Journal of Natural Products 最新文献

Guided by the serine protease inhibition assay, four novel linear peptides, conicamides A−D (1−4), were isolated from the marine sponge Theonella conica collected in two different locations in the Red Sea. Conicamides C (3) and D (4) consist of the unique α-keto-β-amino acid, keto-homo-tyrosine, and were found to inhibit the serine proteases chymotrypsin and elastase. Conicamides C (3) and D (4) are the first characterized linear peptides containing a C-terminal α-keto-amino acid. The structure elucidation of the compounds was established based on ¹H and ¹³C 1D NMR, homo (¹H−¹H) and hetero (¹H−¹³C and ¹H−¹⁵N) nuclear 2D NMR experiments, and HRMS. Marfey’s method was used to determine the absolute configuration of their amino acids (except tyrosine). Synthesis of conicamides A (1) and B (2) and additional analogs was used to confirm the absolute configuration of tyrosine.

Saclipins A and B are ultraviolet (UV)-absorbing oxylipin metabolites isolated from the freshwater cyanobacterium Aphanothece sacrum (Suizenji-nori) and represent promising candidates as naturally derived UV-filter compounds. Here, we identified lipoxygenase AsLOX2 as a key enzyme initiating saclipin biosynthesis and establish a practical route for saclipin production from α-linolenic acid (ALA). Using ALA as a substrate, AsLOX2 catalyzed oxygenation at the C9 and C16 positions, generating a hydroperoxide intermediate associated with saclipin biosynthesis. Although the endogenous enzymatic step converting this intermediate into saclipin remains unresolved, we demonstrate that the AsLOX2-derived intermediate can be chemically converted into saclipins via SnCl₂ reduction followed by MnO₂ oxidation. These findings define the gateway reaction in saclipin biosynthesis and provide an experimental route for saclipin production, facilitating the future development of naturally derived UV-protective materials.

Long-chain alkyl sulfate 1, three new derivatives 2−4, and (−)-loliolide-3-sulfate (7) were isolated from the solitary ascidian Ascidiella aspersa. The structures of compounds 1−4 were elucidated by NMR spectroscopy, HRESI-MS/MS, and chemical degradation. Disulfates 1 and 4 were localized predominantly in the intestinal tissue, whereas monosulfates 2 and 3 were enriched in the gut contents and intestinal lumen. Although monosulfates were minor metabolites compared with the major disulfate 1, they were released into seawater in substantially larger amounts. Mass spectrometry imaging confirmed the distinct spatial distribution of disulfates within the intestinal tissue and monosulfates in the gut contents. Furthermore, compound 1 was contained in larvae and juveniles but was not detected from egg extracts, suggesting that 1 appears after fertilization and larval development. Together, these findings reveal a clear functional differentiation between mono- and di-sulfated alkyl sulfates, suggesting that disulfates are selectively retained as endogenous metabolites, whereas monosulfates are preferentially released into the surrounding seawater. This study provides the first evidence for tissue-specific localization and differential release of long-chain alkyl sulfates, offering new insights into their ecological and physiological functions in ascidians.

A novel series of cannabichromene-derived amine and amide analogues (4−13) was synthesized and evaluated for their anticancer activity against the NCI-60 human tumor cell line panel. Among the synthesized derivatives, compounds 8 and 9 demonstrated the most potent and broad-spectrum anticancer activities, exhibiting significant percent growth inhibition across multiple cancer subtypes. Notably, compound 9 displayed good potency in prostate cancer cell lines PC-3 and DU-145, with GI₅₀ values of 2.01 μM and 1.86 μM, respectively and pronounced cytotoxicity at higher concentrations. Its consistent performance across diverse cancer panels suggests a non-selective yet potent mechanism, likely targeting essential cellular pathways common to malignant cells. Compound 9 was found to induce apoptosis in PC-3 and DU-145 cells. Collectively, these findings highlight 9 as a promising compound for further optimization and mechanistic exploration towards developing new anticancer leads derived from the cannabichromene scaffold.

Calomembranone G, isolated from Calophyllum membranaceum, displays in vivo anti-inflammatory activity in models of arthritis and acute lung injury. Using natural product calomembranone G as a hit compound and leveraging a strategy of structural simplification, a total of 66 pyranochromone derivatives were synthesized and their structure−activity relationships were analyzed. Among these analogues, compound PC-C7 displayed the most potent anti-inflammatory activity, inhibiting NO production with an IC₅₀ value of 0.17 ± 0.07 μM. Surface plasmon resonance, molecular docking, and co-immunoprecipitation assays demonstrated that PC-C7 disrupts the formation of the TLR4−MD2 complex. In vivo, oral administration of PC-C7 (10 or 20 mg/kg) alleviated joint inflammation and chondrocyte catabolism, through suppressing TLR4-mediated inflammatory signaling. These findings demonstrated that PC-C7 might serve as a drug candidate for osteoarthritis therapy.

(±)-Nigronetides A−D (1−4) and nigronetides E−H (5−8), polyketides with complex carbon skeletons, were isolated from cultures of the marine-derived fungus Nigrograna sp. M13, presenting three novel carbon skeletons. While the planar structures and relative configuration of (±)-nigronetides A−D (1−4) were established by analysis of spectroscopic data, the absolute configuration of nigronetides E−H (5−8) was assigned using a combination of analysis of NOESY data, quantum chemical NMR calculations, as well as by comparison between experimental and calculated electronic circular dichroism (ECD) spectra. (±)-Nigronetides A−D (1−4) were isolated as scalemic mixtures of an almost identical ratio between enantiomers. Compounds 1−8 were inactive in antiplasmodial assays against the Plasmodium falciparum 3D7 strain as well as in cytotoxicity assays against several cancer cell lines.

New approaches to induce expression of microbial secondary metabolite biosynthetic pathways can accelerate natural product discovery. Here, we present a high-throughput media screening (HTMS) workflow that builds on classical fermentation optimization strategies in which small changes in media composition alter secondary metabolite production. Rather than relying on predefined media recipes, HTMS uses robotic liquid handling to systematically generate and test combinatorial mixtures of commonly used media components, enabling exploration of hundreds of previously untested growth conditions. To validate the approach, we applied HTMS to three actinomycetes: the model organism Streptomyces coelicolor, an unexplored soil isolate Streptomyces GA7, and Amycolatopsis keratiniphila, selected for its encoding of the cryptic keratinimicin glycopeptide family. HTMS yielded three principal findings. First, production of actinorhodin and undecylprodigiosin in S. coelicolor was strongly dependent on specific media formulations. Second, optimized HTMS conditions increased production of target metabolites in Streptomyces GA7 by up to 22-fold. Finally, HTMS identified a small subset of the tested conditions under which keratinimicin A and C1, a previously unreported member of this family, were produced. Together, these results demonstrate that HTMS is a powerful platform for systematically perturbing secondary metabolism in actinomycetes and may accelerate the discovery of cryptic or bioactive natural products.

We report the genome-guided discovery, isolation, and characterization of floridanemastatin (1), a previously undescribed statine-containing polyketide−peptide from Floridanema evergladense BLCC-F167. Examination of the biosynthetic gene clusters in the F.evergladense genome revealed a hybrid PKS−NRPS biosynthetic gene cluster featuring an NRPS module followed by a PKS ketoextension and ketoreductase domain arrangement diagnostic of statine biosynthesis. Guided by this prediction, LC−MS-based analysis of cultured biomass led to the isolation of floridanemastatin. High-resolution mass spectrometry and comprehensive 1D and 2D NMR spectroscopy defined a polyketide−peptide scaffold incorporating serine, proline, a leucine-derived amino alcohol, and a statine-like residue identified as 4-amino-3-hydroxy-(4-hydroxyphenyl)pentanoic acid. Connectivity and residue assignments were consistent with the predicted biosynthetic logic of the gene cluster, including reductive chain termination to yield an alcohol. Although the statine pharmacophore and in silico target prediction suggested cathepsin D as a plausible target, enzymatic evaluation indicated that apparent inhibition was attributable to nonspecific aggregation under the assay conditions. These findings demonstrate the utility of biosynthetic gene cluster architecture for prospecting statine-containing cyanobacterial natural products and further highlights the genus Floridanema as a source of chemically distinctive specialized metabolites.

Miasporone (1), a new diterpenoid featuring a 6/7/5-fused tricyclic skeleton, was isolated from the deep-sea-derived fungus Microascus algicola C7-37M2. Its planar structure and absolute configuration were elucidated by spectroscopic analysis combined with GIAO/DP4+ NMR and TDDFT-ECD calculations. Miasporone dose-dependently reversed lipopolysaccharide (LPS)-induced M1 macrophage polarization by suppressing nitric oxide (NO) production, scavenging mitochondrial reactive oxygen species (ROS), and downregulating NLRP3 expression without appreciable cytotoxicity. Consistent with its in vitro efficacy, miasporone exhibited potent anti-inflammatory and analgesic activities in a Complete Freund’s Adjuvant-induced mouse model, attenuating hyperalgesia, restoring gait coordination, and alleviating paw hyperemia, with efficacy comparable to that of dexamethasone. These findings highlight miasporone as a structurally distinctive fungal diterpenoid and a promising lead for anti-inflammatory and analgesic drug development.

The red alga, Callophycus serratus, is the source of highly halogenated meroditerpenes, including iodocallophycol E (1e), whose stereostructure was assigned as (2S,6S,7S,10S,14R); however, doubt was raised about the C10 and C14 configuration. Here, we revise the absolute configuration of 1e to (10R,14S) employing van’t Hoff’s principle of optical superposition and comparisons with analogs (proxies) of the ring C of 1e, including β-snyderol (2) and related sesquiterpenes. A brief error analysis shows that the optical superposition method improves the accuracy over single-point comparisons of optical rotations, leading to higher confidence and reliability in stereoassignments.