emerging therapeutic strategy for metabolic disorders, structurally diverse natural inhibitors remain largely unexplored. Here, we identified five natural FIH inhibitors spanning distinct phytochemical classes, including three flavonoids (wogonin, luteolin, morin), a coumarin (isofraxidin), and an anthraquinone (rhein). Co-crystal structures revealed that structurally diverse natural products converge on a common bidentate metal-chelation geometry within the FIH active site despite substantial differences in scaffold architecture. Among these inhibitors, wogonin most closely mimicked the orientation of the HIF-1α Asn803 side chain within the substrate-binding cleft, resulting in inhibitory potency comparable to that of the 2-oxoglutarate analog N-oxalylglycine. These findings establish the first structural framework for natural-product-based FIH inhibition and demonstrate that structurally distinct natural inhibitors adopt a conserved metal-chelation geometry within the FIH active site. This framework provides a basis for the future development of metabolically oriented FIH inhibitors.

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

Nigroepocins A-D (1-4), along with one known compound clavatol (5), were isolated from the fermentation broth of Nigrospora sp. SN56127. Their structures, including absolute configurations, were determined by NMR, MS, and single-crystal X-ray diffraction analyses. Each of the four compounds (1-4) possesses a three-membered epoxy ring, which is rare in other compounds isolated from Nigrospora. All compounds (1-5) were evaluated for their antifungal activities against Fusarium graminearum, and nigroepocin A (1) exhibited inhibition with EC50 values of 110 and 23.1 μM against mycelial growth and conidial germination, respectively.

Thirteen new 4-acyl-5-amino-1H-imidazole alkaloids (1-13) were identified from cultures produced by the marine-derived Streptomyces sp. OUCMDZ-944 using feature-based molecular networking (FBMN)-guided isolation. Notably, compounds 1 and 2 were identified as phenyl-containing derivatives, specifically 5-amino-4-phenylpropionylimidazole (1) and 5-amino-4-phenylbutyrylimidazole (2). Ten isolates (4-13) are hydroxylated, with compound 13 being identified as a novel dimeric analogue. Furthermore, five methylated derivatives, 1a, 4a, 4b, 17a, and 17b, were synthesized. In an in vitro depression model, compounds 1, 4, 4a, 4b, 8, 16, and 17b were found to significantly reduce IL-1β levels, while compounds 1, 1a, 4b, and 10 notably reversed the corticosterone-induced decrease in brain-derived neurotrophic factor (BDNF) expression, suggesting a potential antidepressant-like activity. In the zebrafish anxiety model, compounds 1, 1a, 4b, 16, and 17b significantly enhanced spontaneous locomotor activity, reduced thigmotaxis behavior, and increased time spent in the inner zone under various lighting conditions, demonstrating clear anxiolytic-like effects. These five compounds were identified as promising lead candidates with dual anxiolytic and antidepressant potential.

An investigation into Australian pasture soil-derived microbes led to the prioritization of Streptomyces sp. S4S-00182A09 due to the media extract ability to inhibit the motility of dog heartworm Dirofilaria immitis microfilariae (Mf), and as a source of natural products with molecular formula unprecedented in the scientific literature. Fractionation of a scaled-up cultivation extract of S4S-00182A09 yielded the new terpenyl-p-aminobenzoic acids, craterstatins A-D (1-4), together with the known fatty acid, 2-hydroxy-12-methylmyristic acid (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 storage and handling, especially under acidic conditions, undergoing facile conversion to the stereoisomeric dehydration products craterstatins B (2) and C (3) that feature an unprecedented carbo-heterocyclic framework, with 3 undergoing quantitative conversion to 2 on storage. While the craterstatins 1-4 did not exhibit anthelmintic activity against D. immitis (EC50 > 100 μM), weak activity displayed by the hydroxylated fatty acid 5 prompted screening of a library of synthetic hydroxy fatty acids 6-11, which revealed modest inhibitory activity for (±)-3-hydroxyundecanoic acid (6), (±)-3-hydroxytetradecanoic acid (7), and (±)-3-hydroxypentadecanoic acid (8) (EC50 16.3, 28.2, and 19.0 μM, respectively).

Nucleoside analogs represent one of the largest classes of anticancer and antiviral therapies, many of which have been directly or indirectly developed as a result of nucleoside natural product discovery. Over the past decade, renewed interest in this class has led to the discovery of diverse nucleoside analog natural products from microbial, marine, and fungal sources, often featuring unprecedented modifications to the nucleobase, and/or the ribose sugar 2', 3', 4', and 5' positions. This review provides a comprehensive update of novel nucleoside natural products reported between January 2015 and January 2026, encompassing their isolation, structural elucidation, biological activities, and synthetic and biosynthetic studies. Expansions to key families such as muraymycins, pseudouridimycin, tunicamycins, and puromycin analogs are discussed alongside structural revisions and unique metabolites that expand the chemical space of nucleosides. By consolidating recent advances and highlighting emerging structural and biological trends, this review aims to provide a resource for researchers in natural product chemistry, chemical biology, and medicinal chemistry, and to inspire new nucleoside drug discovery programs.

Increasing exposure to blue light has raised concern about retinal injury, particularly in retinal pigment epithelial (RPE) cells. N-retinylidene-N-retinylethanolamine (A2E), a photosensitive fluorophore associated with age-related macular degeneration, is an important mediator of this process. In this study, feature-based molecular networking guided the identification of cordylutenes A-J (1-10), a new molecular family of blue light-protective fungal pigments from Cordyceps militaris. These metabolites possess a previously unreported symmetric all-E C20 polyene dicarbonyl skeleton with carotenoid-like UV absorption. They were characterized at the molecular-family level by shared UV features and diagnostic, internally consistent MS[2] fragmentation patterns. Cordylutenes A (1) and B (2) were isolated as representative members for structural characterization. In an A2E-mediated blue-light injury model in ARPE-19 cells, the cordylutene complex (CCL, 1 μg/mL) and cordylutene A (1, 0.1 μg/mL) improved cell viability to 84.78 ± 4.02% and 92.14 ± 1.88%, respectively, and reduced intracellular oxidative stress to 63.67 ± 3.33% and 43.89 ± 9.59%, respectively. These findings identify cordylutenes as a new family of fungal pigments with protective effects in an A2E-mediated photo-oxidative retinal cell injury model.

A combined bioassay- and [1]H NMR-guided isolation strategy led to the discovery of four new terpenoids, including three xeniaphyllane-type diterpenoids, sclerohumins P-R (1-3), and a norcaryophyllene-type, sclerophyllene A (4), from the soft coral Sclerophytum humesi. The structures and absolute configurations of these compounds were elucidated by comprehensive spectroscopic analysis, including NMR, HRESIMS, SOR, TDDFT-ECD, and DP4+ probability analysis. The stereogenic centers at C-15 in related xeniaphyllanes were proposed for the first time based on comparative SOR analysis. Compounds 1 and 2 possess a tricyclic 4/9-fused carbocyclic framework featuring an epoxide moiety, whereas compounds 3 and 4 exhibit related bicyclic scaffolds. A plausible biogenetic pathway originating from geranylgeranyl pyrophosphate (GGPP) was proposed to account for their structural diversity. Compounds 1 and 2 showed potent AChE inhibitory activity (IC50 = 1.7 and 4.4 μM, respectively), while being inactive against BChE and noncytotoxic toward normal cell lines (HEK293 and Vero). Mechanistic studies combining enzyme kinetics and molecular docking revealed that 1 and 2 act as mixed-type AChE inhibitors, with Ki values of 1.02 and 1.87 μM, respectively. These findings represent the first report of xeniaphyllane-type diterpenoids with potential for neurotherapeutic development.

Chemical investigation of the fungus Penicillium sp. KYS-21 resulted in the isolation of 16 new curvulinic acid-gregatin hybrids (CAGHs), penicurgretides A-P (1-16), together with the only known analogue (17) of this rare class of natural products. Their structures were unambiguously determined by comprehensive spectroscopic analyses, ECD calculations, single-crystal X-ray diffraction, and the modified Mosher's method. These hybrids exhibit remarkable diversity, featuring a conserved R-configuration at C-5 but variable stereochemistry at other chiral centers. The α,β,γ,δ-unsaturated ketone in the C-5 side chain was established as a critical pharmacophore, as penicurgretides A (1) and G (7), bearing this 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-κB and mitogen-activated protein kinase signaling pathways, with in vivo efficacy confirmed by reducing nitric oxide and ROS production in an LPS-induced zebrafish model. These findings expand the structural diversity of CAGHs and highlight penicurgretide A (1) as a promising lead for anti-inflammatory drug development.

Streptomyces are vital sources of bioactive metabolites. From Streptomyces sp. AN091965 culture extracts, seven secondary metabolites were identified. Five showed nematicidal activity: spectinabilin (1), its unprecedented derivative (Z,E,E,Z)-spectinabilin (2), homoaureothin (3), undecylprodigiosin (4) and metacycloprodigiosin (5), while two spectinabilin derivatives, SNF 4435C (6) and SNF 4435D (7) were immunosuppressive. Subsequent biological assays demonstrated that compound 2 exhibited remarkable nematicidal activity, surpassing the commercial agent fosthiazate and showing comparable efficacy to abamectin. This study not only reports a novel nematicide but also demonstrates the strain's unique capacity to produce multiple nematicides, serving as a promising host strain for biopesticide production.