Natural Products Research Articles

Virtual Screening and Biological Evaluation of Natural Products as Novel VPS34 Inhibitors that Modulate Autophagy.

VPS34 is a sole member of class III phosphoinositide 3-kinase involved in endosomal trafficking and autophagosome formation, making it an interesting target for cancer treatment. Here, we investigated 5,774 natural products using structure-based virtual screening against human VPS34. 10 natural products identified by virtual screening were purchased and tested in VPS34 ADP-Glo assay, yielding several potential VPS34 inhibitors. Amongst, Salvianolic acid A (4) and Ellagic acid (8) inhibited VPS34 with IC50 values of 2.46 and 3.12 uM, respectively, more potent than the positivity control 3-MA. Moreover, in vitro assays demonstrated that both of the compounds suppressed vesicle trafficking in cell-based assay. Significantly, Salvianolic acid (4) effectively prevented autophagy in Hela cells induced either by starvation or Rapamycin, an mTOR inhibitor. In addition, in silico analysis was done to elucidate the binding mechanisms of the ligand in complex with VPS34. Overall, this study highlights the efficacy of structure-based virtual screening and presents several natural products as VPS34 inhibitors that modulate autophagy.

Research Progress on Natural Products Alleviating Liver Inflammation and Fibrosis via NF-κB Pathway.

Liver fibrosis is a key pathological process in chronic liver diseases, regulated by various cytokines and signaling pathways. Among these, the NF-κB signaling pathway plays a significant role in the initiation and progression of liver fibrosis. Recently, natural products have garnered attention as potential anti-fibrotic agents. This review highlights recent studies on how natural products, including flavonoids, terpenoids, polysaccharides, phenols, alkaloids, quinones, phenylpropanoids, steroids, and nitrogen compounds, mitigate liver fibrosis by modulating the NF-κB signaling pathway. Specifically, it examines how these natural products influence NF-κB activation, nuclear translocation, and downstream signaling, thereby inhibiting inflammatory responses, reducing apoptosis, and regulating hepatic stellate cell (HSC) activity, ultimately achieving therapeutic effects against liver fibrosis. A deeper understanding of the mechanisms by which natural products regulate the NF-κB signaling pathway can provide crucial theoretical foundations and valuable insights for the development of novel anti-fibrotic drugs.

The Natural Products Magnetic Resonance Database (NP-MRD) for 2025.

The Natural Products Magnetic Resonance Database (NP-MRD; https://np-mrd.org) is a comprehensive, freely accessible, web-based resource for the deposition, distribution, extraction, and retrieval of nuclear magnetic resonance (NMR) data on natural products (NPs). The NP-MRD was initially established to support compound de-replication and data dissemination for the NP community. However, that community has now grown to include many users from the metabolomics, microbiomics, foodomics, and nutrition science fields. Indeed, since its launch in 2022, the NP-MRD has expanded enormously in size, scope, and popularity. The current version of NP-MRD now contains nearly 7× more compounds (281 859 versus 40 908) and 7× more NMR spectra (5.5 million versus 817278) than the first release. More specifically, an additional 4.6 million predicted spectra and another 11 000 spectra simulated from experimental chemical shifts were deposited into the database. Likewise, the number of NMR raw spectral data depositions has grown from 165 spectra per year to >10000 per year. As a result of this expansion, the number of monthly webpage views has grown from 55 to 20000 and the number of monthly visitors has increased from 7 to 2500. To address this growth and to better support the expanding needs of its diverse community of users, many additional improvements to the NP-MRD have been made. These include significant enhancements to the data submission process, notable updates to the database's spectral search utilities and useful additions to support better NMR spectral analysis/prediction. Significant efforts have also been undertaken to remediate and update many of NP-MRD's database entries. This manuscript describes these database improvements and expansion efforts, along with how they have been implemented and what future upgrades to the NP-MRD are planned.

Total Synthesis of (-)-Cordycicadin D and 3,4-trans-Cordycicadins A and B: Entry to the 3,4-trans-Fused Cordycicadin Framework.

Lost in post-translation. Cordycicadins A-D are four C20polyketides, all containing ag-lactonefused to a 10-membered lactone. The proposed biosynthetic pathway for the cordycicadins anticipates the formation of two more natural products which are unknown. We report the total synthesis of (-)-cordycicadin D and the two anticipated natural products 3,4-trans-cordycicadins A and B. The targets were convergently assembled, in a biomimetic fashion,viaan efficient ketene trapping-intramolecular Michael addition sequence that delivered the requisite 3,4-trans-fused framework with high diastereoselectivity, enabled by the synthesis of complex dioxenones that serve asin situketene precursors. Recognition of the embedded polyketide symmetry enabled the use of a divergent-convergent syntheticstrategy, based on the use of two products from an early-stage enzymatic resolution. The synthetic routes afforded (-)-cordycicadin D in 14 steps and 3,4-trans-cordycicadins A and B in 13 steps (longest linear sequence). This work confirms the structure of (-)-cordycicadin D and the observed instability of the anticipated natural product 3,4-trans-cordycicadin B during purification may explain why it is yet to be isolated.

Study on the Effect of Cinnamon in the Treatment or Auxiliary Treatment of Type 2 Diabetes

Type 2 Diabetes Mellitus(T2DM) is one of the fastest-growing global health emergencies of the 21st century. Currently, more than 500 million people worldwide are living with diabetes. According to the International Diabetes Federation, it is expected to affect 592 million people by 2035 and 784 million by 2045. Therefore, the purpose of this paper is to explore the feasibility of natural medicine in the treatment of type 2 diabetes. Cinnamon, as a natural product, has been used as a spice or traditional Chinese medicine for thousands of years. The present clinical trials on the treatment of type 2 diabetes with cinnamon as an adjuvant were analyzed. By comparing the data of Fasting blood glucose(FBL), Glycosylated Hemoglobin(HbA1c), Total cholesterol(TC) and Triglyceride(TG) in different clinical trials, it can be concluded that cinnamon can be used to help treat patients with type 2 diabetes.

Discovery of nostatin A, an azole-containing proteusin with prominent cytostatic and pro-apoptotic activity.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are intriguing compounds with potential pharmacological applications. While many RiPPs are known as antimicrobial agents, a limited number of RiPPs with anti-proliferative effects in cancer cells are available. Here we report the discovery of nostatin A (NosA), a highly modified RiPP belonging among nitrile hydratase-like leader peptide RiPPs (proteusins), isolated from a terrestrial cyanobacterium Nostoc sp. Its structure was established based on the core peptide sequence encoded in the biosynthetic gene cluster recovered from the producing strain and subsequent detailed nuclear magnetic resonance and high-resolution mass spectrometry analyses. NosA, composed of a 30 amino-acid peptide core, features a unique combination of moieties previously not reported in RiPPs: the simultaneous presence of oxazole/thiazole heterocycles, dehydrobutyrine/dehydroalanine residues, and a sactionine bond. NosA includes an isobutyl-modified proline residue, highly unusual in natural products. NosA inhibits proliferation of multiple cancer cell lines at low nanomolar concentration while showing no hemolysis. It induces cell cycle arrest in S-phase followed by mitochondrial apoptosis employing a mechanism different from known tubulin binding and DNA damaging compounds. NosA also inhibits Staphylococcus strains while it exhibits no effect in other tested bacteria or yeasts. Due to its novel structure and selective bioactivity, NosA represents an excellent candidate for combinatorial chemistry approaches leading to development of novel NosA-based lead compounds.

Metagenomic insights and biosynthetic potential of Candidatus Entotheonella symbiont associated with Halichondria marine sponges.

Korea, being surrounded by the sea, provides a rich habitat for marine sponges, which have been a prolific source of bioactive natural products. Although a diverse array of structurally novel natural products has been isolated from Korean marine sponges, their biosynthetic origins remain largely unknown. To explore the biosynthetic potential of Korean marine sponges, we conducted metagenomic analyses of sponges inhabiting the East Sea of Korea. This analysis revealed a symbiotic association of Candidatus Entotheonella bacteria with Halichondria sponges. Here, we report a new chemically rich Entotheonella variant, which we named Ca. Entotheonella halido. Remarkably, this symbiont makes up 69% of the microbial community in the sponge Halichondira dokdoensis. Genome-resolved metagenomics enabled us to obtain a high-quality Ca. E. halido genome, which represents the largest (12 Mb) and highest quality among previously reported Entotheonella genomes. We also identified the biosynthetic gene cluster (BGC) of the known sponge-derived Halicylindramides from the Ca. E. halido genome, enabling us to determine their biosynthetic origin. This new symbiotic association expands the host diversity and biosynthetic potential of metabolically talented bacterial genus Ca. Entotheonella symbionts.IMPORTANCEOur study reports the discovery of a new bacterial symbiont Ca. Entotheonella halido associated with the Korean marine sponge Halichondria dokdoensis. Using genome-resolved metagenomics, we recovered a high-quality Ca. E. halido MAG (Metagenome-Assembled Genome), which represents the largest and most complete Ca. Entotheonella MAG reported to date. Pangenome and BGC network analyses revealed a remarkably high BGC diversity within the Ca. Entotheonella pangenome, with almost no overlapping BGCs between different MAGs. The cryptic and genetically unique BGCs present in the Ca. Entotheonella pangenome represents a promising source of new bioactive natural products.

Recent Developments in the Photochemical Reactions of N‐Heterocyclic Compounds

The adoption of clean and renewable light sources is becoming increasingly prevalent in organic synthesis due to their welfare, workability and economic benefits. In recent times, photo‐redox catalysis has emerged as a valuable tool in organic transformations owing to its environmentally friendly nature and utilization of abundant resources. Since harmful or polluting reagents are not needed for the organic photochemical reactions, these reactions provide insights into sustainable processes and green chemistry. N‐Heterocyclic compounds (NHC’s) constitute fundamental structural motifs in numerous organic compounds and are widely encountered in natural products and pharmaceuticals with diverse biological activities. Consequently, investigations into the synthesis and modification of these NHC’s such as indole, carbazole, benzimidazole, quinoline, isoquinoline and pyridine hold particular significance for chemists and pharmacologists. This review provides an overview of the impact of photocatalysis on synthesis of NHC’s and their modification from 2019 to 2024. These transformations are achieved through the utilization of both metal photocatalysts (e.g., Ir, Pd, Co, Gd etc.) and non‐metallic photocatalysts (e.g., Eosin‐Y, 4CzIPN, Mes‐Acr+ClO4‐ etc.), or even without the necessity of photocatalysts. It is anticipated that this review will serve as a valuable resource for researchers delving into the promising realm of photocatalyzed transformations.

Non-canonical C16 Homoterpene Biosynthesis Widespread in Actinobacteria.

A novel biosynthetic pathway towards the rare and underexplored non-canonical family of homoterpenes was discovered in actinobacteria through targeted genome mining and enzymatic in vitro reconstitution. The pathway comprises initial methylation-induced double bond isomerization of farnesyl diphosphate (FPP) to (2E,7E)-6-methyl-farnesyl diphosphate, catalyzed by a novel family of methyltransferases with unique dual function. The resulting linear C16 double bond isomer of FPP constitutes the specific substrate for a distinct family of type I terpene cyclases, catalyzing diverse cyclization reactions. Functional characterization of nine enzyme pairs led to discovery of five unprecedented homoterpene natural products. The enzymological novelty enable the development of novel biocatalytic and genetically programmable synthetic strategies towards methylated terpenoids with potentially unique properties ("magic methyl effect").

THE CONTRAPOSITION OF AGROECOLOGY TO THE INDUSTRIALIZATION OF ORGANIC FOOD

The article deals with the relationship between organic production and agroecology. When analyzing data from the federal government, it is clear that food production in Brazil is large and concentrated in the power of a small group of people, while most producers, who come from family farming or small properties, find it very difficult to produce and market their produce. An alternative to conventional production on large rural properties would be the planting of organic products, since this way, there would be no control by large agricultural groups over production, giving small producers productive and financial autonomy. However, realizing that organic agriculture could be produced on a large scale, the capitalist market took over the organic agricultural technique, transforming the natural product into something industrial, and consequently, excluding two social groups from the food market, namely, small producers and low-income people. In this sense, agroecology emerges as an alternative for small producers, since it involves not only the technique, but also a broad set of factors that make this concept something different in rural areas.

Diversified ring expansion of saturated cyclic amines enabled by azlactone insertion.

Saturated N-heterocycles are ubiquitous structures among natural products and biologically active compounds. Therefore, the development of synthetic methods for the construction of N-heterocycles is of great importance in the synthetic community. Altering the ring system of these motifs to analogues with different ring sizes by employing molecular editing techniques would be highly appealing in medicinal chemistry. We present herein the direct insertion of glycine derivatives as two-carbon synthons into unstrained five- or six-membered saturated cyclic amines at predictable sites, enabling the construction of synthetically challenging medium-sized azacycles through sequential Ru-catalysed C‒C bond formation, retro-aza-Michael addition and a lactamization process. Upon further derivation, we leverage this homologation platform to realize modular insertion of one- or two-carbon units into the aliphatic rings. The conversion of a single azacycle into up to five others provides a promising toolbox for diversifying existing drug candidates and increasing the prospects for clinical success.

Oxidation of four monoterpenoid indole alkaloid classes by three cytochrome P450 monooxygenases from Tabernaemontana litoralis.

Cytochrome P450 monooxygenases (CYPs) are well known for their ability to catalyze diverse oxidation reactions, playing a significant role in the biosynthesis of various natural products. In the realm of monoterpenoid indole alkaloids (MIAs), one of the largest groups of alkaloids in nature, CYPs are integral to reactions such as hydroxylation, epoxidation, ring opening, ring rearrangement, and aromatization, contributing to the extensive diversification of these compounds. In this study, we investigate the transcriptome, metabolome, and MIA biosynthesis in Tabernaemontana litoralis (milky way tree), a prolific producer of rare pseudoaspidosperma-type MIAs. Alongside known pseudoaspidosperma biosynthetic genes, we identify and characterize three new CYPs that facilitate regio- and stereospecific oxidation of four MIA skeletons: iboga, aspidosperma, pseudoaspidosperma, and quebrachamine. Notably, the tabersonine 14,15-β-epoxidase catalyzes the formation of pachysiphine, the stereoisomer of 14,15-α-epoxytabersonine (lochnericine) found in Catharanthus roseus (Madagascar periwinkle) roots. The pseudovincadifformine 18-hydroxylase is the first CYP identified to modify a pseudoaspidosperma skeleton. Additionally, we demonstrate that the enzyme responsible for C10-hydroxylation of the iboga MIA coronaridine also catalyzes C10-hydroxylation of voaphylline, which bears a quebrachamine skeleton. With the discovery of a new MIA, 11-hydroxypseudovincadifformine, this study provides a comprehensive understanding of MIA biosynthesis and diversification in T. litoralis, highlighting its potential for further exploration.

Design, synthesis and biological evaluation of (E)-kojyl-styryl-sulfones: Novel recilisib hybrids as promising radioprotectors.

Radioprotectors are synthetic compounds, natural products, or biological agents that are administered before irradiation to protect normal cells against ionizing radiation (IR)-induced injuries. We have designed novel hybrid (E)-kojyl-styryl-sulfones 10a-n by applying the pharmacophore hybridization strategy to combine key structural motifs of the natural antioxidant kojic acid and the emerging radioprotector Ex-RAD (recilisib sodium). These hybrids were successfully synthesized and characterized with (E)-geometry. In vitro radioprotective activity along with the corresponding O-benzylated and O-methoxylated derivatives (9a-n, 14, and 15) was evaluated on human foreskin fibroblast 1 (HFF-1) cells irradiated with a 10-Gy dose of X-rays. In particular, hybrids 10b, 10d, 10f, 10g, and 10n exhibited the highest radioprotection effect at the 10 µM concentration, more effective than the parent compounds. It should be noted that the 3,4,5-trimethoxystyryl analog 10n was the most effective compound. Surprisingly, the O-benzylated 3,4,5-trimethoxystyryl analog (9n) also showed an excellent radioprotective effect. Moreover, the antioxidant evaluation of these selected hybrids on the IR-induced reactive oxygen species (ROS) generation and lipid peroxidation in the HFF-1 cells revealed that they could significantly downregulate IR-induced oxidative stress in the HFF-1 cells, while mechanistically recilisib is not a well-established ROS scavenger. The obtained results suggest that these privileged (E)-kojyl-styryl-sulfones can serve as promising radioprotectors for further studies and development.

High-throughput screening-based design of multifunctional natural polyphenol nano-vesicles to accelerate diabetic wound healing

Oxidative stress is a major pathological factor that impedes the diabetic wound healing process. Procyanidins (PC) form nanoparticle-vesicles (PPNs) through hydrogen bonding and exhibit good drug delivery capability; however, their application in diabetic wounds is unsatisfactory. To meet the antioxidant needs for treating, high-throughput screening in the natural product library (NPL) under in vitro oxidative stress conditions was conducted to enhance the antioxidant activity of PPNs. HUVECs treated with tert-Butyl Hydroperoxide (TBHP) were established as screening model in vitro. Baicalein (BAI) was identified from over 600 products in the library as the most effective one to combat oxidative stress. Further study showed that PC and BAI may react in equal proportions to synthesize new vesicles, named BAI-PC Polyphenolic nanovesicles (BPPNs), which possess reactive oxygen species (ROS) responsive and antioxidant effects. Network pharmacology indicated that in diabetic wounds, the target genes of PC are mainly enriched in the vascular endothelial growth factor (VEGF)-related pathways, while BAI primarily regulates tyrosine phosphorylation. The complementarity between the two has been validated in both in vitro and in vivo experiments. In summary, the antioxidant drug BAI, identified through high-throughput screening of NPL, could optimize the biological function of PPNs; the newly-synthesized BPPNs may accelerate diabetic wound healing through dual mechanisms of promoting angiogenesis and combating oxidative stress.Graphical abstract

Directed Evolution of an Adenylation Domain Alters Substrate Specificity and Generates a New Catechol Siderophore in Escherichia coli.

Nonribosomal peptide synthetases (NRPS) biosynthesize numerous natural products with therapeutic, agricultural, and industrial significance. Reliably altering substrate selection in these enzymes has been a longstanding goal, as this would enable the production of tailor-made peptides with desired activities. In this study, the NRPS EntF and the associated biosynthesis of the siderophore enterobactin (ENT) were used as a model system to interrogate substrate selection by an adenylation (A) domain. We employed a directed evolution pipeline that harnesses an in vivo genetic selection for siderophore production to alter A domain substrate selection. Surprisingly, this led to the formation of a new, physiologically active catechol siderophore in Escherichia coli. We characterized the enzyme variants in vitro and demonstrated transferability of our findings to the well-studied TycC and GrsB NRPSs. This work identifies critical binding pocket residues that allow for altered substrate selection in our model system and expands upon our understanding of iron acquisition in E. coli.

Spiro[bicyclo[3.2.0]heptane-2,2'-[1,3]dioxolan]-6-one - a versatile intermediate for the synthesis of cyclopentane-derived natural products

Spiro[bicyclo[3.2.0]heptane-2,2'-[1,3]dioxolan]-6-one - a versatile intermediate for the synthesis of cyclopentane-derived natural products

Chemical structure metagenomics of microbial natural products: surveying nonribosomal peptides and beyond

Bioactivity-guided fractionation (BGF) has historically been a fruitful natural product discovery workflow. However, it is plagued by increasing rediscovery rates in recent years and new methods capable of exploring the natural product chemical space more broadly and more efficiently is in urgent need. Chemical structure metagenomics as one such method is the theme of this Perspective. It emphasizes a chemical-structure-centered viewpoint toward natural product research. Key to chemical structure metagenomics is the ability to predict the structure of a natural product based on its biosynthetic gene sequences, which facilitated the discovery of numerous new bioactive molecules and helped uncover oversampled/underexplored niches of decades of BGF based discovery. While microbial nonribosomal peptides have been the focus of chemical structure metagenomics efforts thus far, it is in principle applicable to other natural product families. The future outlook of this new approach will also be discussed.

Microbial communities associated with marine sponges from diverse geographic locations harbor biosynthetic novelty.

Marine sponges are a prolific source of biologically active small molecules, many of which originate from sponge-associated bacteria. Identifying the producing bacteria is a key step in developing sustainable routes for the production of these metabolites. To facilitate the required computational analyses, we developed MetaSing, a reproducible singularity-based pipeline for assembly, identification of high-quality metagenome-assembled genomes (MAGs), and analysis of biosynthetic gene clusters (BGCs) from metagenomic short-read data. We applied this pipeline to metagenomic sequencing data from 16 marine sponges collected from New Zealand, Tonga, and the Mediterranean Sea. This analysis yielded 643 MAGs representing 510 species. Of the 2,670 BGCs identified across all samples, 70.8% were linked to a MAG. Comparison of BGCs to those identified from previously sequenced bacteria revealed high biosynthetic novelty in variety of underexplored phyla, including Poribacteria, Acidobacteriota, and Dadabacteria. Alongside the observation that each sample contains unique biosynthetic potential, this holds great promise for natural product discovery and for furthering the understanding of different sponge holobionts.IMPORTANCEDiscovery of new chemical compounds such as natural products is a crucial endeavor to combat the increasing resistance to antibiotics and other drugs. This manuscript demonstrates that microbial communities associated with marine sponges investigated in this work encode the potential to produce novel chemistry. Lesser studied bacterial taxa that are often difficult to cultivate are particularly rich in potential.

A dual-inducible control system for multistep biosynthetic pathways

BackgroundThe successful production of industrially relevant natural products hinges on two key factors: the cultivation of robust microbial chassis capable of synthesizing the desired compounds, and the availability of reliable genetic tools for expressing target genes. The development of versatile and portable genetic tools offers a streamlined pathway to efficiently produce a variety of compounds in well-established chassis organisms. The σ70lac and tet expression systems – adaptations of the widely used lac and tet regulatory systems developed in our laboratory – have shown effective regulation and robust expression of recombinant proteins in various Gram-negative bacteria. Understanding the strengths and limitations of these regulatory systems in controlling recombinant protein production is essential for progress in this area.ResultsTo assess their capacity for combinatorial control, both the σ70lac and tet expression systems were combined into a single plasmid and assessed for their performance in producing fluorescent reporters as well as the terpenoids lycopene and β-carotene. We thoroughly characterized the induction range, potential for synergistic effects, and metabolic costs of our dual σ70lac and tet expression system in the well-established microorganisms Escherichia coli, Pseudomonas putida, and Vibrio natriegens using combinations of fluorescent reporters. The dynamic range and basal transcriptional control of the σ70 expression systems were further improved through the incorporation of translational control mechanisms via toehold switches. This improvement was assessed using the highly sensitive luciferase reporter system. The improvement in control afforded by the integration of the toehold switches enabled the accumulation of a biosynthetic intermediate (lycopene) in the β-carotene synthesis pathway.ConclusionThis study presents the development and remaining challenges of a set of versatile genetic tools that are portable across well-established gammaproteobacterial chassis and capable of controlling the expression of multigene biosynthetic pathways. The enhanced σ70 expression systems, combined with toehold switches, facilitate the biosynthesis and study of enzymes, recombinant proteins, and natural products, thus providing a valuable resource for producing a variety of compounds in microbial cell factories.Graphical

Computational Screening of HPLC-Identified Phytochemicals from Corn Silk (Stigma Maydis) as Protein Tyrosine phosphatase 1B (PTP1B) Inhibitors for the Management of Type 2 Diabetes

Protein tyrosine phosphatase 1B (PTP1B) has emerged as a promising therapeutic target for the treatment of the escalating global burden of disease, diabetes, due to its critical role in insulin signaling regulation. Natural products, like those derived from a traditional plant like Corn silk, offer a valuable source of innovative antidiabetic compounds, but their bioactive constituents and molecular mechanisms remain poorly understood. This study aimed at identifying the standard constituents of Corn silk using a High-performance liquid chromatography (HPLC) approach and investigates the binding energy of potential ligands against protein tyrosine phosphatase 1B (PTP1B) target protein using a computational approach in analogy to the standard drug of diabetes. Based on molecular docking, induced-fit docking, calculation of free binding energy, and ADMET screening. 15 compounds were identified, with which most of the ligands displayed significant inhibitory activity with docking scores, ranging from -4.037 to -8.497 kcal/mol when compared with the control drug, metformin, and glyburide, with -4.624 and -0.976 kcal/mol respectively. The five top-scoring compounds showed good hydrophobic communications and hydrogen bonding associations to hinder PTP1B. The ADMET profiles of most of the compounds fell within desirable ranges, and subsequent MM-GBSA post-docking analysis validated the binding stability of selected compounds to the PTP1B protein structure. This study showed that compounds from Corn silk like Maysin, Orientin, Quercetin, Caffeic acid, and Ferulic acid are worth further investigation as promising PTP1B inhibitors as an antidiabetic agent.