Journal of Natural Products 最新文献

Herein, we report the first total synthesis and structural revision of the recently isolated natural product trichindole B (1). Discrepancies observed between the spectral data of the synthetic and natural product prompted us to do a structural re-evaluation, which was subsequently confirmed through the synthesis of target compounds bearing C5- and C6-isopentenyl substituents on the indole moiety. Detailed spectroscopic analysis revealed that the C6-isopentenyl regioisomer is in complete agreement with the reported spectral data of the natural product. Furthermore, we showed that routinely used tools such as Chemdraw can be handy for predicting and distinguishing positional isomers, thereby facilitating structural elucidation.

To synthesize a natural 28-norlupane endoperoxide previously isolated from an herbal source and displaying antiplasmodial activity, a four-step semisynthetic pathway was designed from natural betulinic acid and performed via Isayama–Mukaiyama cobalt-catalyzed hydroperoxyl silylation. The target 28-norlupane endoperoxide (2) was obtained along with its endoperoxide analogs (compd. 7–11) and other products (compd. 12–16). All products were identified by 1D and 2D nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS), and some were characterized by X-ray diffraction. All compounds were tested for their antiplasmodial activity against both Plasmodium falciparum chloroquine-sensitive 3D7 and chloroquine-resistant W2 strains as well as for their cytotoxicity. Compound 2 presented broad-spectrum activity by inhibiting both chloroquine-sensitive (3D7) and -resistant (W2) P. falciparum strains. Compound 11, featuring a novel rearranged seven-membered ring scaffold, showed potent antiplasmodial activity with a favorable selectivity index, while compound 13 exhibited moderate activity. These findings highlight the potential of novel 28-norlupane endoperoxides as promising leads in antimalarial drug discovery.

Piperazic acid (Piz)-containing compounds are a distinctive class of microbial metabolites characterized by a unique N–N bond and diverse bioactivities, rendering them as promising scaffolds for drug discovery. Herein, we utilized an integrated discovery strategy combining PCR-based genetic screening, genome mining and MS/MS-based molecular networking to target Piz-containing metabolites from an actinomycetes library. This effort led to the isolation of nine new Piz-containing linear pseudopeptides, saccharothriotides A–I (1–9), along with the known compound Sch 382583 (10), from a desert-derived actinomycete Saccharothrix sp. 275. Their planar structures and absolute configurations were elucidated by spectroscopic analysis, advanced Marfey’s method, phenylglycine methyl ester (PGME) derivatization, and biosynthetic pathway deduction. Bioactivity assays revealed compounds 1–3, which feature a hydroxamic acid moiety, exhibited significant activity against Gram-positive pathogens (MIC = 0.5–16 μg/mL). Notably, antibacterial efficacy of 1–3 against vancomycin-resistant Enterococcus faecium (MIC = 2–4 μg/mL) markedly outperformed the antibiotic levofloxacin (MIC = 64 μg/mL). They also moderately inhibited Gram-negative bacteria such as Escherichia coli and Acinetobacter baumannii (MIC = 16–64 μg/mL). As the first Piz-containing metabolites reported from the genus Saccharothrix, this work underscores the effectiveness of combining genetic and metabolomic strategies for discovering bioactive natural products from underexplored microorganisms.

The configurational assignment of some epoxides is challenging because of their quasi-planar structure. On the basis of density functional theory calculations of ⁿJ_CH, we developed a protocol for predicting the configurations of epoxides by correlating the conformation of the epoxide oxygen and its vicinal hydrogens with the HMBC signal intensities observed for the two epoxide carbons. When the dihedral angle between the model epoxide oxygens and their vicinal hydrogen was used as the x-axis, the ²J_CH and ³J_CH values formed nearly symmetric curves. This finding allowed us to determine the epoxide configuration by analyzing the HMBC signals between the proton adjacent to the epoxide and the two epoxide carbons on the basis of the associated conformation relative to the epoxide oxygen, which was divided into conformational sectors, such as synperiplanar (SP), synclinal (SC), anticlinal (AC), and antiperiplanar (AP). However, slight angular adjustments at the borders between the SP and SC conformations were required, along with the introduction of auxiliary conformations to handle the boundary regions. The reliability and generality of this approach were evaluated using 15 epoxides. Except for an epoxide bearing an acetal oxygen, the present rule correctly assigned the configurations of ring epoxides, consistent with conventional analyses.

The defining feature of calcium-dependent antibiotics (CDAs) is that they require the presence of calcium cation (Ca(II)) as a cofactor to exert antibacterial activity. We recently showed that substituting two key aspartic acids (Asp) with serine (Ser) in laspartomycin C (LspC) converts it from a CDA into a boron-dependent antibiotic (BDA). This synthetic analog (termed B1) no longer depends on Ca(II) and requires only 10 μM of phenylboronic acid (PBA) to become fully active. Such a calcium-to-boron dependence conversion provides a new entry point to study the mechanistic details of the cofactor dependence of CDAs, a rare phenomenon among bioactive small molecules. Herein, we show that electron withdrawing substituents on PBA enhance the antibacterial activity of B1. The friulimicin and daptomycin synthetic analogs with the same Asp-to-Ser substitution were inactive, whereas the CDA4b synthetic analog exhibited dual cofactor dependence. CDA4b was fully activated when both Ca(II) and PBA were present and was 4-fold less potent in the presence of only one or the other. These findings suggest that not only do CDAs often have distinct cellular targets, the way they are activated by Ca(II) are also different. Such mechanistic diversity underscores the strong potential of CDAs in drug development.

In this study, the phytochemical profile of Conchocarpus mastigophorus was investigated, leading to the isolation of four pyranoquinolinone alkaloids, including huajiaosimuline (1) and three new compounds: 3′-acetoxy-4′-hydroxyzanthosimuline (2), epoxyzanthosimuline (3), and mastigophorine (4). All new compounds possess two chiral centers and exist as a 1:1 mixture of epimers, differing in the configuration of a chiral center at the pyran ring. The absolute configurations of the epimers 2 and 3 were determined by data comparison with identical synthetic compounds, revealing mixtures of (2S,3'R)- and (2R,3'R)-configured epimers in both cases. By employing Sharpless asymmetric dihydroxylation and Shi epoxidation as key stereoselective steps, stereocontrol at C3 was achieved in the synthesis of compounds 2 and 3, respectively. Our synthesis approach provided 3'R- and 3'S-configured 2 in three steps (41–46% overall yield, 95% dr) and 3'R-configured 3 in 2 steps (61% overall yield, 90% dr) from 4-hydroxy-1-methyl-2(1H)-quinolinone and citral.

Endogenous antimicrobial peptides (AMPs) derived from host proteins represent a largely underexplored class of natural products tied to innate immunity. Here, we investigated collagen proteins as a source of latent α-helical AMPs encoded within nonfibrous extracellular matrix domains. Using a targeted in silico approach, verified collagen sequences were mined and prioritized based on secondary structure and three essential physicochemical properties: net charge, Boman index, and hydrophobic moment, yielding 107 predicted α-helical AMP candidates. The highest ranked peptides were synthesized and experimentally evaluated alongside benchmark AMPs and peptides prioritized by machine learning-based prediction tools. Three collagen-derived peptides identified by the targeted physicochemical approach exhibited broad-spectrum bioactivity against bacterial and fungal pathogens with minimum inhibitory concentrations comparable to those of LL-37 and melittin. In contrast, peptides ranked highly by machine learning predictors showed reduced or no activity. Collagen-derived peptides disrupted bacterial mimicking lipid membranes yet displayed markedly reduced cytotoxicity toward human cells, maintaining high viability at concentrations well above their antimicrobial MICs. These findings demonstrate that nonfibrous domains of extracellular matrix collagens constitute a previously underexplored reservoir of endogenous antimicrobial peptides with favorable biocompatibility, expanding the natural product space of host defense peptides and identifying collagen-derived AMPs as promising scaffolds for future antimicrobial discovery.

Twenty-two new monoterpene-coumarins, comprising the initial disclosure of 11 enantiomeric pairings, were isolated from the rhizomes of Luvunga scandens with the aid of LC–MS/MS based on molecular networking. Luvunscandins A–G (1–7) are dihydrofurancoumarins with a furan ring connection, and luvunscandins H–K (8–11) are dihydrofurancoumarins connected through a pyran ring. Chemical structures and absolute configurations were determined by analysis of spectroscopic data and X-ray diffraction analysis. The neuroprotective effects of all the isolates on LPS-stimulated NO production in BV2 microglia were evaluated. Compounds 6a, 7a, 7b, 8b, 9a, 9b, 11a, and 11b demonstrated more potent inhibitory effects than the positive control PDTC. Structural–activity relationship analysis revealed that neuroprotective activity was primarily associated with pyran-type dihydrofurancoumarins or compounds bearing a C3′R,6′R configuration, whereas furan-type analogs or compounds with a C3′S,6′S configuration exhibited weak or no activity. (+)-Luvunscandin I (9a) showed the most significant inhibitory activity (IC₅₀ = 4.9 ± 0.6 μg/mL) through suppression of the inflammatory transcription factors p65NF-κB and iNOS.

Cyclotides are plant-derived macrocyclic peptides stabilized by a cystine-knot motif, found in a limited number of angiosperm plants. This study reports the discovery of the cyclotide, Spat1, from Spigelia anthelmia (Loganiaceae), expanding the phylogenetic range of known cyclotide-producing plants. Spat1, a 30-residue bracelet-type cyclotide, was isolated, purified, and sequenced de novo. It demonstrated strong bactericidal activity against the Gram-positive Bacillus subtilis (LC_99.9 = 20 μM) via rapid membrane disruption but showed no activity against Staphylococcus aureus or Gram-negative Escherichia coli (LC_99.9 > 400 μM). The selective lack of activity against S. aureus is unusual for antimicrobial peptides. The data suggest that Spat1’s activity is independent of lipoteichoic acid (LTA) in B. subtilis, suggesting that its mechanism involves interactions with cytoplasmic membrane phospholipids. The lack of phosphatidylethanolamine (PE) in S. aureus membranes and Spat1’s weak binding to LTA, combined with its low net positive charge (+1), likely explains its inefficacy against this bacterial species. Structural modeling using AlphaFold AfCycDesign indicated that Spat1 adopts a cyclotide-typical β-sheet architecture and a 3₁₀-helix within its loop regions. Overall, Spat1 broadens understanding of cyclotide diversity and evolution, highlighting their functional specialization and the convergent evolutionary pressures that shape their distribution across plant lineages.

Colobognatha, a group of millipedes (Diplopoda) known for their unique biological traits (e.g., brood care and sociality), is the only group among millipedes to produce terpenoid alkaloids. Before 2020, only four terpenoid alkaloids had been identified; however, recent studies have resulted in a surge of new chemical discoveries and research into their ecological and biochemical roles. In this review, we outline the social characteristics of Colobognatha, the chemical investigations of their defensive secretions, and the bioactivity of the terpenoid alkaloids with a particular emphasis on new findings. We conclude by summarizing gaps in the research on these chemicals and provide insights into future research directions.