Journal of Natural Products 最新文献

Stereochemical assignments of thiazoline-containing cyanobactins, a family of ribosomally synthesized and post-translationally modified peptides, are often complicated due to the propensity of the exomethine and C-4 chiral centers of thiazolines to epimerize under basic and acidic conditions. In this work, we re-evaluate the proposed configuration of the leucine-thiazoline moiety of the cyanobactin-like cyclopeptide keenamide A. Using a fast and adaptable strategy for the synthesis of thiazoline-containing cyclopeptides, we synthesized four possible keenamide A stereoisomers, one of which was oxidized to mollamide C, the thiazole analogue of keenamide A. Comparison of the NMR spectra of synthetic keenamide A stereoisomers with that of natural keenamide A combined with X-ray crystallographic analysis indicates that the originally proposed (R)-configuration of the thiazoline ring of keenamide A must be revised to (S)-configuration. This work highlights the power of synthetic methods to inform the structure elucidation and structural revision of natural products, especially in cases where isolation and purification of natural material are not readily achieved.

The utilization of protecting groups is a well-established strategy in the organic synthesis of natural products. Protecting groups are introduced as temporary masks for reactive functional groups in synthetic intermediates to prevent side reactions and enhance chemoselectivity under synthetic conditions. In contrast, it has long been believed that biosynthetic systems do not require protecting groups because enzymes catalyze reactions with remarkable regioselectivity and chemoselectivity. However, recent studies have revealed that certain biosynthetic systems in microorganisms and plants employ protection–deprotection strategies in natural product biosynthesis. These biosynthetic systems use temporary protecting group modifications to regulate the reactivity of biosynthetic intermediates, thereby preventing undesired side reactions that would otherwise derail pathway fidelity. After fulfilling their protective roles, these protecting groups are enzymatically removed to produce the final bioactive metabolites. Understanding these natural protection–deprotection mechanisms deepens our knowledge of enzymatic chemistry and provides valuable inspiration for pathway engineering and the development of chemoenzymatic synthetic methodologies. This review summarizes the current understanding of protection–deprotection mechanisms in natural product biosynthesis.

Gliotoxin, an epipolythiodioxopiperazine (ETP) toxin, has been reported in several fungal species, but its distribution remains unclear. We analyzed 140 clinical isolates from two major hospitals using HPLC and LC–MS/MS to assess gliotoxin production. Gliotoxin was detected only in Aspergillus fumigatus isolates, with no production observed in any other species under multiple culture conditions. Molecular networking and comparative genomics revealed distinct ETP-related pathways in non-A. fumigatus species, including aspirochlorine derivatives in Aspergillus flavus and aranotin-related metabolites in Aspergillus terreus. These findings clarify species-specific ETP profiles and confirm A. fumigatus as the sole gliotoxin producer among the isolates examined.

Marine mollusks of the order Nudibranchia produce a wide array of secondary metabolites that play key roles in predator-prey interactions and often exhibit remarkable bioactivity. In this study, a chemical investigation of the Mediterranean aeolid nudibranchs Cratena peregrina and Paraflabellina ischitana led to the isolation and characterization of a novel oxylipin, designated cratenin (1). This unique metabolite shows an unusual alkylated monosubstituted tetrahydrofuran (THF) moiety, a structural feature rarely encountered among marine natural products. The planar structure of 1 was fully elucidated by high-resolution mass spectrometry (HRMS) and comprehensive 1D and 2D NMR spectroscopy, while the absolute configuration of the substituted THF ring was rigorously established by chemical degradation, derivatization, and NMR-based stereochemical comparison with known diasteromeric derivatives of (tetrahydrofuran-2-yl)methanol. The co-occurrence of cratenin (1) in the hydrozoan Eudendrium racemosum, a known prey of C. peregrina and other aeolid nudibranchs, strongly suggests its role as a semiochemical which mediates predator-prey interactions. The proposed biosynthetic origin of cratenin (1) from algal docosahexaenoic acid (DHA) further corroborates the hypothesis of dietary acquisition and provides compelling molecular evidence for kleptopredation, a sophisticated foraging behavior where nudibranchs consume prey that has recently ingested phytoplankton. In this view, this study reveals a clear metabolic and ecological link connecting phytoplankton, hydrozoans, and nudibranchs, underscoring the pivotal role of lipid-derived natural products in shaping chemical communication and interphyletic trophic interactions involving opisthobranchs.

α-Glucosidase inhibitory activity-guided isolation led to the discovery of ten alkaloids from the medicinal mushroom Vanderbylia robiniophila SY636, including six new compounds ((+)-1a, (−)-1b, (+)-2a, (−)-2b, 3, and (+)-4a) and four newly reported natural products ((−)-4b and 5–7). Compounds (+)-1a, (−)-1b, (+)-2a, and (−)-2b possess a unique lactam–furan ring system, whereas 3 features a rare tetrahydrobenzo[c]oxepine–furan ring system. (+)-1a, (−)-1b, (+)-4a, and (−)-4b exhibited notable α-glucosidase inhibitory activities, with IC₅₀ values of 160–330 μM (acarbose as the positive control, IC₅₀ = 660 μM). Guided by docking results of bioactive compounds with α-glucosidase, derivatives D1–D28 were designed and synthesized, among which D15 and D19 exhibited stronger activities (IC₅₀ = 28 and 130 μM). Molecular docking and kinetic studies suggested that D15 and D19 interact with α-glucosidase at a single binding site, exhibiting an uncompetitive or mixed type of inhibition mechanism. D19 also exhibited notable antioxidant activity (IC₅₀ = 35 μM), comparable to l-ascorbic acid, suggesting its dual role in combating the development of diabetes. This study provides a foundation for the development of natural medicines from V. robiniophila and offers valuable guidance for future structural optimization toward the discovery of more potent and safer antidiabetic agents.

Two new picolinic acid derivatives, ethylfusaric acid A (1) and ethylfusaric acid B (2), along with two known picolinic acid derivatives (3–4), were isolated from the culture of Rehmannia glutinosa endophytic fungus Epicoccum sorghinum SDU-F549. The chemical structures of the compounds were elucidated by the combination of 1D and 2D nuclear magnetic resonance spectroscopy and electronic circular dichroism calculations. Compounds 1–4 exhibited antibacterial activity against a panel of Staphylococcus aureus strains, with MIC values ranging from 16 to 32 μg/mL. In contrast, they showed no significant cytotoxic activity against a range of human tumor cell lines at 10 μM. Furthermore, bioinformatic analysis revealed that the bty biosynthetic gene cluster in E. sorghinum SDU-F549 is responsible for assembling the picolinic acid derivatives, enabling us to propose the biosynthetic pathways of compounds 1–4.

Encouraging results after assessing the biosynthetic potential of Nocardia sungurluensis YINM00009 with the OSMAC strategy prompted its genomic investigation and the identification of biosynthetic gene clusters encoding putatively novel nonribosomal peptide natural products. Subsequent chemical investigation of this strain resulted in the isolation and characterization of eight new cyclic lipodepsipeptides, designated as nocacyclomycins A–H (1–8). Their structures, including absolute configurations, were unequivocally elucidated through comprehensive spectroscopic analysis, incorporating NMR, HRESIMS/MS, X-ray crystallography, and Marfey’s method. Biological evaluation demonstrated that compounds 5 and 7 displayed significant cytotoxic activities against four human cancer cell lines (A549, HepG2, MDA-MB-231, and SW480) with IC₅₀ values ranging from 3.23 to 9.43 μM and exhibited negligible cytotoxicity in normal cells. A plausible biosynthetic pathway for nocacyclomycins 1–8 has been proposed based on bioinformatic analysis and the structural features of this family.

Five new rifamycin derivatives, named salinirifamycins A–E (1–5), were isolated from a Brazilian marine Salinispora arenicola (BRA-213) strain extract. The structures of the new rifamycins were elucidated using a combination of NMR, IR, UV, and MS spectroscopic techniques, quantum-chemical calculations (DFT-calculated ¹³C NMR chemical shifts and DP4+ probability analysis), and comparison of experimental and calculated electronic circular dichroism (ECD) spectra. Compounds 1, 2, and 4 displayed antibacterial activity against Staphylococcus aureus and Enterococcus faecalis with MIC values ranging from 2.0 to 125.0 μg/mL, whereas 5 exhibited an MIC of 0.02 μg/mL to S. aureus, similar to the positive control rifampicin (MIC 0.03 μg/mL).

Nonheme iron(II) α-ketoglutarate-dependent dioxygenases (Fe/αKGs) play important roles in functionalizing biological substrates from individual amino acids to macromolecules. BesE, a unique homologue from the actinobacterial β-ethynylserine biosynthetic pathway, catalyzes a highly selective hydroxylation on dipeptide substrate γ-l-glutamyl-l-propargylglycine (1). Inspired by this transformation, our year-long Course-based Undergraduate Research Experience (CURE) laboratory interrogated BesE catalysis using an interdisciplinary approach. After establishing a modular chemical synthesis of 1, we rationally designed 14 non-native analogues with key alterations to specific substrate moieties putatively involved in enzymatic recognition. Following in vitro enzymology and the application of chemical derivatization techniques compatible with all substrate analogues and putative products, we determined that the terminal alkyne moiety is not essential while reinforcing the significance of the γ-glutamyl moiety for hydroxylation activity. Thirteen rationally designed BesE mutants established the importance of polar active site residues for substrate recognition and catalysis. This work establishes a baseline of BesE recognition from both a chemical and biochemical perspective and contributes to the growing understanding of Fe/αKG recognition on biomedically relevant targets. Moreover, this contributes to the growing examples of using natural products and their biosynthetic enzymology as a vibrant platform for the interdisciplinary training of early career biomedical researchers.

Natural products (NPs) have long played a pivotal role in medicine, serving as both lead compounds and approved drugs in diverse therapeutic areas. Inspired by the 2004 review “The Role of Natural Product Chemistry in Drug Discovery”, we adopted a data-driven approach to assess the current role of NPs in drug discovery. We identified 119 NP-derived (NP-D) drugs, including 16 antibody-drug conjugates (ADCs), that were first approved globally between January 2000 and September 2025. Their development timelines, source organisms, manufacturing methods, indications, and routes of administration were analyzed. Six NP-D case studies illustrating successful progression from discovery to clinical use were highlighted: omaveloxolone (novel pharmacology, first-in-class), fidaxomicin, ibrexafungerp, epoxomicin, eribulin (known pharmacology, new drug class), and the gliflozin drug family (13 members). We also examined the presence and sales of NP-D agents among the top 200 brand name drugs in 2006, 2015, and 2024. Although overall NP-D drug sales have declined, dapagliflozin and empagliflozin demonstrate that blockbuster status is still achievable. While growth is modest, NPs remain highly valuable active pharmaceutical ingredients (APIs) with substantial clinical impact. Significant opportunities persist for drug-focused NP R&D efforts, as many recently validated therapeutic targets remain underexplored for NP-D chemotypes.