Journal of Natural Products 最新文献

The human sigma-2 receptor/transmembrane protein 97 (σ₂R/TMEM97) has been identified as a promising target to modulate neuronal excitability in chronic pain and address the unmet need for nonopioid therapeutics. We report the chemical and biological characterization of the cyclic depsipeptide, veraguamide E (Ver E), isolated from a Panamanian marine cyanobacterial collection, as a novel σ₂R/TMEM97 ligand and modulator of calcium in neurons. Ver E’s structure was confirmed using 1D and 2D-NMR, HRMS, and MS/MS molecular networking analyses. NMR titration and computational docking confirmed direct, saturable, and tight binding of Ver E to σ₂R/TMEM97. Functional calcium imaging in primary mouse sensory neurons revealed that Ver E increases intracellular Ca²⁺ levels without modulating store-operated calcium entry (SOCE). Multiwell microelectrode array experiments using human induced pluripotent stem cell (hiPSC) nociceptors showed that Ver E reduced neuronal activity at physiological temperatures, but not under heat-stress. Ver E exhibited no cytotoxicity in HEK293 cells, and immunocytochemistry confirmed it does not alter phosphorylated eIF2α (p-eIF2α) expression, indicating a mechanism distinct from integrated stress response modulators. Collectively, these findings position Ver E as a nontoxic σ₂R/TMEM97 ligand capable of selectively modulating neuronal excitability, creating a starting point for developing novel pain therapeutics.

Natural products derived from symbiotic microbes remain a rich source of structurally diverse and bioactive molecules. In this study, we report de novo genome sequencing of the termite-associated isolate Micromonospora sp. RB23. Genome mining uncovered a type I polyketide synthase (T1PKS) biosynthetic gene cluster encoding five halogenases, predicted to produce pyrrolomycin-like antimicrobial compounds. Mass-spectrometry-based molecular networking facilitated the identification and isolation of N-methylated pyrrolomycin K and mycothiol-adduct, pyrrolomycin L. Structure elucidation was accomplished based on liquid chromatography high-resolution tandem mass spectrometry (LC-HRMS/MS) alongside 1D and 2D nuclear magnetic resonance (NMR) spectroscopy. Based on the evaluated of antimicrobial activity, we propose that N-methylation and mycothiol-based conjugation in pyrrolomycins are possible detoxification mechanisms that play a role in enhancing self-tolerance.

Photochemistry and total synthesis are deeply rooted in the history of organic chemistry, each developing independently while also intersecting frequently. Indeed, mild reaction conditions, versatility of transformations, and complementary selectivities to thermal methods make photochemistry an especially powerful tool for the synthesis of complex target molecules. In this Review, we highlight recent examples of total syntheses (from 2020 to 2025) featuring photochemical reactions as pivotal steps. Although the application of photochemistry in total synthesis has been consistently reviewed throughout the past decades, we feel that the wider emergence of photocatalytic methods, together with the continued importance of certain direct irradiation approaches, warrants its own discussion. We hope that our analytical approach and strategic insights will help us to identify cases where photochemical reactions could prove useful, thereby further encouraging their use in total syntheses.

Tambjamines are a class of bacterial bipyrrolic natural products with potent biological activity. Recently, the first actinomycete biosynthetic gene cluster (BGC) responsible for the production of a tambjamine (BE-18591) was discovered in Streptomyces albus, and bioinformatic analysis suggested the alkylamine tail component is constructed using different biosynthetic logic than employed by Proteobacteria to assemble structurally similar tambjamines YP1 and MYP1. Here, we report the experimental characterization of four novel streptomycete proteins and demonstrate that these enable the unique, late-stage assembly of the alkylamine tail of BE-18951. Specifically, a fatty acyl-carrier protein (TabQ) is loaded with a 12-carbon acyl chain, selected for, in part, through the action of an editing type II thioesterase (TabJ). The resulting C₁₂–TabQ adduct is then processed to an aldehyde by a novel acyl-ACP reductase (TabE) that harbors none of the telltale amino acid signatures that typically identify these proteins. The resulting aldehyde is finally converted to the amine by an ω-transaminase (TabA) that demonstrates some degree of promiscuity. Our findings highlight the disparate chemical logic employed by Proteo- and Actinobacteria for the biosynthesis of the alkylamine components of tambjamine natural products.

Forsyshiyanine A (8), a trinorditerpene alkaloid isolated from Forsythia suspensa exhibiting in vitro anti-inflammatory and antiviral activities, has been synthesized for the first time from trans-communic acid (12a) and labdane cupressic acid (13). Furthermore, a series of derivatives were efficiently prepared and screened for cytotoxic activities against five human tumoral cell lines. Derivative 25 showed cytotoxicity (IC₅₀ = 6.5 μM) against the Mia PaCa-2 pancreatic cancer cell line, making it an interesting candidate for future structure–activity relationship (SAR) investigations.

Hepatic fibrosis is a major contributor to liver-related mortality and overall mortality. Currently, there is no established treatment for hepatic fibrosis. Research indicates that the transforming growth factor (TGF-β) signaling pathway is one of the key pathways involved in hepatic stellate cell (HSC) activation and fibrosis progression. Consequently, inhibiting the TGF-β signaling pathway represents a potential therapeutic strategy to combat hepatic fibrosis progression. Betulinic acid (BA) was widely extractable from natural plants, exhibits significant antifibrotic therapeutic effects. Three series of BA derivatives were synthesized and evaluated their antihepatic fibrosis activities. Most compounds showed no significant cytotoxicity in vitro. At nontoxic concentrations, these compounds effectively suppressed the TGF-β-induced upregulation of the liver fibrosis markers type I collagen and α-SMA. Notably, compound 3d dose-dependently inhibited extracellular matrix (ECM) deposition in TGF-treated HSCs and suppressed HSC activation. These findings indicate that compound 3d, acting as an antihepatic fibrosis agent, attenuates hepatic fibrosis by inhibiting the TGF-β signaling pathway.

Culture supernatants of the veiled oyster mushroom Pleurotus dryinus from the phylum Basidiomycota develop a deep burgundy-red coloration when supplemented with phenylalanine. This marks the first time that color formation for P. dryinus, a fungus that is ordinarily colorless, has been reported. The two main coloring secondary metabolites, named dryinones, were isolated, and their structures were elucidated by HR-ESI(+)–MS/MS, UV/vis, and multidimensional NMR spectroscopy. The colorants were structurally characterized as highly oxygenated meroterpenoids with an aminoquinone moiety as the main chromophore. The absolute configuration of the isolated dryinone A (1) was determined through NOESY correlations, ECD experiments, and DFT computations. These findings not only expand the chemical diversity of colorants within the phylum Basidiomycota but also demonstrate the biosynthetic versatility of P. dryinus under controlled culture conditions. The discovery of these aminoquinone-containing meroterpenoids provides new insights into fungal secondary metabolism and highlights the potential of edible mushrooms as underexplored sources of structurally unique natural products.

Aromatic polyketide synthase (PKS) products undergo diverse tailoring reactions in the biosynthesis of natural products. S-Adenosyl-l-methionine (SAM)-dependent C-methyltransferases (C-MTs) play a key role in this diversification. In the biosynthesis of napyradiomycins, the C-MT NapB5 from Streptomyces aculeolatus catalyzes the C2 monomethylation of an 1,3,6,8-tetrahydroxynaphthalene (T₄HN) building block. Biochemical characterization reveals that NapB5 exhibits chemoselective C-dimethylation activity in vitro, accepting both T₄HN and its oxidized derivative flaviolin as substrates. Structure-guided mutagenesis and docking studies suggest that precise substrate positioning governs the enzyme’s regio- and chemoselectivity. The proximity between the nucleophilic carbon and the SAM methyl donor is crucial for this selectivity. Furthermore, comparative gene cluster analysis identifies homologous C-MTs in other actinomycetes, underscoring their role in diversifying naphthoquinone-based meroterpenoid natural products.

The absolute configurations at five stereogenic centers in symbiodinolactone A, a 12-membered macrolide isolated from the symbiotic marine dinoflagellate Symbiodinium sp. associated with an acoelomorpha Amphiscolops sp., were determined to be 7R,11R,12R,13R,14R. A combination of different techniques was applied in this regard such as Rychnovsky’s method, Kishi’s universal NMR databases, the modified Mosher’s method, and comparison of the NMR data of the bis(S)-MTPA ester of a degradation product of symbiodinolactone A with those of synthesized reference compounds. In addition, symbiodinolactone A was found to exhibit cytotoxicity against L1210 murine leukemia cells.

Culture-independent metagenomic approaches have proven to be effective tools for identifying previously hidden biosynthetic gene clusters (BGCs) encoding novel natural products with potential medical relevance. However, producing these compounds remains challenging as metagenomic BGCs often originate from organisms phylogenetically distant from available heterologous hosts. Lasso peptides, a subclass of ribosomally synthesized and post-translationally modified peptide (RiPP) natural products, exhibit diverse bioactivities, yet no lasso peptide has previously been discovered directly from a metagenome. Here, we report the discovery and heterologous expression of the first soil metagenome-derived lasso peptide. Expression of its biosynthetic gene cluster in Escherichia coli, followed by mass spectrometry analysis, strongly supported the predicted amino acid sequence and lasso structure of the peptide. Notably, this lasso peptide is the first to feature asparagine as the ring-forming residue at position one. Taxonomic analysis of the corresponding BGC identified an uncultivated member of the Steroidobacterales family (Gammaproteobacteria) as the closest known relative of the potential native host. These findings underscore the potential of metagenomic genome mining to reveal structurally novel RiPPs and to expand our understanding of the natural diversity of lasso peptides.