Journal of Natural Products 最新文献

Natural products represent a growing class of bioactive compounds with significant therapeutic relevance in modern drug discovery. Especially peptides gained growing attention in pharmaceutical research due to their biological potency, selectivity, and synthetic accessibility. Among these, amphibian skin secretions were recognized as a rich source of bioactive peptides. In this study, we report the synthesis and analysis of the antioxidant and antimicrobial bioactivities of peptides derived from the skin of caudate amphibians, a largely underexplored group in peptide-based drug discovery. Seven caudate amphibian skin peptides, namely salamandrin-I (1), tylotoin (2), ramosin (3), CCK-TV (4), andricin-I (5), Ad-Cath (6), and infraim-I (7) were synthesized by solid-phase peptide synthesis and analytically characterized. Their antioxidant potential was assessed using a radical scavenging assay, while antimicrobial efficacy was evaluated against Gram-positive and Gram-negative bacterial strains as well as yeast as a fungal representative. Finally, their structural features were analyzed by molecular dynamics simulations and circular dichroism spectroscopy. Salamandrin-I and CCK-TV exerted the strongest antioxidant potential, while salamandrin-I and ramosin showed distinct antimicrobial activities. These results highlight the therapeutic potential of caudate amphibian peptides as scaffolds for novel bioactive compounds in natural product-based drug discovery.

The monoterpene citronellol often represents the substrate for the synthesis of other natural products and fragrances bearing α-branched tetrahydropyran moieties. In this contribution, we developed a process that combines in one-pot condition photocatalytic Schenck-ene reaction and biocatalytic halocyclization to synthesize enantiopure α-branched tetrahydropyrans starting from natural monoterpene citronellol. The reaction pathway of the enzymatic haloetherification, studied by combining experimental and theoretical studies, showed for the first time the key role played by the hydroperoxide functional group in the control of the regioselectivity of the cyclization step. Overall, a novel and sustainable synthetic procedure is reported as a new approach for α-branched tetrahydropyrans.

Tetrodotoxin (TTX, 1) is a potent neurotoxin that selectively blocks voltage-gated sodium channels and occurs in various marine and terrestrial organisms, yet its biosynthetic pathway remains unresolved. In this study, five deoxy-type TTX analogues were identified from the toxic newt Cynops ensicauda popei. The structures of four analogues, 6-epi-11-deoxyTTX (2), 8-epi-6-deoxyTTX (3), 1-hydroxy-8-epi-6,11-dideoxyTTX (4), and 1-hydroxy-4,9-anhydro-8-epi-10-hemiketal-5,6,11-trideoxyTTX (5), were elucidated by NMR spectroscopy, and an additional natural TTX analogue, 8-epi-6,11-dideoxyTTX (6), was characterized by high-resolution LCMS/MS. The structural features of these analogues suggest that stepwise oxidation at C-6 and C-11 occurs after formation of a TTX- or 10-hemiketal-type skeleton. Although this oxidative logic parallels that proposed for marine TTX-producing organisms, the analogue profile in newts is clearly distinct from that of marine organisms and is characterized by the presence of deoxy analogues in the 6-epi and 8-epi forms. These findings indicate that, although late-stage oxidative steps in TTX biosynthesis may be conserved, structural diversification has proceeded differently in terrestrial and marine systems, reflecting divergence in their biosynthetic pathways. This study provides insight into stepwise oxidation processes potentially involved in terrestrial TTX biosynthesis. A cell-based assay showed that 6-epi-11-deoxyTTX (2) retains voltage-gated sodium channel inhibitory activity, consistent with previously reported structure-activity trends.

Secondary metabolites (a.k.a. natural products) are believed to play beneficial roles for the producing organisms, such as coping with environmental stress or outcompeting other organisms. Some of them may function as signals. One such class of natural products is the cyclitol/aminocyclitol family of compounds, which includes myo-inositol and its derivatives, the aminoglycoside antibiotics, and the C₇-cyclitols and C₇N-aminocyclitols. While the function of inositol and its derivatives as intracellular signaling molecules has been well established, more recent studies have also demonstrated their important ecological roles. Studies have also shown that aminoglycoside antibiotics may function as signals that regulate biofilm formation in bacteria and secondary metabolite production in fungi. Several C₇-cyclitols and C₇N-aminocyclitols, e.g., acarbose, validamycin, and kirkamide, have been associated with gut microbiota modulation, gene regulation in fungi and insects, and/or plant-bacteria endosymbiosis. While mycosporine-like amino acids (MAAs) are well known for their UV-protective activities, studies with human cells and animals have shown intriguing biological activities involving gene regulation and activation of signaling pathways. This article reviews the roles of this family of natural products as signaling molecules involved in various biological events, including bacterial colonization and gene regulation, with physiological and ecological implications that may affect human health and other organisms.

The rice sheath rot pathogens Sarocladium attenuatum and Sarocladium oryzae share a conserved biosynthetic gene cluster (sarc), which encodes colocalized highly reducing polyketide synthases (HR-PKSs) and type III polyketide synthases (T3PKSs). Heterologous expression of the sarc cluster in the Aspergillus nidulans strain LO8030 led to the production of six previously unreported alkylresorcinols, sarocladones A-D (1-4) and H-I (5-6), along with three putative artifacts arising from 4, sarocladones E-G (4a-4c). Biological screening revealed that 1 and 4c both exhibit mild cytotoxicity against murine NS-1 myeloma cells, with IC₅₀ values of 13 μM and 9 μM, respectively. In addition, 1, 3, 6 and 7 displayed antiphagocytotic activity against THP1 macrophages. Subsequent bioinformatic analysis identified a homologous biosynthetic gene cluster (col) in the genome of the fungal plant pathogen Colletotrichum fructicola. To expand the structural diversity of alkylresorcinols, we employed a gene-mixing strategy, coexpressing the HR-PKS gene colA with the T3PKS gene sarcB in A. nidulans. This resulted in the production of two new sarocladone analogues, collecladones A (7) and B (8), lacking the C-2-C-3 double bond present in the sarocladones. These findings establish HR-PKS-T3PKS collaboration as an underexplored source of fungal chemical diversity.

The fruits of Mallotus philippinensis are an underexplored source of chemically diverse and biologically active natural products, previously reported to exhibit anti-inflammatory, antiviral, and cytotoxic activities. In this study, ion identity molecular networking (IIMN) resulted in the discovery of four previously undescribed phenolic derivatives (runakamalas A-D (1-4)), together with the known compounds mallotophilippen F (5), 3',4'-dihydroxyrottlerin (6), and 4'-hydroxyrottlerin (7). Their structures were elucidated by HRESIQTOF-MS, MS/MS fragmentation analysis, and NMR spectroscopy. The absolute configurations of 1 and 2 were clarified by vibrational circular dichroism (VCD) spectroscopy supported by quantum-chemical calculations, while the enantiomers of racemic 3 were separated by chiral-phase HPLC, and their absolute configurations were determined by a comparison of experimental and TDDFT-calculated ECD spectra. Among the new isolates, 4 is distinguished by a linear C-8-C-1'-C-4' chain, an unusual structural feature compared with other phloroglucinol derivatives reported from this species. In addition, the structure of compound 5 was confirmed. All isolated compounds were evaluated for their cytotoxicity against the human neuroblastoma SH-SY5Y cell line and for their antioxidant activity using the DPPH radical scavenging assay.

Seven new arylalkenyl α,β-unsaturated-δ-lactones, triplinones I-O (1-7), were isolated from the leaves of the Australian rainforest plant Cryptocarya triplinervis B. Hyland (Lauraceae). The chemical structures of these compounds were established by NMR spectroscopic data analysis, while their relative and absolute configurations were established using a combination of Mosher ester analysis utilizing both Riguera's and Kishi's methods and CD experiments. Compounds 2 and 4 were identified as epimers, where the relative stereochemistry of the 1,3-diol moiety in both structures was first confirmed by Kishi's method, followed by their absolute configuration determination using Riguera's method. Compounds 1-7 exhibited good inhibitory activities toward nitric oxide (NO) production in lipopolysaccharide (LPS) and interferon (IFN)-γ-induced RAW 264.7 macrophages, in particular compounds 6, 2, and 4, with IC₅₀ values of 2.1 ± 1.4, 8.5 ± 0.6, and 8.5 ± 0.7 μM, respectively.

The conformational dynamics of flexible compounds can meaningfully influence their NMR spectra and biological activities, yet these effects are easily overlooked. The dibenzocyclooctadiene lignans provide a clear example of this. Although >350 naturally occurring dibenzocyclooctadienes have been published, discrete spectral features have gone unnoticed, and misconceptions about their conformational dynamics pervade the literature. Our attention was drawn to this after observing ¹³C NMR signal broadening at several resonances in a series of new dibenzocyclooctadienes isolated from Kadsura heteroclita, (kadheterins I-K, 1-3). To understand this, we reviewed the ¹³C NMR spectra of 71 published dibenzocyclooctadienes and found that >70% displayed the same broadening, yet the underlying cause had not been clearly rationalized. Systematic analysis revealed that this broadening is associated with key benzylic substituents at C-6. Computational and VT-NMR analyses revealed that these introduce destabilizing steric interactions in the twist-boat chair (TBC) conformation, promoting exchange with the less stable twist-boat (TB). In contrast, certain substituents (e.g., at C-7/C-8) were found to stabilize the TBC. Therefore, many dibenzocyclooctadienes previously described as adopting discrete TB/TBC conformers are interconverting mixtures. We have condensed our observations into a set of rules that predict how common substituents affect ring dynamics in this class of compounds.

The observation that a lactone ring is present in structurally distinct natural classes of sesquiterpenoid and diterpenoid activators of bitter receptor TAS2R46 provided a rationale to investigate the potency of a set of these natural products across the whole range of human bitter receptors. TAS2Rs are responsible for detecting bitter taste and, with some exceptions, are broadly tuned to recognize a wide range of compounds. The ectopical expression of TAS2Rs suggests additional role(s) beyond sensory perception, but no general bitter chemotype has emerged so far to inspire the design of a specific agonist. From our study, a complex pattern of TAS2Rs activation emerged, showing that the lactone pharmacophore is not specific for TAS2R46 but, depending on its framework, can also activate different sets of taste receptors. Taken together, our results expand the role of the lactone ring as a bitter chemotype and qualify dietary terpenoid lactones as excellent lead for the design of specific bitter receptors modulators.

Ten-membered lactones (TMLs) produced by phytopathogenic fungi are considered model compounds for the development of nature-inspired agrochemicals with novel mechanisms of action. Despite their structural simplicity, TMLs display a broad range of biological activities. Although total synthesis methods for many TMLs have been developed, systematic data on their chemical properties remain highly limited. To address this gap, we investigated the reactivity of herbarumin I, 2-epi-herbarumin II, stagonolides J and K, pinolidoxin, and their C-7 oxidized analogs in oxidation, hydrogenation, and isomerization reactions. We demonstrate that their spatially constrained architecture and functional group topology promote distinctive and reproducible reactivity patterns, including stereospecific epoxidation at the C5-C6 bond, mild oxidative cleavage at C7-C8, Pd/Pt-catalyzed allylic transposition, transannulation to chromone derivatives, and base-induced dimerization into fused tetrahydrofuran scaffolds. As a result, 31 new compounds were synthesized, three new reactions were discovered with mechanistic insights provided, and the absolute configuration was established for stagonolide J and stagochromene A and revised for 5,6-epoxypinolidoxin. Preliminary conclusions were drawn about the chemical lability of unsaturated C7-keto derivatives of TMLs in protic media. Such mapping of structure-reactivity relationships within this subclass of TMLs provides a foundation for future semisynthetic derivatization, chemical stability assessment, and rational expansion of biologically relevant scaffolds.