Journal of Natural Products 最新文献

Six new N-alkylpyrrole alkaloids (1-6) were isolated from the marine-derived actinomycete Streptomyces xiamenensis 1310KO-148 from a sponge sample. The structures of xiapyrroles A-F (1-6) were elucidated by detailed analysis of extensive spectroscopic data, including 1D, 2D NMR, and HRESIMS data. The absolute configurations of 2, 3, 4, and 6 were determined by a comparison of their calculated and experimental electronic circular dichroism (ECD) spectra. The position of the hydroxamate group in 6 was confirmed through NO-methylation and NOESY data analysis. All compounds (1-6) were tested for their anti-inflammatory effects in LPS-stimulated RAW 264.7 cells, a mouse macrophage cell line. The treatment of RAW 264.7 cells with 30 μM of 1-6 showed no significant cytotoxic effects. However, 1 dose-dependently suppressed the LPS-induced production of NO (IC₅₀ = 29.5 μM) and interleukin-6 (IL-6) (IC₅₀ = 10.9 μM). Compound 1 exhibited no potential cytotoxicity against six solid cancer cell lines and eight blood cancer cell lines at a concentration of 30 μM.

An investigation of living phosphatic stromatolites from Schoenmakerskop barrage pool near Gqeberha (Port Elizabeth), South Africa, yielded new cyclic octadepsipeptides, amatyemides A (1) and B (2), named using the Xhosa word 'amatye' for 'rock'. The amatyemides were isolated from methanol extracts of a targeted stromatolite sample collection, following an initial metabolomic survey of the Schoenmakerskop pool. Planar structure elucidation of 1 and 2 relied on NMR and LCMS² data, which delineated the same six amino acids and one 2-hydroxy-3-methylpentanoic acid (Hmpa) residues in each compound. The two octadepsipeptides differed only in the presence of a 2-hydroxydodecanoic acid (Hdda) residue in 1 and a 2-hydroxydecanoic acid (Hda) residue in 2. The absolute configurations of most amino acid residues in 1 were determined using an enhanced Marfey's reagent. The configurations of the 2-hydroxy acids and O-methylthreonine were assigned, and the absolute structures of amatyemides A (1) and B (2) were confirmed, by total solid-phase peptide synthesis of two possible diastereomers for each natural product. Biological testing of natural and synthetic amatyemides against human U87-MG glioblastoma, HCT116 colon, and SH-SY5Y neuroblastoma cells revealed weak, cell-type specific, cytotoxic potential where 2 > 1, and this was attributed to induction of oxidative stress by 2.

Phosphorylation of checkpoint kinase 1 at Ser-345 (p-CHK1(S345)) mediates the replication stress response in cancer cells, leading to chemotherapy resistance. Therefore, finding inhibitors of p-CHK1(S345) is currently a promising strategy to prevent acquired drug resistance. In this study, 14 ingenane diterpenoids (1-14), involving two undescribed compounds possessing an unprecedented exocyclic double bond Δ⁶⁽²⁰⁾, were identified from Euphorbia peplus. The inhibitory effects of the isolated compounds on p-CHK1(S345) and their structure-activity relationship (SAR) were investigated. Compounds 7 and 8 presented the strongest inhibitory effects, abrogated cell cycle arrest, and caused the accumulation of DNA damage, improving the sensitivity of cancer cells to chemotherapeutic drugs. An in vivo assay confirmed the enhancement of 8 on the anticancer effect of topotecan via blocking of p-CHK1(S345). Mechanistically, 8 increased CHK1 ubiquitination to inhibit p-CHK1(S345) via activation of protein kinase C (PKC). PKC activation was first found to enhance CHK1 ubiquitination to block p-CHK1(S345). Above all, this finding not only indicates that compound 8 could be developed as a novel CHK1 inhibitor but also reveals a previously unrecognized role of PKC in regulating cancer chemotherapy sensitivity.

Four cinnamoyl-containing nonribosomal peptides (CCNPs), coprisamides E-H (1-4), were isolated from the marine algae-associated actinomycete strain Streptomyces thermolineatus NAK03196. Their structures were elucidated to be unreported coprisamides by comprehensive analyses of HRESIMS, 1D and 2D NMR spectroscopic data, Marfey's method, and MS/MS analysis. Coprisamides E (1) and F (2) bear a characteristic nonproteinogenic amino acid, 2,3-diaminopropanoic acid. The biosynthetic pathways for these isolates were proposed through a comparison of their biosynthetic gene clusters with reported homologous gene clusters. Coprisamide E (1) exhibited weak antibacterial activity against the Gram-positive strain Staphylococcus aureus.

This Perspective seeks to reconnect the current practice of nuclear magnetic resonance (NMR) spectroscopy in chemical structure and quantitative (qNMR) analysis with its roots in classical physics and quantum mechanics (QM). Rationales for this approach are derived from various angles, including focused reviews of the key parameters of the nuclear resonance phenomenon, the structural information richness of NMR spectra, and significant progress in both computational and spectrometer hardware. This provides collective reasoning for the reintegration of computational quantum mechanical spectral analysis (QMSA) into the contemporary practice of NMR spectral interpretation. Retethering operator-dependent visual phenotypic with QM-driven computational genotypic analysis yields more objective and accurate information by taking advantage of QM as the foundational reference point for NMR. Powerful computational tools for compound genotyping are available and evolve rapidly toward automation. In addition to enhancing the rigor and reproducibility of structure elucidation of new and the dereplication of known compounds, QM anchoring enables competent resolution of peak overlap, with resulting benefits in qNMR and low-field/benchtop NMR analysis. Furthermore, examination of common definitions and documentation practices shows that an evolutionary reconciliation of NMR terminology helps resolve ambiguities: shifting from phenotypic peak focus to genotypic QM-based pattern analysis is not only the logical next step when communicating structures of natural products and other molecules reproducibly but also a timely approach, as it yields QMSA-verified data for evolving knowledge bases for molecules of biomedical relevance.

The structure determination and occurrence of curvisetone (1), a tricyclic nor-diterpenoid from the tiny Collembola Sinella curviseta, is reported. Utilizing NMR analysis and mass spectrometry, we identified curvisetone's unique carbon skeleton and its occurrence in various sex and life stages. Curvisetone, carrying an unprecedented carbon tricyclic ring system, is an example of the distinct terpene usage of Collembola, which differentiates them from other arthropods.

N-Methyltransferases involved in indole methylation have seldom been discovered in natural product biosynthesis. This study focuses on the enzyme CyaF, which catalyzes a critical N-methylation step of indole in the β-carboline skeleton during cyanogramide biosynthesis. Seven β-carboline analogues (3-9) were isolated from the recombinant strain Streptomyces coelicolor YF11/cyaABC, including three new compounds (5-7). In vitro assays revealed CyaF's substrate flexibility. The crystal structure of the CyaF/S-adenosyl-L-homocysteine (SAH) complex, combined with the AlphaFold-predicted model and site-directed mutagenesis, elucidated the catalytic mechanism and structural features that enable CyaF to accommodate diverse substrates, highlighting its potential for biocatalytic applications.

The first total synthesis of (±)-talaroenamine B was achieved through a concise four-step procedure. The key feature of this synthetic strategy lies in a one-pot reaction involving I (III)-mediated oxidative dearomatization to construct a racemic cyclohexanedione unit, followed by imination using a chiral auxiliary to afford a separable mixture of diastereoisomers. A further acid-catalyzed substitution reaction of aniline with the diastereoisomers led to the natural product (-)-talaroenamine B and its enantiomer (+)-talaroenamine B. Additionally, virtual screening was utilized to expand the chemo-diversity of talaroenamines, and (±)-talaroenamine B diphenylene derivatives 6-11 were obtained by replacing aniline with selected aniline derivatives in the final step of synthesis. The structures of the synthetic compounds were elucidated using NMR, HRESIMS, and electronic circular dichroism (ECD) data. Compound 6b displayed an acetylcholinesterase (AChE) inhibitory effect with an IC₅₀ value of 4.5 μM, as well as cytotoxicity against the K562 cell line with an IC₅₀ value of 5.6 μM.

Bladder cancer is a common malignancy known for its high recurrence rate and poor survival rate. New strategies are urgently needed to reduce recurrence and improve prognosis. Arf1 and BMX are potential targets associated with the prognosis of bladder cancer. In this study, niacin ester derivatives of brefeldin A were synthesized by introducing nicotinic acid moieties at the 4-OH and 7-OH positions. Notably, the 4-monoester derivative, CHNQD-01228 (2), could significantly inhibit the proliferation of T24 cells (IC₅₀ = 0.22 μM) in a time-dependent manner. Furthermore, it dose-dependently inhibited T24 cell migration and colony formation, induced G1 phase arrest, and triggered apoptosis. Based on molecular modeling, CHNQD-01228 was evaluated to exhibit high binding affinity toward both Arf1 and BMX proteins. Further verification was conducted using cellular thermal shift assays and drug affinity responsive target stability assays. It suppressed the AKT/p-AKT and STAT3/p-STAT3 signaling pathways by targeting BMX in T24 cells, eliminated bladder cancer stem cells, and activated antitumor immunity via Arf1 inhibition. In vivo data further demonstrated that the dual-target inhibitor exhibited a potential antitumor efficacy against MB49 allograft tumors (TGI = 51.0%) and thus represents a promising therapeutic strategy for bladder cancer.

The recent popularity of indoor farming has brought about problems with parasites spreading among pollinator colonies. The natural product callunene (1) can be used in the prophylaxis of bumblebees against Crithidia infection. Here, we report the synthesis of callunene (1), its enantioseparation, and a method for analyzing its optical purity. The approach was applied to determine the configuration of callunene extracted from heather honey. The proposed method is also applicable to the analysis of mixtures of diastereomers obtained during callunene synthesis, which allows the stereospecificity of individual reaction steps to be determined.