Journal of Natural Products 最新文献

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by the absence of estrogen, progesterone, and HER2 receptors, limiting treatment options due to the lack of targeted therapies. Survivin (BIRC5), an inhibitor of apoptosis (IAP) protein, is overexpressed in TNBC and contributes to tumor progression, chemoresistance, and poor prognosis. Cephalochromin, a fungal-derived bioactive compound, has demonstrated cytotoxic activity in various cancer models; however, its effects on breast cancer remain unexplored. In this study, we evaluated the antineoplastic potential of cephalochromin in breast cancer cells, focusing on its impact on cell viability, apoptosis, cell cycle regulation, and survivin modulation. Cephalochromin exhibited potent cytotoxic effects in TNBC models, inducing apoptosis, disrupting cell cycle progression, and downregulating survivin expression. Mechanistically, cephalochromin treatment induced PARP1 cleavage and increased the expression of γH2AX, SQSTM1/p62, and LC3BII. Gene expression analysis revealed the broad modulation of key regulators involved in apoptosis, DNA damage response, and macroautophagy. Furthermore, cephalochromin enhanced the cytotoxicity of paclitaxel and doxorubicin, showing additive synergistic interactions. In conclusion, our study provides compelling evidence of cephalochromin’s antineoplastic activity in breast cancer, highlighting its potential to improve treatment outcomes. Further preclinical studies are warranted to validate their therapeutic efficacy and safety.

Thirteen previously unreported ascochlorin-type meroterpenoids, acrocholrins A–M (1–13), together with seven known analogues (14–20) were characterized from the deep-sea-derived fungus Acremonium sclerotigenum LW14 guided by LC-MS/MS-based molecular networking. Their structures and absolute configurations were determined unambiguously by spectroscopic analysis, electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction experiments. Compounds 1/3, 2/14, 6/7, 8/17, and 15/16 are diastereomers isomerized at C-10. Additionally, compounds 5, 11, 12, and 13 represent rare ascochlorin analogues featuring an uncommon 19S configuration in the cyclohexanone ring. Compounds 9, 11, and 19 exhibited antifungal activity against Cryptococcus gattii 3271G1 with the same minimum inhibitory concentration (MIC) of 4 μg/mL. Preliminary mechanistic studies showed that compound 9 exhibited its anti-C. gattii activity by inhibiting capsule formation and increasing cell membrane permeability.

Phytochemical investigation on the aerial parts of Oreomecon nudicaulis resulted in the identification of eight new benzylisoquinoline-derived secondary metabolites, including four unusual C-6–N-17 bond cleaved isopavine alkaloids oreonudines A–D (1–4), two isopavine alkaloids oreonudines E (5) and F (6), one rhoeadine alkaloid oreonudine G (7), and one morphinane alkaloid oreonudine H (8), along with 10 previously reported analogues 9–18. Their structures were determined by comprehensive spectroscopic and spectrometric analyses, single-crystal X-ray diffraction, and quantum chemical calculations of ECD spectra. In vitro studies using HT22 mouse hippocampal neuronal cells revealed that the previously reported compounds 12, 15, and 16 exhibited potent inhibition of serotonin (5-HT) and/or norepinephrine (NE) reuptake. Among them, mecoquitupline (15) showed significant inhibitory activity against 5-HT (88.0%) and NE (58.8%) reuptake, outperforming the tricyclic antidepressant amitriptyline (53.6% and 35.5%, respectively), and notably activated the neurotrophic BDNF/CREB signaling pathway. Molecular docking and drug affinity responsive target stability (DARTS) assays further confirmed the binding of 15 to both serotonin transporter (SERT) and norepinephrine transporter (NET). In contrast, 12 and 16 selectively inhibited NE and 5-HT reuptake, respectively, by targeting the corresponding transporters. These findings highlight mecoquitupline (15) as a promising dual-action antidepressant candidate with potent activity.

Here we disclose the total synthesis of two regioisomeric ribose-linked 1,2,3,4-tetrahydroquinoxaline-6-carboxylic acids (1) for the first time. This effort helped to reassign the originally proposed structure of a natural product isolated from a Chinese medicinal plant, Caulis Sinomenii, and correct the biological activity reported in the patent. The use of commercially available methyl 4-fluoro-2-methyl-5-nitrobenzoate as a starting material to access both regioisomers, installation of the amino-sugar moiety, and construction of the quinoxalinedione ring using diethyl oxalate are the key highlights. In addition, we showed that readily available riboflavin can also be converted to the natural product (revised structure). Evaluation of the antibacterial activity of both target compounds showed no activity (up to 512 μg/mL) under the test conditions employed in this study.

Naphthoquinones can be found in Nature in various formats, both as standalone molecules and as building blocks for larger structures. A study of the fungus, Pyrenochaetopsis sp. (strain MSX63699), led to the isolation of naphthoquinone analogues (1-21), including both monomers and heterodimers and seven new compounds─three kirschsteinin analogues (11-13) and four perenniporides (18-21). The structures of these were elucidated through analysis of data from 1D and 2D NMR, HRESIMS, and ECD experiments, and several compounds displayed cytotoxic activity against melanoma (MDA-MB-435) and ovarian (OVCAR3) cancer cell lines, with structure–activity trends suggesting key roles for specific substituents in enhancing bioactivity. Notably, compounds 3-6, 9, 11, 15, and 19–20 had IC₅₀ values that ranged from about 1 to 5 μM against both cell lines. Overall, this work expands the chemical diversity of fungal naphthoquinones by identifying new heterodimeric and perenniporide-type analogues and underscores the untapped biosynthetic potential of the Pyrenochaetopsis species.

We report a new optically active sulfoxide containing natural product isolated from an Alaskan Latrunculia spp. collection off the shores of the Aleutian Islands which we term aleutianamine B. It was identified and characterized in part via contemporary computational tools. Global Natural Products Social Molecular Networking (GNPS) analysis was a key tool used in identifying aleutianamine B in the crude extract. The relative configuration of the unique stereogenic sulfur atom was determined by DFT computational analysis. We also report the synthesis of aleutianamine B from aleutianamine. Aleutianamine B was evaluated against ovarian cancer and normal cell lines. This revealed that aleutianamine B retained submicromolar potency against A2780 cells while being ≥50-fold less potent on noncancerous cells; this was in stark contrast to the parent compound, aleutianamine, which displayed potent cytotoxicity against normal cell lines. Overall, the pyrroloiminoquinone (PIQ) class increasingly reveals unique selectivity and potency for tumor cell groups that are currently resistant to available chemotherapy, providing significant leads for therapeutics and biochemical probes.

Spiroconyone B (1) and C (2), two unique steroids bearing rare spiro[4.5]decane and oxaspiro[4.5]decane scaffolds, along with four analogues (3–6) were isolated from the sea star Patiria pectinifera. Structures were established by comprehensive spectroscopic analysis, quantum-chemical nuclear magnetic resonance calculations, electronic circular dichroism data, and single-crystal X-ray diffraction. Compounds 1, 4, and 5 exhibited cytotoxicity toward HL-60 cells with IC₅₀ values of 7.6 ± 0.3, 3.6 ± 0.1, and 6.0 ± 0.5 μM, respectively. Flow cytometry indicated that 4 induced G₂/M phase arrest, and annexin V/PI assays showed dose-dependent increases in the level of total apoptosis for 1 and 4. Western blotting revealed downregulation of cyclin B1 and cdc2 (CDK1) by 4; both 1 and 4 decreased Bcl-2 and increased Bax, consistent with mitochondria-mediated apoptosis. Network pharmacology, supported by mechanistic assays, further suggested the engagement of the PI3K/Akt pathway by 4.

A chemical investigation of the basidiomycete Cyathus striatus led to the isolation of 17 polyoxygenated cyathane diterpenoid xylosides, cyathstrines A–K (1–17), including 11 new ones sharing five distinct ring skeletons, two sesquiterpenoids (18 and 19), and two lupane triterpenoids (20 and 21), as well as three sterols (22–24), based on the OSMAC (One Strain–Many Compounds) strategy. Among them, compound 5 represents the first example of cyathane diterpenoids with an undescribed 5/6/7/6/5/6/6-fused ring skeleton incorporating an extra 2H-pyran moiety, and compound 7 bears an unconventional 9/7/6/5/6-fused pentacyclic ring skeleton. The structures of these compounds were elucidated by means of NMR spectroscopic analyses, HRESIMS and ECD calculations. Compounds 7 and 9 exhibited moderate antibacterial effects against six human pathogenic bacteria, with MIC values ranging from 8 to 32 μg/mL. Meanwhile, compound 8 showed significant neuroprotective activity at 20 μM, with cell viability improved to 82.4% from the MPP⁺-treated cell viability of 51.20%, which was comparable to the positive control. Additionally, compounds 3, 13, 15, and 17 demonstrated notable neuroprotective effects, with cell viabilities of more than 70%. These findings expanded the chemical space of cyathane diterpenoids and provided the new template molecules for the development of anti-infective and neuroprotective drugs.

Bacillus species, particularly those investigated as biocontrol agents, are known to produce a cocktail of bioactive lipopeptides that act synergistically to shape the ecological function of these beneficial microbes. However, while certain families of lipopeptides are well-characterized, others remain elusive. Herein, we describe the characterization of the kurstakins, a family of lipopeptides associated with promising biocontrol properties but that lack adequate characterization. Metabolomic analyses of a semipurified Bacillus cereus EM195W extract fraction revealed the presence of approximately 50 cyclic- and linear-peptide analogs. Deeper analyses revealed that the chemical diversity stems from the diverse lipid tails, including linear, iso-, and anteiso-lipid tails ranging from C₈–C₁₈, along with several hydroxylated lipid tails. Isolation and complete structural analysis of two new analogs represented the first kurstakin analogs characterized by NMR and provided the first experimental analyses for deducing their absolute configuration. Finally, analysis of publicly available genomic and MS data provided insights into the true chemical diversity and distribution of the kurstakins. These results expand our understanding of this family of compounds, opening the door for determining their ecological functions and the role they play in the broader activity of biocontrol agents.

Biological screening of marine sponge extracts against transient receptor potential ankyrin 1 (TRPA1) identified Stellitethya ingens as a promising source of secondary metabolites with potential antagonistic activity. A comprehensive investigation yielded 13 nitrogen-containing sesquiterpenoids (1–13) and eight glycerophosphocholines (16–23), including four previously undescribed bisabolene-type analogues (3 and 6–8) and one new phosphatidylcholine derivative (23). Structures were elucidated by extensive NMR and HR-ESIMS/MS analyses. The absolute configuration of 6 was determined via asymmetric synthesis, while that of 7 was assigned from NOE correlations and pyridine-induced deshielding effects. Isolated compounds were evaluated for TRPA1 antagonistic activity using a FLIPR-based calcium mobilization assay, and compounds 1, 3, and 12 exhibited moderate inhibitory effects without cytotoxicity against HEK cells. This study represents the first report of secondary metabolites from the genus Stellitethya and highlights bisabolene- and pupukeanane-type scaffolds as novel frameworks for TRPA1 antagonists, thereby expanding the chemical diversity of the underexplored order Tethyida and offering new chemotypes with potential relevance to analgesic drug discovery.