Natural Products Research Articles

Inhibitory effect of 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone against NSCLC with L858R/T790M/C797S mutant EGFR

Epidermal growth factor receptor (EGFR)-activating mutations are critical factors in the development of EGFR-driven non-small-cell lung cancer (NSCLC), and molecular targeted therapies have focused on inhibiting these mutations. EGFR tyrosine kinase inhibitors (TKIs) have remarkable inhibitory effects on NSCLC with EGFR mutations. However, acquired resistance limits the clinical application of EGFR-TKIs, highlighting the need for discovery of novel therapeutic strategies. 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone is a natural product derived from Garcinia xanthochymus, has shown potential anti-tumor activity, but the underlying mechanism needs further elucidation. In this study, we developed Ba/F3 and NIH/3T3 cells harboring EGFR L858R/T790M/C797S mutation, and then found that 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone exerted inhibitory effects against cells with EGFR L858R/T790M/C797S mutation. Additionally, 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone exhibited potent anti-tumor activity against cells harboring the triple-mutant EGFR by promoting apoptosis and inducing changes in cell cycle distribution. Furthermore, 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone was found to significantly reduce tumor growth via suppressing the phosphorylation of EGFR in tumor tissues. These effects are associated with binding of 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone to EGFR resulting in the suppression of extracellular signal-regulated kinase (Erk) phosphorylation. In conclusion, our results suggest that 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone may be a potential novel candidate for further investigation and treatment of NSCLC with the triple-mutant EGFR.

Macrophage‑driven pathogenesis in acute lung injury/acute respiratory disease syndrome: Harnessing natural products for therapeutic interventions (Review)

Macrophage‑driven pathogenesis in acute lung injury/acute respiratory disease syndrome: Harnessing natural products for therapeutic interventions (Review)

Stereodivergent Synthesis of 6,12-Guaianolide C1 Epimers via a Rationally Designed Oxy-Cope/Ene Reaction Cascade.

Nature synthesizes epimeric C1 guaianolide congeners, key components of major natural product classes, through a single structurally flexible macrocyclic germacranolide core. Our rationally designed elemanolide-type scaffold (5) now mimics this natural process, enabling the stereodivergent synthesis of both C1 epimers of 6,12-guaianolide lactone motifs. An oxy-Cope/ene cascade acts as the key step of this process, generating two distinct conformers of an intermediate germacranolide, each leading to a specific C1 epimer. Highly stereoselective redox manipulations follow, culminating in the efficient syntheses of diverse osmitopsin-type guaianolides.

Unexpected proteins involved in the regulation of secondary metabolism in Myxococcus xanthus DK1622.

Regulating secondary metabolite (SM) in Myxococcus xanthus bears the potential to influence the formation of important natural products with various biological activities. The authors of this study have previously found that the detectable levels of two proteins (4-hydroxyphenylpyruvate dioxygenase [HppD] and a Hsp90-like protein [HtpG]) are affected by ROK inactivation. As evidence, the current study was designed to elucidate the possible role of these two proteins in regulating the SMs' biosynthesis in this bacterium. To begin with, inactivation of the corresponding genes was carried out, and two mutant strains (M. xanthus hppD- and htpG-) were constructed. Subsequently, high-performance liquid chromatography coupled with mass spectrometry analysis for the metabolic extracts of the mutants revealed a significant reduction in the production of several SMs, like DKxanthene, myxalamide A, and myxochromide A, in comparison to the wild type. Furthermore, electrophoretic mobility shift assays using purified ROK protein suggested a direct binding on the genes' promoter region encoding the two proteins under study. It is therefore possible to conclude that hppD and htpG genes are implicated in the bacterium SMs' biosynthetic regulatory cascade, which seems to be directly regulated by the ROK protein. The present study provides additional evidence to a previous investigation showing the pleiotropic regulatory role of ROK on the production of SMs in M. xanthus.

Integrated strategy of mass spectrometry imaging and LC/MS-based GNPS for spatial characterization of alkaloids from Menispermi Rhizoma and study on potential anti-inflammatory mechanism by network pharmacology and molecular docking

Menispermi Rhizoma (MR) is the dried rhizome of Menispermum dauricum DC, which has been used to treat sore throat, enteritis, and rheumatic arthralgia. These therapeutic effects are attributed to its alkaloid ingredient. However, the chemical composition, anti-inflammatory mechanisms and the spatiotemporal distribution of the bioactive ingredients in MR have seldom been investigated. This study aims to clarify the anti-inflammation mechanism, material basis, and their spatial distribution of MR. Here, a LC/MS-based Global Natural Products Social Molecular Networking (GNPS) strategy was used to rapidly exhibit alkaloid molecular clusters that improve annotation accuracy and discover more unknown compounds. Then, a high-sensitive air flow-assisted ionization mass spectrometry imaging (AFAI-MSI) method was developed to visualize the spatial distributions alkaloids in different botanical parts of MR. The anti-inflammation mechanism was investigated based on network pharmacology and verified by molecular docking experiment. Finally, a total of 106 alkaloids including 24 aporphines, 23 monobenzylisoquinolines, 20 morphinanes, 20 proberberines, 12 bisbenzylisoquinolines, and 7 amides were identified in MR as well as 24 alkaloids were visualized in the medullary ray, cortex and epidermis regions. Moreover, the targets with a higher degree in the PPI network were TNF, GAPDH, AKT1, ALB, STAT3. GO and KEGG analysis revealed that MR in anti-inflammatory mechanism mainly involved plasma membrane, ATP binding, cytoplasm, identical protein binding and ATP binding. The signaling pathways mainly included NOD-like receptor signaling pathway, PI3K-Akt signaling pathway, AGE-RAGE signaling pathway in diabetic complications. The molecular docking results indicated that stepharanine-2-O-glucoside, bianfugedine, bianfugecine, dehydrostephanine had excellent affinity with SRC, MMP9 AKT1, STAT3 and TNF. This study comprehensively characterized the alkaloid ingredients and spatial distribution of MR, and revealed potential mechanism of MR in inflammation, which provides a reference for development and application of MR and other Traditional Chinese medicines (TCMs).

Terpestacin and Its Derivatives: Bioactivities and Syntheses.

Terpestacin (1), fusaproliferin (2), and their derivatives are a class of sesterterpenes featured by a trans-fused 5/15-membered ring skeleton. There are 45 natural products (1, 2, 4-27, 65-83) isolated from various wild fungi (Fusarium sp., Bipolaris sorokiniana, Arthrinium sp., etc.) or from genetic mutants via biosynthetic gene clusters mining, and 37 derivatives (28-64) produced by semi-synthetic modifications. These compounds show a diverse range of important bioactivities such as antivirus, antimicrobial, cytotoxic, phytotoxic, anti-flammatory, and brine shrimp lethal activities. To date, two racemic and five enantioselective chemical total syntheses of 1 (including 2 and their isomers) have been developed. Over the past decade, a number of biosynthetic gene clusters or their mutants, along with their encoding enzymes responsible for producing sesterterpenes such as terpestacin and its derivatives, have also been identified. This review covers the literature from the year 1993, when 1 was firstly discovered, to May 2024, focusing on the bioactivities and syntheses of 1 and its derivatives or isomers.

Systematic analysis of natural topoisomerase I inhibitors from Forsythiae Fructus by ultrafiltration-UPLC-ESI-MS/MS, pharmacophore modelling, and molecular dynamics simulation

This study conducted a systematic analysis to explore natural DNA topoisomerase I (topo I) inhibitors from Forsythiae Fructus (FF). Crude extract of FF exhibited notable toxic and anti-proliferative effects on A549 cells. A total of 36 components were identified using bioaffinity ultrafiltration UPLC-ESI-MS/MS. Pinoresinol, 1,8-dihydrox­yanthraquinone, quercetin, and lariciresinol were screened as topo I inhibitors. Their ESI fragmentation patterns were analysed. An obvious repair effect on damaged DNA strands was observed by topo I inhibitory binding assay. Moreover, a common feature-based pharmacophore model was constructed and another 7 topo I inhibitors were screened. Molecular docking indicated that hydrogen bond, π-anion, and π-alkyl interaction were major interactions. Molecular dynamics simulation revealed important residues determining the binding of amentoflavone, forsythoside B and topo I. The results improved current understanding of natural topo I inhibitors from FF. Moreover, the combination of multi-disciplinary approaches provided a new tool to investigate natural antitumor products.

Comparative Ecotoxicity Assessment of highly bioactive Isomeric monoterpenes carvacrol and thymol on aquatic and edaphic indicators and communities

The growing demand for sustainable natural products to replace harmful synthetic ones requires comprehensive ecotoxicity assessments to ensure their eco-friendly nature. This study explored for the first time the changes in microbial community growth and metabolic profiles from river and natural soil samples exposed to the two structural isomers, thymol (THY) and carvacrol (CARV), utilizing Biolog EcoPlate™ assays and 16S rRNA gene sequencing for taxonomic analysis. In addition, we addressed existing ecotoxicity data gaps for these two compounds by using aquatic (Daphnia magna and Vibrio fischeri) and soil (Eisenia fetida and Allium cepa) indicators. Results show acute toxicity of both CARV and THY on all indicators. V. fischeri (LC50=0.59 mg/L) >D. magna (4.75 mg/L) >A. cepa (6.47 mg/L) for CARV, and V. fischeri (LC50=1.71 mg/L) >A. cepa (4.05 mg/L) >D. magna (8.13 mg/L) for THY. E. fetida showed LC50 = 7.68 mg/Kg for THY and 1.04 for CARV. River and soil microbial communities showed resilience, likely because they contain taxa capable of biodegrading these products. No significant growth inhibition effects were observed up to 100 mg/L, though substrate utilization decreased at higher concentrations, particularly for polymers and amines in soil microorganisms and polymers in aquatic communities. Soil microorganisms were more affected than aquatic ones, with CARV being more toxic than THY (EC50120h = THY 94.13 and CARV 29.79 mg/L in soil microorganisms). These findings suggest that an increase in the consumption of these products and their subsequent ecotoxicity effects from environmental discharge should still be monitored before being ruled out. However, long-term effects are unlikely due to microbial degradation of these natural products, potentially reducing risks to other target species and opening the way for their use as substitutes for commercial antibiotics.

Virtual screening, ADMET prediction, molecular docking, and dynamic simulation studies of natural products as BACE1 inhibitors for the management of Alzheimer’s disease

Alzheimer’s disease (AD) is a degenerative neurological disorder that chronically and irreversibly affects memory, cognitive function, learning ability, and organizational skills. Numerous studies have demonstrated BACE1 as a critical therapeutic target for AD, emphasizing the need for specific inhibition of BACE1 to develop effective therapeutics. However, current BACE1 inhibitors have certain limitations. Therefore, the aim of this study was to identify potential novel candidates derived from natural products that can be utilized for the treatment of AD. To achieve this, 80,617 natural compounds from the ZINC database were subjected to virtual screening and subsequently filtered according to the rule of five (RO5), leading to the identification of 1,200 compounds. Subsequently, the 1,200 compounds underwent molecular docking studies against the BACE1 receptor, utilizing high-throughput virtual screening (HTVS), standard precision (SP), and extra precision (XP) techniques to identify high-affinity ligands. Of the 50 ligands that exhibited the highest G-Scores in HTVS, further analysis was conducted using SP docking and scoring methods. This analysis led to the identification of seven ligands with enhanced binding affinities, which were then subjected to additional screening via XP docking and scoring. Finally, the stability of the most promising ligand in relation to BACE1 was assessed through molecular dynamics (MD) simulations. The computational screening demonstrated that the docking energy values for seven ligands binding to target enzymes ranged between − 6.096 and − 7.626 kcal/mol. Among these, ligand 2 (L2) exhibited the best binding energy at -7.626 kcal/mol with BACE1. MD simulations further confirmed the stability of the BACE1-L2 complex, emphasizing the formation of a robust interaction between L2 and the target enzymes. Additionally, pharmacokinetic and drug-likeness evaluations indicated that L2 is non-carcinogenic and able to permeate the blood-brain barrier (BBB). The findings of this study will contribute to narrowing down the selection of candidates for subsequent in vitro and in vivo testing.

CUTTING EFFECTS ON ALFALFA (MEDICAGO SATIVA) GROWN UNDER UREA WITHOUT RHIZOBIUM MELILOTI FORAGE DYNAMICS

In order to see the effects of cutting on the forage dynamics of alfalfa to which urea was added instead of Rhizobium meliloti, this study was conducted in one year.A randomised full block design was used to conduct the trials. Four treatments were carried out with different doses of urea in experimental plots of 3 m by 1 m: a dose of 30g/plot; a dose of 40g/plot, a dose of 50g/plot and a last dose of 60g/plot. In addition to these treatments, there is the control which is alfalfa whose seeds have been inoculated.Forage production has fluctuated over the course of ten cuts done. The results are as follows : dose 1, the minimum obtained is 1597.71 kg DM/ha obtained in section 1 and the maximum is 2704 kg DM/ha obtained in section 5 ; dose 2, the minimum is 1943.97 kg DM/ha obtained in section 1 and the maximum is 3394.8 kg DM/ha in section 5 ; dose 3, the minimum obtained is 2424.00 kg DM/ha obtained in section 8 and the maximum is 4255.97 kg DM/ha in section 3; dose 4, the minimum is 2288.00 kg DM/ha in section 8 and the maximum is 4501.01 kg DM/ha in section 1. For the control, the minimum dry biomass obtained is 1549.00 kg DM/ha obtained in section 3 and the maximum is 2719.01 kg DM/ha obtained in section 3. In every cut, leaf/stem ratio was superior to 0.5. The results of this work show that cutting has a strong impact on alfalfa forage production. After this, alfalfa yield producted in this study is better than natural forage yield production, it means that alfalfa can be a solution for animal feed to face forage problems.

Ruta graveolens, but Not Rutin, Inhibits Survival, Migration, Invasion, and Vasculogenic Mimicry of Glioblastoma Cells

Glioblastoma (GBM) is the most aggressive type of brain tumor, characterized by poor outcome and limited therapeutic options. During tumor progression, GBM may undergo the process of vasculogenic mimicry (VM), consisting of the formation of vascular-like structures which further promote tumor aggressiveness and malignancy. The resulting resistance to anti-angiogenetic therapies urges the identification of new compounds targeting VM. Extracts of natural plants may represent potential therapeutic tools. Among these, components of Ruta graveolens water extract (RGWE) display a wide range of biological activities. To test the effect of RGWE on human GBM and rat glioma cell line VM, tube formation on a gelled matrix was monitored. Quantitative assessment of VM formation shows the clear-cut inhibitory activity of RGWE. Unlike rutin, one of the most abundant extract components, the whole RGWE strongly reduced the migration and invasion of GBM tumor cells. Moreover, RGWE induced cell death of GBM patient-derived cancer stem cells and impaired VM at sub-lethal doses. Overall, our data reveal a marked RGWE-dependent inhibition of GBM cell survival, migration, invasion, and VM formation. Thus, the clear-cut ability of RGWE to counteract GBM malignancy deserves attention, holding the promise to bring natural products to clinical use, thus uncovering new therapeutic opportunities.

Effects of some anti-ulcer and anti-inflammatory natural products on cyclooxygenase and lipoxygenase enzymes: insights from in silico analysis.

The online version contains supplementary material available at 10.1007/s40203-024-00269-2.

Synthesis of Non‐canonical Tryptophan Variants via Rh‐catalyzed C−H Functionalization of Anilines

AbstractTryptophan and its non‐canonical variants play critical roles in pharmaceutical molecules and various enzymes. Facile access to this privileged class of amino acids from readily available building blocks remains a long‐standing challenge. Here, we report a regioselective synthesis of non‐canonical tryptophans bearing C4−C7 substituents via Rh‐catalyzed annulation between structurally diverse tert‐butyloxycarbonyl (Boc)‐protected anilines and alkynyl chlorides readily prepared from amino acid building blocks. This transformation harnesses Boc‐directed C−H metalation and demetalation to afford a wide range of C2‐unsubstituted indole products in a redox‐neutral fashion. This umpolung approach compared to the classic Larock indole synthesis offers a novel mechanism for heteroarene annulation and will be useful for the synthesis of natural products and drug molecules containing non‐canonical tryptophan residues in a highly regioselective manner.

Investigating the potential effect of Holothuria scabra extract on osteogenic differentiation in preosteoblast MC3T3-E1 cells

The present medical treatments of osteoporosis come with adverse effects. It leads to the exploration of natural products as safer alternative medical prevention and treatment. The sea cucumber, Holothuria scabra, has commercial significance in Asian countries with rising awareness of its properties as a functional food. This study aims to investigate the effects of the inner wall (IW) extract isolated from H. scabra on extracellular matrix maturation, mineralization, and osteogenic signaling pathways on MC3T3-E1 preosteoblasts. The IW showed the expression of several growth factors. Molecular docking revealed that H. scabra BMP2/4 binds specifically to mammal BMP2 type I receptor (BMPR-IA). After osteogenic induction, the viability of cells treated with IW extract was assessed and designated with treatment of 0.1, 0.5, 1, and 5 µg/ml of IW extract for 21 consecutive days. On days 14 and 21, treatments with IW extract at 1 and 5 µg/ml showed increased alkaline phosphatase (ALP) activity and calcium deposit levels in a dose-dependent manner compared to the control group. Moreover, the transcriptomic analysis of total RNA of cells treated with 5 µg/ml of IW extract exhibited upregulation of TGF-β, PI3K/Akt, MAPK, Wnt and PTH signaling pathways at days 14. This study suggests that IW extract from H. scabra exhibits the potential to enhance osteogenic differentiation and mineralization of MC3T3-E1 preosteoblasts through TGF-β, PI3K/Akt, MAPK, Wnt and PTH signaling pathways. Further investigation into the molecular mechanisms underlying the effect of IW extract on osteogenesis is crucial to support its application as a naturally derived supplement for prevention or treatment of osteoporosis.

Research Progress of Natural Products with the Activity of Anti-nonalcoholic Steatohepatitis.

Nonalcoholic steatohepatitis (NASH), a multi-target disease, is becoming a global epidemic. Although several anti-NASH drug candidates are being evaluated in late-stage clinical trials, none have been approved by the FDA to date. Given the global prevalence of the disease, the lack of effective drugs, and the very limited therapeutic efficacy of most of the existing synthetic drugs focusing on a single target, there is an urgent need to continue to develop new therapeutic agents. In contrast, many natural products, including pure compounds and crude extracts, possess hepatoprotective activities. Usually, these natural components are characterized by multi-targeting and low side effects. Therefore, natural products are important resources for the development of new anti- NASH drugs. In this paper, we focus on reviewing the anti-NASH potential, structure, and some of the side effects of natural products based on structural classification. We hope this mini-review will help researchers design and develop new anti-NASH drugs, especially based on the structure of natural products.

Harnessing Gram-negative bacteria for novel anti-Gram-negative antibiotics.

Natural products have proven themselves as a valuable resource for antibiotics. However, in view of increasing antimicrobial resistance, there is an urgent need for new, structurally diverse agents that have the potential to overcome resistance and treat Gram-negative pathogens in particular. Historically, the search for new antibiotics was strongly focussed on the very successful Actinobacteria. On the other hand, other producer strains have been under-sampled and their potential for the production of bioactive natural products has been underestimated. In this mini-review, we highlight prominent examples of novel anti-Gram negative natural products produced by Gram-negative bacteria that are currently in lead optimisation or preclinical development. Furthermore, we will provide insights into the considerations and strategies behind the discovery of these agents and their putative applications.

Ionic Liquid-Based Green Solvents for Extraction and Purification of Natural Plant Products

Introduction: This research paper explores the environmental sustainability of ionic liquid-based green solvents in the extraction and purification of natural plant products, with a focus on their entire life cycle. The objectives of the study were to assess the environmental impact of ionic liquid synthesis, energy consumption, water usage, emissions, recycling rates, policy effects, and stakeholder perceptions. Methods: Methodologically, we conducted a comprehensive Life Cycle Assessment (LCA) that involved primary data collection through field surveys and interviews with key stakeholders in the ionic liquid production and usage industry across various regions in India. The data were analyzed using specialized LCA software tools to quantify environmental impacts. Key findings include the identification of synthesis as a major contributor to environmental impact, emphasizing the need for greener synthesis methods. Results: The study revealed the significant carbon footprint, energy consumption, and water usage during production, highlighting opportunities for improvement. Emissions data underscored the importance of emission control measures, particularly for greenhouse gases and volatile organic compounds. Recycling and reuse were identified as environmentally friendly disposal methods. Policy compliance varied among stakeholders, indicating room for stricter regulations. Stakeholder perceptions varied, with researchers having the most positive outlook. Implications of the findings extend to sustainable chemistry practices, emphasizing interdisciplinary collaboration and the importance of considering the entire life cycle of chemical processes. Conclusion: This research contributes to a deeper understanding of green solvents and provides a foundation for promoting sustainable practices in industrial processes in India and globally.

Neuroprotective Effect of Natural Indole and β-carboline Alkaloids against Parkinson's Disease: An Overview.

Parkinson's disease (PD) is a devastating neurodegenerative condition that mostly damages dopaminergic neurons in the substantia nigra and impairs human motor function. Males are more likely than females to have PD. There are two main pathways associated with PD: one involves the misfolding of α-synuclein, which causes neurodegeneration, and the other is the catalytic oxidation of dopamine via MAO-B, which produces hydrogen peroxide that can cause mitochondrial damage. Parkin (PRKN), α-synuclein (SNCA), heat shock protein (HSP), and leucine-rich repeat kinase-2 (LRRK2) are some of the target areas for genetic alterations that cause neurodegeneration in Parkinson's disease (PD). Under the impact of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which is also important in Parkinson's disease (PD), inhibition of mitochondrial complex 1 results in enhanced ROS generation in neuronal cells. Natural products are still a superior option in the age of synthetic pharmaceuticals because of their lower toxicity and moderate side effects. A promising treatment for PD has been discovered using beta-carboline (also known as " β-carboline") and indole alkaloids. However, there are not many studies done on this particular topic. In the herbs containing β-carbolines and indoles, the secondary metabolites and alkaloids, β-carbolines and indoles, have shown neuroprotective and cognitive-enhancing properties. In this review, we have presented results from 18 years of research on the effects of indole and β-carboline alkaloids against oxidative stress and MAO inhibition, two key targets in PD. In the SAR analysis, the activity has been correlated with their unique structural characteristics. This study will undoubtedly aid researchers in looking for new PD treatment options.

Gene-Directed In Vitro Mining Uncovers the Insect-Repellent Constituent from Mugwort (Artemisia argyi).

Plants contain a vast array of natural products yet to be discovered, particularly those minor bioactive constituents. Identification of these constituents requires a significant amount of plant material, presenting considerable technical challenges. Mugwort (Artemisia argyi) is a widely recognized insect repellent herb, particularly renowned for its extensive usage during the Dragon Boat Festival in China, but the specific constituent responsible for its repellent activity remains unknown. Here, we employed a gene-directed in vitro mining approach to characterize mugwort terpene synthases (TPSs) systematically in a yeast expression system. Based on the establishment of "Terpene synthase-standard library", we have successfully identified 54 terpene products, including a novel compound designated as cyclosantalol. Through activity screening, we have identified that (+)-intermedeol, which presents in trace amount in plants, exhibits significant repellent activity against mosquitoes and ticks. After establishing its safety and efficacy, we then achieved its biosynthetic production in a yeast chassis, with an initial yield of 2.34 g/L. The methodology employed in this study not only identified a highly effective, safe, and commercially viable insect repellent derived from mugwort but also holds promise for uncovering and producing other valuable plant natural products in future research endeavors.

Inside Cover Picture

Pyridine and piperidine are common structural motifs in natural products and pharmaceutical compounds, underscoring the importance of their synthesis. Our group has developed chiral spiro‐bicyclic bisborane catalysts that enable the efficient and highly enantioselective reduction of pyridines to chiral piperidines. Subsequent transformations allow the conversion of the piperidine products into bioactive natural products. More details are discussed in the article by Wang et al. on pages 3088—3092. image