Natural Products Research Articles

Modular Synthesis of [6,6]‐Oxaspirolactones Enabled by Palladium‐Catalyzed Carbonylative Spirolactonization

An expedient and efficient carbonylative protocol proceeded via palladium‐catalyzed tandem cyclic ketonization and carbonylative spirolactonization has been developed. This carbonylation reaction is compatible with a wide range of hydroxyalkyl ketone tethered benzyl chlorides bearing different functional groups and can be proceeded under comericially available Pd2(dba)3/BINAP catalyst system, providing a straithfowrd and practical approach to a broad range of [6,6]‐oxaspirolactones. The synthesized [6,6]‐oxaspirolactones are commonly found as core structures in natural products and can potentially serve as C2‐symmetric ligand synthons.

C(sp)-C(sp) Lever-Based Targets of Orientational Chirality: Design and Asymmetric Synthesis

In this study, the design and asymmetric synthesis of a series of chiral targets of orientational chirality were conducted by taking advantage of N-sulfinylimine-assisted nucleophilic addition and modified Sonogashira catalytic coupling systems. Orientational isomers were controlled completely using alkynyl/alkynyl levers [C(sp)-C(sp) axis] with absolute configuration assignment determined by X-ray structural analysis. The key structural element of the resulting orientational chirality is uniquely characterized by remote through-space blocking. Forty examples of multi-step synthesis were performed, with modest to good yields and excellent orientational selectivity. Several chiral orientational amino targets are attached with scaffolds of natural and medicinal products, showing potential pharmaceutical and medical applications in the future.

Effect of formaldehyde exposure on phytochemical content and functional activity of Agaricus bisporus (Lge.) Sing.

In this study, the effect of formaldehyde on phytochemical content and antioxidant activity of Agaricus bisporus was investigated. Synthetic compost based on wheat straw was prepared by fermentation and disinfection. After steam pasteurization, 5 g of A. bisporus mycelia were inoculated into 1 kg of compost. To determine the effects of formaldehyde, 2, 4, and 6% concentrations were added to the composts, while compost without formaldehyde was used for the control group. The harvesting period was set at 10 weeks. Total phenolic and flavonoid content, macro- and microelement profile, and phenolic content were analyzed in the harvested A. bisporus samples. Macro- and microelement content was determined by ICP-OES, and phenolic compound profile was determined by LC-MS/MS analysis. Formaldehyde levels in A. bisporus samples were determined by the acetylacetone spectrophotometry method. The antioxidant capacity of A. bisporus samples was determined by DPPH scavenging activity; antimutagenic effects of samples were determined by Allium test. Application of 2, 4, and 6% formaldehyde resulted in a 1.12-, 1.19-, and 2.07-fold reduction in total phenolic content, respectively. The total phenolic content was reduced between 34.4% and 71.8%. These changes were confirmed by LC-MS/MS analysis. Compounds such as protocatechuic acid, salicylic acid, ferulic acid, and 4-OH benzoic acid, which were detected in the control group, could not be detected in the samples treated with 6% formaldehyde, and it was found that the application of formaldehyde reduced the phenolic content. Similar changes were also observed in macro- and microelements, and significant changes in elemental contents were observed after formaldehyde application. While the presence of formaldehyde at a low level, which may be due to natural production, was detected in the control group, a residue of 11.41 ± 0.93 mg/kg was determined in the 6% FMD applied group. All these changes resulted in a decrease in the antioxidant activity of A. bisporus. The DPPH scavenging activity, which was determined in the range of 21.6-73.3% in the control samples, decreased to 12.3-56.7% in the samples treated with formaldehyde. These results indicate that the application of formaldehyde at different stages of A. bisporus cultivation leads to significant changes in the nutritional value and biological activity of A. bisporus.

An integrated multi-omics approach reveals polymethoxylated flavonoid biosynthesis in Citrus reticulata cv. Chachiensis

Citrus reticulata cv. Chachiensis (CRC) is an important medicinal plant, its dried mature peels named “Guangchenpi”, has been used as a traditional Chinese medicine to treat cough, indigestion, and lung diseases for several hundred years. However, the biosynthesis of the crucial natural products polymethoxylated flavonoids (PMFs) in CRC remains unclear. Here, we report a chromosome-scale genome assembly of CRC with the size of 314.96 Mb and a contig N50 of 16.22 Mb. Using multi-omics resources, we discover a putative caffeic acid O-methyltransferase (CcOMT1) that can transfer a methyl group to the 3-hydroxyl of natsudaidain to form 3,5,6,7,8,3’,4’-heptamethoxyflavone (HPMF). Based on transient overexpression and virus-induced gene silencing experiments, we propose that CcOMT1 is a candidate enzyme in HPMF biosynthesis. In addition, a potential gene regulatory network associated with PMF biosynthesis is identified. This study provides insights into PMF biosynthesis and may assist future research on mining genes for the biosynthesis of plant-based medicines.

Integrated Metabolomic and Transcriptomic Analysis Reveals the Underlying Antibacterial Mechanisms of the Phytonutrient Quercetin-Induced Fatty Acids Alteration in Staphylococcus aureus ATCC 27217

The utilization of natural products in food preservation represents a promising strategy for the dual benefits of controlling foodborne pathogens and enhancing the nutritional properties of foods. Among the phytonutrients, flavonoids have been shown to exert antibacterial effects by disrupting bacterial cell membrane functionality; however, the underlying molecular mechanisms remain elusive. In this study, we investigated the effect of quercetin on the cell membrane permeability of Staphylococcus aureus ATCC 27217. A combined metabolomic and transcriptomic approach was adopted to examine the regulatory mechanism of quercetin with respect to the fatty acid composition and associated genes. Kinetic analysis and molecular docking simulations were conducted to assess quercetin’s inhibition of β-ketoacyl-acyl carrier protein reductase (FabG), a potential target in the bacterial fatty acid biosynthesis pathway. Metabolomic and transcriptomic results showed that quercetin increased the ratio of unsaturated to saturated fatty acids and the levels of membrane phospholipids. The bacteria reacted to quercetin-induced stress by attempting to enhance fatty acid biosynthesis; however, quercetin directly inhibited FabG activity, thereby disrupting bacterial fatty acid biosynthesis. These findings provide new insights into the mechanism of quercetin’s effects on bacterial cell membranes and suggest potential applications for quercetin in bacterial inhibition.

Superior Oxygen Evolution Electrocatalyst based on Ni‐Ellagic Acid Coordination Polymer

AbstractThe oxygen evolution reaction (OER) is central to energy conversion technologies, but the high cost and scarcity of commercial noble metal catalysts limit their widespread application. Natural products exhibit great potential in preparing high‐performance electrocatalysts due to their cost‐effectiveness and sustainability. Here, a kind of 1D polymers [M‐EA (M═Co, Cu, Ni)] for oxygen evolution reaction via the complexation of ellagic acid (EA) with metal ions are reported. It is found that Ni‐EA displays a low overpotential (190 mV at 10 mA cm−2) and an ultralow Tafel slope (28 mV dec−1), with a production cost of only 3.6 × 10−2% of IrO2. Density functional theory investigations reveal the electrocatalytic mechanism of the OER. A rechargeable Zn‐Air battery using Ni‐EA+Pt/C as the air electrode shows a lower charging potential and better cycling stability than the IrO2+Pt/C‐based battery. This work provides a train for the development of state‐of‐the‐art OER catalysts.

ASSESSMENT OF DERMAL IRRITATION OF LAO NHA QUE COCONUT OIL IN EXPERIMENTAL ANIMALS

Lao Nha Que virgin coconut oil (LNQ VCO) is a natural product inteneded to treat some skin diseases such as burns, atopic dermatitis, and xerosis.... To provide information on its local irritation, this study was carried out to evaluate the dermal irritation of LNQ VCO. 0.5 ml of VCO was applied on the skin in one side of the spine while 0.5 ml of distilled water was applied on the other side. After 4-hour exposure period, the residual LNQ VCO was removed and the skin reactions for erythema and oedema was described and scored at 1 hour, 24 hours, 48 hours and 72 hours after removing the patches. The results showed that the erythema appeard on the LNQ VCO-applied skin in two out of three rabbits and recovered up to 72h. The primary irritation index was calculated to catogorize the skin irritation of LNQ VCO. The primary irritation index of LNQ VCO was 0.78. Thus, LNQ VCO might cause slight irritation on the rabbit’s skin.

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. Method: 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. Result: 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

Radical Acylfluoroalkylation of 1,3-Enynes via N-Heterocyclic Carbene/Photoredox Cooperative Catalysis.

We report a novel three-component radical acylfluoroalkylation of 1,3-enynes by synergistic N-heterocyclic carbene (NHC)/photoredox catalysis toward various fluorinated allenic aryl ketones. This protocol features a broad substrate scope and excellent functional group tolerability, with examples of late-stage modification of drug molecules and natural products. Notably, seven different fluoroalkyl motifs can be introduced to 1,3-enynes, further demonstrating the robustness and generality of this method. The generation of the fluoroalkyl radical from each sulfinate reagent was individually supported by EPR experiments.

Inflammation and cancer: friend or foe?

Chronic inflammation plays a crucial role in the onset and progression of pathologies like neurodegenerative and cardiovascular diseases, diabetes, and cancer, since tumor development and chronic inflammation are linked, sharing common signaling pathways. At least 20% of breast and colorectal cancers are associated with chronic inflammation triggered by infections, irritants, or autoimmune diseases. Obesity, chronic inflammation, and cancer interconnection underscore the importance of population-based interventions in maintaining healthy body weight, to disrupt this axis. Given that the dietary inflammatory index is correlated with an increased risk of cancer, adopting an anti-inflammatory diet supplemented with nutraceuticals may be useful for cancer prevention. Natural products and their derivatives offer promising antitumor activity with favorable adverse effect profiles; however, the development of natural bioactive drugs is challenging due to their variability and complexity, requiring rigorous research processes. It has been shown that combining anti-inflammatory products, such as non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and statins, with plant-derived products demonstrate clinical utility as accessible adjuvants to traditional therapeutic approaches, with known safety profiles. Pharmacological approaches targeting multiple proteins involved in inflammation and cancer pathogenesis emerge as a particularly promising option. Given the systemic and multifactorial nature of inflammation, comprehensive strategies are essential for long term success in cancer therapy. To gain insights into carcinogenic phenomena and discover diagnostic or clinically relevant biomarkers, is pivotal to understand genetic variability, environmental exposure, dietary habits, and TME composition, to establish therapeutic approaches based on molecular and genetic analysis. Furthermore, the use of endocannabinoid, cannabinoid, and prostamide-type compounds as potential therapeutic targets or biomarkers requires further investigation. This review aims to elucidate the role of specific etiological agents and mediators contributing to persistent inflammatory reactions in tumor development. It explores potential therapeutic strategies for cancer treatment, emphasizing the urgent need for cost-effective approaches to address cancer-associated inflammation.

Pseudovirus-Based Systems for Screening Natural Antiviral Agents: A Comprehensive Review

Since the outbreak of COVID-19, researchers have been working tirelessly to discover effective ways to combat coronavirus infection. The use of computational drug repurposing methods and molecular docking has been instrumental in identifying compounds that have the potential to disrupt the binding between the spike glycoprotein of SARS-CoV-2 and human ACE2 (hACE2). Moreover, the pseudovirus approach has emerged as a robust technique for investigating the mechanism of virus attachment to cellular receptors and for screening targeted small molecule drugs. Pseudoviruses are viral particles containing envelope proteins, which mediate the virus’s entry with the same efficiency as that of live viruses but lacking pathogenic genes. Therefore, they represent a safe alternative to screen potential drugs inhibiting viral entry, especially for highly pathogenic enveloped viruses. In this review, we have compiled a list of antiviral plant extracts and natural products that have been extensively studied against enveloped emerging and re-emerging viruses by pseudovirus technology. The review is organized into three parts: (1) construction of pseudoviruses based on different packaging systems and applications; (2) knowledge of emerging and re-emerging viruses; (3) natural products active against pseudovirus-mediated entry. One of the most crucial stages in the life cycle of a virus is its penetration into host cells. Therefore, the discovery of viral entry inhibitors represents a promising therapeutic option in fighting against emerging viruses.

Exploring a Non-Comfort Zone: Central Chirality-Generating Macrocyclizations.

Macrocyclization reactions that are capable of stereoselectively co-creating one or more stereogenic centers have become useful strategies for the effective syntheses of structurally and functionally diverse organic molecules. This JOCSynopsis summarizes the recent progress in the field of natural product and analogue syntheses, including both bioinspired and non-bioinspired macrocyclic disconnections. Selected examples are organized on the basis of the sources of the asymmetric inductions.

Short Formal Syntheses of Lycorine and Congeners Using a 5-Endo-Trig/6-Endo-Trig Radical Cyclization Sequence.

Here, we report a practical route to medicinally interesting lycorine congeners alongside formal syntheses of various lycorine-type natural products, including lycorine itself. The efficiency of our strategy derives from a back-to-back 5-endo-trig/6-endo-trig radical cyclization sequence, which we systematically studied both experimentally and computationally. The results of our work will facilitate future development of urgently needed antiviral therapeutics based on lycorine.

A Comparative Study on the Antioxidant and Insecticidal Activities of <i>Eucalyptus camaldulensis </i>Essential Oil and Hydrosol

The study investigates the hydrosol of <i>Eucalyptus camaldulensis</i> to assess its value and potential applications within the essential oil (EO) industry. Following steam distillation of <i>E. camaldulensis</i> leaves to extract essential oil, the resulting hydrosol underwent liquid-liquid extraction to yield a secondary essential oil (SEO). Comparative chemical analysis was performed using GC/MS. Comparative chemical analysis of the SEO and EO revealed distinct compositions, with 24 compounds identified in the SEO compared to 41 in the EO. Oxygenated compounds predominated in the SEO while non-oxygenated compounds were the most abundant in the EO (63.61%). Eucalyptol emerged as the primary constituent in both, with higher concentrations observed in the SEO (60.41%) than in the EO (28.53%). Additionally, antioxidant activity assessed using the DPPH assay demonstrated significant radical reduction in the SEO compared to the EO. In insecticidal tests targeting Callosobruchus maculatus, the SEO exhibited pronounced toxicity, with an IC<sub>50</sub> value lower than that of the EO. This study showed the abundance of oxygenated compounds in <i>E. camaldulensis</i> hydrosol compared to pure essential oil, suggesting its potential as an antioxidant agent and for integrated pest management in agriculture. The research highlights the value of hydrosols in the EO industry and their potential applications in natural product formulations and pest control strategies.

Rapid Access to Tigliane, Ingenane, and Rhamnofolane Diterpenes from a Lathyrane Precursor via Biomimetic Skeleton Transformation Strategy.

Bioinspired skeleton transformation of a tricyclic lathyrane-type Euphorbia diterpene was conducted to efficiently construct a tetracyclic tigliane diterpene on a gram scale via a key aldol condensation. The tigliane diterpene was then respectively converted into naturally rare ingenane and rhamnofolane diterpenes through a semipinacol rearrangement and a visible-light-promoted regioselective cyclopropane ring-opening reaction. This work provides a concise strategy for high-efficiency access to diverse polycyclic Euphorbia diterpene skeletons from abundant lathyrane-type natural products and paves the way for biological activity investigation of naturally rare molecules.

Untargeted Metabolomic to Access Chemical Differences Induced by Dual Endophyte Cultures Isolated from Euphorbia Umbellata.

Endophytic fungi live asymptomatically inside vegetal tissues, and such uncommon habitat contributes to their exceptional chemical diversity. Isolating natural products from endophytic fungi could fail due to silent biosynthetic gene clusters under ordinary in vitro culture conditions, and co-culturing has been assayed to trigger their metabolism. We carried out single and dual cultures with 13 endophyte strains isolated from Euphorbia umbellata leaves. Multivariate statistics applied to untargeted metabolomics compared the chemical profiles of all endophyte cultures. PCA analysis guided the selection of the Aspergillus pseudonomiae J1 - Porogramme brasiliensis J9 dual culture for its most significant chemical differentiation: Five compounds were putatively annotated in the J1-J9 culture according to UHPLC-HRMS data, kojic acid, haliclonol and its diastereoisomer, caffeic acid, and 2-(3,4-dihydroxyphenyl)acetaldehyde. Analysis by PLS-DA using VIP score showed that kojic acid displayed the most significative importance in discriminating single and dual J1-J9 cultures.

Structural and Functional Analyses of Inhibition of Human Dihydroorotate Dehydrogenase by Antiviral Furocoumavirin.

Natural products are important sources of seed compounds for drug discovery. However, it has become difficult in recent years to discover new compounds with valuable pharmacological activities. On the other hand, among the vast number of natural products that have been isolated so far, a considerable number of compounds with specific biological activities are thought to be overlooked in screening that uses biological activity as an index. Therefore, it is conceivable that such overlooked useful compounds may be found by screening compound libraries that have been amassed previously through specific assays. Previously, NPD723, a member of the Natural Products Depository library comprised of a mixture of natural and non-natural products developed at RIKEN, and its metabolite H-006 were found to inhibit growth of various cancer cells at low nanomolar half-maximal inhibitory concentration. Subsequent analysis revealed that H-006 strongly inhibited human dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme in the de novo pyrimidine biosynthetic pathway. Here, we elucidated the crystal structure of the DHODH-flavin mononucleotide-orotic acid-H-006 complex at 1.7 Å resolution to determine that furocoumavirin, the S-enantiomer of H-006, was the actual inhibitor. The overall mode of interaction of furocoumavirin with the inhibitor binding pocket was similar to that described for previously reported tight-binding inhibitors. However, the structural information together with kinetic characterizations of site-specific mutants identified key unique features that are considered to contribute to the sub-nanomolar inhibition of DHODH by furocoumavirin. Our finding identified new chemical features that could improve the design of human DHODH inhibitors.

Graphene and Natural Products: A Review of Antioxidant Properties in Graphene Oxide Reduction

This review article addresses the antioxidant properties of different natural products, including ascorbic acid, gallic acid, oxalic acid, L-glutathione (GSH), bacteriorhodopsin, green tea polyphenols, glucose, hydroxycinnamic acid, ethanoic acid, betanin, and L-glutathione, in the reduction of graphene oxide (rGO). rGO can cause damage to cells, including oxidative stress and inflammation, limiting its application in different sectors that use graphene, such as technologies used in medicine and dentistry. The natural substances reviewed have properties that help reduce this damage, neutralizing free radicals and maintaining cellular integrity. This survey demonstrates that the combination of these antioxidant compounds can be an effective strategy to minimize the harmful effects of rGO and promote cellular health.

Monomeric compounds from natural products for the treatment of pulmonary fibrosis: a review.

Pulmonary fibrosis (PF) is the end stage of lung injury and chronic lung diseases that results in diminished lung function, respiratory failure, and ultimately mortality. Despite extensive research, the pathogenesis of this disease remains elusive, and effective therapeutic options are currently limited, posing a significant clinical challenge. In addition, research on traditional Chinese medicine and naturopathic medicine is hampered by several complications due to complex compositionand lack of reference compounds. Natural product monomers, possessing diverse biological activities and excellent safety profiles, have emerged as potential candidates for preventing and treating PF. The effective anti-PF ingredients identified can be generally divided into flavonoids, saponins, polysaccharides, and alkaloids. Specifically, these monomeric compounds can attenuate inflammatory response, oxidative stress, and other physiopathological processes of the lung through many signaling pathways. They also improve pulmonary factors. Additionally, they ameliorate epithelial-mesenchymal transition (EMT) and fibroblast-myofibroblast transdifferentiation (FMT) by regulating multiple signal amplifiers in the lungs, thereby mitigating PF. This review highlights the significant role of monomer compounds derived from natural products in reducing inflammation, oxidative stress, and inhibiting EMT process. The article provides comprehensive information and serves as a solid foundation for further exploration of new strategies to harness the potential of botanicals in the treatment of PF.

Animal-derived natural products for hepatocellular carcinoma therapy: current evidence and future perspectives

Hepatocellular carcinoma (HCC) has a high morbidity and mortality rate, and the survival rate of HCC patients remains low. Animal medicines have been used as potential therapeutic tools throughout the long history due to their different structures of biologically active substances with high affinity to the human body. Here, we focus on the effects and the mechanism of action of animal-derived natural products against HCC, which were searched in databases encompassing Web of Science, PubMed, Embase, Science Direct, Springer Link, and EBSCO. A total of 24 natural products from 12 animals were summarized. Our study found that these natural products have potent anti-hepatocellular carcinoma effects. The mechanism of action involving apoptosis induction, autophagy induction, anti-proliferation, anti-migration, and anti-drug resistance via phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), Ras/extracellular signal regulated kinases (ERK)/mitogen-activated protein kinase (MAPK), Wnt/β-catenin, and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways. Huachansu injection and sodium cantharidate have been used in clinical applications with good efficacy. We review the potential of animal-derived natural products and their derivatives in the treatment of HCC to date and summarize their application prospect and toxic side effects, hoping to provide a reference for drug development for HCC.