Natural Products Research Articles

Protopine and Allocryptopine Interactions with Plasma Proteins

A comprehensive study of the interactions of human serum albumin (HSA) and α-1-acid glycoprotein (AAG) with two isoquinoline alkaloids, i.e., allocryptopine (ACP) and protopine (PP), was performed. The UV-Vis spectroscopy, molecular docking, competitive binding assays, and circular dichroism (CD) spectroscopy were used for the investigations. The results showed that ACP and PP form spontaneous and stable complexes with HSA and AAG, with ACP displaying a stronger affinity towards both proteins. Molecular docking studies revealed the preferential binding of ACP and PP to specific sites within HSA, with site 2 (IIIA) being identified as the favored location for both alkaloids. This was supported by competitive binding assays using markers specific to HSA’s drug binding sites. Similarly, for AAG, a decrease in fluorescence intensity upon addition of the alkaloids to AAG/quinaldine red (QR) complexes indicated the replacement of the marker by the alkaloids, with ACP showing a greater extent of replacement than PP. CD spectroscopy showed that the proteins’ structures remained largely unchanged, suggesting that the formation of complexes did not significantly perturb the overall spatial configuration of these macromolecules. These findings are crucial for advancing the knowledge on the natural product–protein interactions and the future design of isoquinoline alkaloid-based therapeutics.

Chemoenzymatic Synthesis of 2‐Aryl Thiazolines from 4‐Hydroxybenzaldehydes Using Vanillyl Alcohol Oxidases

Nitrogen heterocycles are commonly found in bioactive natural products and drugs. However, the biocatalytic tools for nitrogen heterocycle synthesis are limited. Herein, we report the discovery of vanillyl alcohol oxidases (VAOs) as efficient biocatalysts for the one‐pot synthesis of 2‐aryl thiazolines from various 4‐hydroxybenzaldehydes and aminothiols. The wild‐type biocatalyst features a broad scope of 4‐hydroxybenzaldehydes. Though the scope of aminothiols is limited, it could be improved via semi‐rational protein engineering, generating a variant to produce previously inaccessible cysteine‐derived bioactive 2‐aryl thiazolines using the wild‐type VAO. Benefiting from the derivatizable functional groups in the enzymatic products, we further chemically modified these products to expand the chemical space, offering a new chemoenzymatic strategy for the green and efficient synthesis of structurally diverse 2‐aryl‐thiazoline derivatives to prompt their use in drug discovery and catalysis.

Nonclassical Zwitterions as a Design Principle to Reduce Lipophilicity without Impacting Permeability.

The ionization of bioactive molecules impacts many ADME-relevant physicochemical properties, in particular, solubility, lipophilicity, and permeability. Ampholytes contain both acidic and basic groups and are distinguished as ordinary ampholytes and zwitterions. An influential review states that zwitterions only exist if the acidic pKa is significantly lower than the basic pKa. Through concordance of measured and calculated pKa and log P, we show that the zwitterionic behavior of several marketed drugs and natural products occurs despite a low or negative ΔpKa. These nonclassical zwitterions are characterized by a weak acidic and basic pKa and conjugation through an extended aromatic system, often including pseudorings via intramolecular hydrogen bonds. In contrast to most classical zwitterions, nonclassical zwitterions can exhibit excellent permeability. As permeability and lipophilicity are typically correlated, the combination of low lipophilicity and high permeability makes nonclassical zwitterions an attractive design principle in medicinal chemistry.

Bioguided Fractionation of Phyllanthus spp.: Unveiling Anticancer Potential through Metabolomic Correlation and ADMETox Insights.

Cancer remains a significant global health concern, with mortality rates steadily rising and prompting an urgent search for effective treatments. This study focuses on the medicinal properties of plants from the Phyllanthus genus, specifically Phyllanthus amarus and Phyllanthus niruri, which have shown promise in traditional medicine. Through bioguided fractionation using preparative high-performance liquid chromatography (HPLC), bioactive compounds were isolated and identified using ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry (UHPLC-QTOF-MSE) and nuclear magnetic resonance (NMR) spectroscopy. Chemometric analyses such as principal component analysis (PCA) aided in understanding metabolite distribution. Biological assays demonstrated cytotoxic activities of specific fractions against cancer cell lines, notably the PhyN 4n fraction from P. niruri, which induced S-phase cell cycle arrest and apoptosis in HL60 cells. These findings underscore the anticancer potential of Phyllanthus species and lay the groundwork for future drug development efforts. The study's integration of advanced analytical techniques, chemometrics, and biological assays provides valuable insights for harnessing natural products in the fight against cancer.

PHYTOCHEMICALS SCREENING, ANTIOXIDANT AND ANTIMICROBIAL ACTIVITY OF CARICA PAPAYA LEAF EXTRACTS

Objective: The objective of the present study aimed at investigating the phytochemical antioxidant and anti-microbial properties of Carica papaya leaf extracts. Methods: As phytochemicals are biologically active compounds and a powerful group of plant chemicals believed to stimulate the immune system along with antioxidants, the molecules which hinder oxidation of other molecules by the process of inhibiting or by generating the oxidizing chain reactions and preventing diseases. The anti-microbial activity on various gram-positive and gram-negative bacteria were determined using zone of inhibition and antioxidant by the 2,2,1-diphenyl-1-picrylhydrazyl method. Results: Phytochemical screening, antioxidant and antibacterial potential were determined using different aqueous and organic solvents in addition to the determination of trace element in leaves of C. papaya. Antioxidant activity using DPPH free radical scavenging assay indicated leaves extracts leaves showed inhibition of per oxidation. The result showed that the ethanolic extract of C. papaya possessed a significant antioxidant activity as compared to methanol and aqueous extract. The antibacterial study showed leaves extract is the best to cope infectious action of bacteria. Conclusion: This study was conducted to test the medicinal profile of C. papaya by extracting secondary metabolites with organic and aqueous solvents. Ethanol was found to be the best solvents of choice to extract natural products to get maximum medicinal benefits and could be used to medicinal formulation against different infectious diseases.

Chemoenzymatic Synthesis of 2-Aryl Thiazolines from 4-Hydroxybenzaldehydes Using Vanillyl Alcohol Oxidases.

Nitrogen heterocycles are commonly found in bioactive natural products and drugs. However, the biocatalytic tools for nitrogen heterocycle synthesis are limited. Herein, we report the discovery of vanillyl alcohol oxidases (VAOs) as efficient biocatalysts for the one-pot synthesis of 2-aryl thiazolines from various 4-hydroxybenzaldehydes and aminothiols. The wild-type biocatalyst features a broad scope of 4-hydroxybenzaldehydes. Though the scope of aminothiols is limited, it could be improved via semi-rational protein engineering, generating a variant to produce previously inaccessible cysteine-derived bioactive 2-aryl thiazolines using the wild-type VAO. Benefiting from the derivatizable functional groups in the enzymatic products, we further chemically modified these products to expand the chemical space, offering a new chemoenzymatic strategy for the green and efficient synthesis of structurally diverse 2-aryl-thiazoline derivatives to prompt their use in drug discovery and catalysis.

Unlocking the biosynthetic potential and taxonomy of the Antarctic microbiome along temporal and spatial gradients.

Extreme environments, such as Antarctica, select microbial communities that display a range of evolutionary strategies to survive and thrive under harsh environmental conditions. These include a diversity of specialized metabolites, which have the potential to be a source for new natural product discovery. Efforts using (meta)genome mining approaches to identify and understand biosynthetic gene clusters in Antarctica are still scarce, and the extent of their diversity and distribution patterns in the environment have yet to be discovered. Herein, we investigated the biosynthetic gene diversity of the biofilm microbial community of Whalers Bay, Deception Island, in the Antarctic Peninsula and revealed its distribution patterns along spatial and temporal gradients by applying metagenome mining approaches and multivariable analysis. The results showed that the Whalers Bay microbial community harbors a great diversity of biosynthetic gene clusters distributed into seven classes, with terpene being the most abundant. The phyla Proteobacteria and Bacteroidota were the most abundant in the microbial community and contributed significantly to the biosynthetic gene abundances in Whalers Bay. Furthermore, the results highlighted a significant correlation between the distribution of biosynthetic genes and taxonomic diversity, emphasizing the intricate interplay between microbial taxonomy and their potential for specialized metabolite production.IMPORTANCEThis research on antarctic microbial biosynthetic diversity in Whalers Bay, Deception Island, unveils the hidden potential of extreme environments for natural product discovery. By employing metagenomic techniques, the research highlights the extensive diversity of biosynthetic gene clusters and identifies key microbial phyla, Proteobacteria and Bacteroidota, as significant contributors. The correlation between taxonomic diversity and biosynthetic gene distribution underscores the intricate interplay governing specialized metabolite production. These findings are crucial for understanding microbial adaptation in extreme environments and hold significant implications for bioprospecting initiatives. The study opens avenues for discovering novel bioactive compounds with potential applications in medicine and industry, emphasizing the importance of preserving and exploring these polyextreme ecosystems to advance biotechnological and pharmaceutical research.

Uncovering Cocrystal Formation and Competition Mechanism of Polyhydroxy Natural Products: Cases of Quercetin, Hesperidin, Resveratrol, and Curcumin

Uncovering Cocrystal Formation and Competition Mechanism of Polyhydroxy Natural Products: Cases of Quercetin, Hesperidin, Resveratrol, and Curcumin

Hit-to-Lead Optimization of the Natural Product Oridonin as Novel NLRP3 Inflammasome Inhibitors with Potent Anti-Inflammation Activity.

Targeting NLRP3 inflammasome with inhibitors is a novel strategy for NLRP3-driven diseases. Herein, hit compound 5 possessing an attractive skeleton was identified from our in-house database of oridonin, and then a potential lead compound 32 was obtained by optimization of 5, displaying two-digit nanomolar inhibition on NLRP3. Moreover, compound 32 showed enhanced safety index (SI) relative to oridonin (IC50 = 77.2 vs 780.4 nM, SI = 40.5 vs 8.5) and functioned through blocking ASC oligomerization and interaction of NLRP3-ASC/NEK7, thereby suppressing NLRP3 inflammasome assembly and activation. Furthermore, diverse agonists-induced activations of NLRP3 could be impeded by compound 32 without altering NLRC4 or AIM2 inflammasome. Crucially, compound 32 possessed tolerable pharmaceutical properties and significant anti-inflammatory activity in MSU-induced gouty arthritis model. Therefore, this work enriched the SAR of NLRP3 inflammasome inhibitors and provided a potential candidate for the treatment of NLRP3-associated diseases.

Linking Variability in Phytochemical Composition with Safety Profile of Thymus carnosus Boiss. Extracts: Effect of Major Compounds and Evaluation of Markers of Oxidative Stress and Cell Death

Natural products are generally considered safe for human consumption, but this classification is often based on ethnobotanical surveys or their use in traditional medicine over a long period of time. However, edaphoclimatic factors are known to produce different chemotypes, which may affect the safety profile and bioactivities, and are not commonly considered for plants exploited as crops worldwide. Thymus carnosus Boiss., a thyme species with various health-promoting effects, has potential pharmaceutical applications, but edaphoclimatic factors were found to significantly impact its phytochemical composition. Thus, we aimed to assess the safety profile of T. carnosus extracts obtained from plants harvested in two locations over three consecutive years and to establish an association with specific components, an essential study in the search for new sources of nutraceuticals. Thus, the antiproliferative effect of an aqueous decoction (AD), hydroethanolic (HE) extracts, and major extracts’ components of T. carnosus was evaluated on intestinal (Caco-2) and hepatic (HepG2) cell models, revealing effects dependent on extract type, cell line, and tested compounds. Flavonoids induced different cytotoxic patterns, which could be attributed to molecular structural differences. Flow cytometry analysis showed apoptosis and necrosis induction, mediated by the modulation of intracellular reactive oxygen species and mitochondrial membrane potential, effects that were dependent on the cell line and phytochemical composition and on the synergism between extracts components, rather than on the activity of an isolated compound. While ursolic acid was the component with the strongest impact on the difference between extraction methods, flavonoids assumed a pivotal role in the response of different cell lines to the extracts. We report for the first time, for Thymus spp. extracts, that variations in the phytochemical composition clearly influence the cellular response, thus highlighting the need for extract standardization for medicinal applications.

Carbene-Catalyzed Enantioselective Addition of Sulfinate to Ketones.

A carbene-catalyzed enantioselective addition of sulfinate to ketones between 2-benzoylbenzaldehyde and sulfonyl chloride is disclosed. Up to now, the carbon and heteroatom nucleophiles have effectively undergone catalytic enantioselective addition to carbonyl molecules to introduce functionalities and chirality. Sulfone, as an important class of sulfur-containing functional groups, represents highly valuable motifs in medicines and natural products. It remains undeveloped for the catalytic asymmetric addition of sulfinate to carbonyls. Herein we disclosed the first catalytic enantioselective addition of sulfinate to ketones for the synthesis of sulfones via N-heterocyclic carbene (NHC) catalysis. The sulfonyl chloride behaves both as an oxidant and as a nucleophilic substrate in this carbene-catalyzed process. Experimental studies suggested that the Breslow intermediate can be SET oxidized by sulfonyl chloride to generate the sulfonyl radical. This novel synthetic approach for the asymmetric addition of sulfinate to carbonyls can also be used to modify the commercially available functional molecules.

Easy Access to Functionalized Indolines and Tetrahydroquinolines via a Photochemical Cascade Cyclization Reaction.

Herein, the development of a light-mediated synthesis of functionalized indolines and tetrahydroquinolines is reported. These structural motifs are considered as highly valuable targets, attributed to their widespread occurrence in pharmaceuticals and natural products. The gold-mediated approach offers a direct route to functionalized indolines in yields of up to 81% under mild photochemical conditions. Thereby, easily accessible Boc-protected N-aryl-allylamine and homoallylamine derivatives were reacted with sp3-hybridized haloalkanes in an intermolecular cascade cyclization reaction. A broad scope of substrates, including a variety of different substituents on the aromatic backbone as well as various haloalkanes, could be utilized. Indoline derivatives, which are functionalized in position 2, are also accessible by applying ortho-allylic anilines. Moreover, the synthetic appeal was demonstrated for a total synthesis of the anti-inflammatory agent AN669 in three reaction steps in an overall yield of 64%.

Aminosulfonylation of Alkenes for the Synthesis of β-Amino Sulfone Derivatives.

β-amino sulfones are important motifs found in natural products and active pharmaceutical compounds. Herein, we report a general and highly regioselective intermolecular aminosulfonylation of alkenes via the homolysis of sulfinyl oximes from ketoximes and sulfinyl chloride. This method features catalyst-free, step-efficient functionalization and prominent functional group tolerance, providing a straightforward, green, and widely applicable approach to accessing β-amino sulfone derivatives.

Computational identification of potential bioactive compounds from Triphala against alcoholic liver injury by targeting alcohol dehydrogenase.

Alcoholic liver injury resulting from excessive alcohol consumption is a significant social concern. Alcohol dehydrogenase (ADH) plays a critical role in the conversion of alcohol to acetaldehyde, leading to tissue damage. The management of alcoholic liver injury encompasses nutritional support and, in severe cases liver transplantation, but potential adverse effects exist, and effective medications are currently unavailable. Natural products with their potential benefits and historical use in traditional medicine emerge as promising alternatives. Triphala, a traditional polyherbal formula demonstrates beneficial effects in addressing diverse health concerns, with a notable impact on treating alcoholic liver damage through enhanced liver metabolism. The present study aims to identify potential active phytocompounds in Triphala targeting ADH to prevent alcoholic liver injury. Screening 119 phytocompounds from the Triphala formulation revealed 62 of them showing binding affinity to the active site of the ADH1B protein. Promising lipid-like molecule from Terminalia bellirica, (4aS, 6aR, 6aR, 6bR, 7R, 8aR, 9R, 10R, 11R, 12aR, 14bS)-7, 10, 11-trihydroxy-9-(hydroxymethyl)-2, 2, 6a, 6b, 9, 12a-hexamethyl-1, 3, 4, 5, 6, 6a, 7, 8, 8a, 10, 11, 12, 13, 14b-tetradecahydropicene-4a-carboxylic acid showed high binding efficiency to a competitive ADH inhibitor, 4-Methylpyrazole. Pharmacokinetic analysis further confirmed the drug-likeness and non-hepatotoxicity of the top-ranked compound. Molecular dynamics simulation and MM-PBSA studies revealed the stability of the docked complexes with minimal fluctuation and consistency of the hydrogen bonds throughout the simulation. Together, computational investigations suggest that (4aS, 6aR, 6aR, 6bR, 7R, 8aR, 9R, 10R, 11R, 12aR, 14bS)-7, 10, 11-trihydroxy-9-(hydroxymethyl)-2, 2, 6a, 6b, 9, 12a-hexamethyl-1, 3, 4, 5, 6, 6a, 7, 8, 8a, 10, 11, 12, 13, 14b-tetradecahydropicene-4a-carboxylic acid from the Triphala formulation holds promise as an ADH inhibitor, suggesting an alternative therapy for alcoholic liver injury.

Anti-inflammatory oleanane triterpenoids with mono-, di-, and tri-palmitoyl chains from the stamen of Nelumbo nucifera Gaertn

Ten undescribed compounds were isolated from the stamen of Nelumbo nucifera Gaertn., including seven oleanane triterpenoid glycosides with 1–3 palmitoyl chains (1–7), an oleanane triterpenoid aglycon (8), and two degraded cycloartane triterpenoids (9 and 10). In addition, seven known oleanane triterpenoids (11–17) were isolated. Among these compounds, 9 was an artificial and 14 was novel and natural product. The anti-inflammatory activity of the 10 undescribed compounds was evaluated by analyzing their inhibitory effects on the release of NO in LPS-induced RAW264.7 macrophages. Nelmnucifergenin A (8) and nelmnucifergenin B (9) showed the maximum inhibitory effects with IC50 values of 16.79 and 20.78 μM, respectively. Additionally, they inhibited the production of TNF-α and IL-6 and down-regulated the key inflammation-related enzymes (iNOS and COX-2).

Recent Advances in the Synthesis of Diarylheptanoids.

In the quest for synthesizing biologically important natural products, medicinal chemists embark on an endless journey. This review focuses on the reports published towards the syntheses of diarylheptanoids, classifying them into linear, tetrahydropyran, diarylether, and biphenyl categories. The synthesis methods for each class from 2013 to 2023 are discussed, providing a comprehensive overview of the advancements in the field. Representative natural product examples are highlighted for each category. The review emphasizes the importance of diarylheptanoids in the realms of chemistry and medicine, showcasing their potential as valuable compounds for medicinal and synthetic chemists.

Rhein suppresses esophageal cancer development by regulating cell cycle through DNMT3B gene.

The mechanism by which DNMT3B facilitates esophageal cancer (ESCA) progression is currently unknown, despite its association with adverse prognoses in several cancer types. To investigate the potential therapeutic effects of the Chinese herbal medicine rhubarb on esophageal cancer (ESCA), we adopted an integrated bioinformatics approach. Gene Set Enrichment Analysis (GSEA) was first utilized to screen active anti-ESCA components in rhubarb. We then employed Weighted Gene Co-expression Network Analysis (WGCNA) to identify key molecular modules and targets related to the active components and ESCA pathogenesis. This system-level strategy integrating multi-omics data provides a powerful means to unravel the molecular mechanisms underlying the anticancer activities of natural products, like rhubarb. To investigate module gene functional enrichment, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted. In addition, we evaluated the predictive impact of DNMT3B expression on ESCA patients utilizing the Kaplan-Meier method. Finally, we conducted experiments on cell proliferation and the cell cycle to explore the biological roles of DNMT3B. In this study, we identified Rhein as the main active ingredient of rhubarb that exhibited significant anti-ESCA activity. Rhein markedly suppressed ESCA cell proliferation. Utilizing Weighted Gene Co-expression Network Analysis (WGCNA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, we determined that the blue module was associated with Rhein target genes and the cell cycle. Additionally, DNMT3B was identified as a Rhein target gene. Analysis of The Cancer Genome Atlas (TCGA) database revealed that higher DNMT3B levels were associated with poor prognosis in ESCA patients. Furthermore, Rhein partially reversed the overexpression of DNMT3B to inhibit ESCA cell proliferation. In vitro studies demonstrated that Rhein and DNMT3B inhibition disrupted the S phase of the cell cycle and affected the production of cell cycle-related proteins. In this study, we found that Rhein exerts its anti-proliferative effects in ESCA cells by targeting DNMT3B and regulating the cell cycle.

Impact of Cuminaldehyde and Indomethacin Co-Administration on Inflammatory Responses in MIA-Induced Osteoarthritis in Rats

Impact of Cuminaldehyde and Indomethacin Co-Administration on Inflammatory Responses in MIA-Induced Osteoarthritis in Rats

Chemical Derivatization Leads to the Discovery Of Novel Analogs of Azotochelin, a Natural Siderophore, as Promising Anticancer Agents.

Siderophores are structurally unique medicinal natural products and exhibit considerable therapeutic potential. Herein, we report the design and synthesis of azotochelin, a natural siderophore, and an extensive library of azotochelin analogs and their anticancer properties. We modified the carboxylic acid and the aromatic ring of azotochelin using various chemical motifs. We evaluated the cytotoxicity of the compounds against six different cancer cell lines (KB-3-1, SNB-19, MCF-7, K-562, SW-620, and NCI-H460) and a non-cancerous cell line (HEK-293). Among the twenty compounds tested, the IC50 values of nine compounds (14, 32, 35-40, and 54) were between 0.7 and 2.0 μM against a lung cancer cell line (NCI-H460). Moreover, several compounds showed good cytotoxicity profile (IC50 <10 μM) against the tested cancer cell lines. The flow cytometry analysis showed that compounds 36 and 38 induced apoptosis in NCI-H460 in a dose-dependent manner. The cell cycle analysis indicated that compounds 36 and 38 significantly arrested the cell cycle at the S phase to block cancer cell proliferation in the NCI-H460 cell line. The study has produced various novel azotochelin analogs that are potentially effective anticancer agents and lead compounds for further synthetic and medicinal chemistry exploration.

Quinomycins with an unusual N-methyl-3-methylsulfinyl-alanine residue from a Streptomyces sp.

Four new echinomycin congeners, quinomycins M-P (1-4) were isolated from the cultures of the soil-derived Streptomyces sp. CPCC205575. The planar structures were determined by comprehensive analyses of NMR and HRESIMS/MS data. The absolute configurations were elucidated by the advanced Marfey's method combined with biosynthetic gene analysis. Compounds 1-4 represent the first examples of quinomycin-type natural products with the sulfur atom at the N,S-dimethylcysteine residue oxidized as a sulfoxide group forming the unusual N-methyl-3-methylsulfinyl-alanine residue. Bioassay results revealed that the oxidation of the sulfur atom at the Cys or Cys' residues led to dramatic decrease of cytotoxicity and antimicrobial activity.