Anti-Inflammatory Effect of Xanthones from Hypericum beanii on Macrophage RAW 264.7 Cells through Reduced NO Production and TNF-α, IL-1ß, IL-6, and COX-2 Expression.

Hypericum beanii N. Robson, a perennial upright herb, predominantly inhabits temperate regions. This species has been utilized for the treatment of various inflammation-related diseases. One new xanthone 3,7-dihydroxy-1,6-dimethoxyxanthone (1) and twenty-three known xanthones (2-24) were isolated from the aerial parts of H. beanii. The structure of the new compound was determined based on high-resolution electrospray ionization mass spectroscopy (HR-ESIMS), nuclear magnetic resonance (NMR), Infrared Spectroscopy (IR), ultraviolet spectrophotometry (UV) spectroscopic data. The anti-inflammatory effects of all the isolates were assessed by measuring the inhibitory effect on nitric oxide (NO) production in LPS-stimulated RAW 264.7 macrophages. Compounds 3,4-dihydroxy-2-methoxyxanthone (15), 1,3,5,6-tetrahydroxyxanthone (19), and 1,3,6,7-tetrahydroxyxanthone (22) exhibited significant anti-inflammatory effects at a concentration of 10 µM with higher potency compared to the positive control quercetin. Furthermore, compounds 15, 19, and 22 reduced inducible NO synthase (iNOS), tumor necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), IL-6, and cyclooxygenase 2 (COX-2) mRNA expression in the LPS-stimulated RAW 264.7 macrophages, suggesting that these compounds may mitigate the synthesis of the aforementioned molecules at the transcriptional level, provisionally confirming their anti-inflammatory efficacy.

Deciphering molecular mechanisms underlying the inhibition of ß-glucuronidase by xanthones from Centaurium spicatum.

Herein, we scrutinized the inhibitory potential of five xanthones and a flavonoid, sourced from Centaurium spicatum, against ß-glucuronidase activity. The results showed that gentisin and azaleatin emerged as the most potent inhibitors, with significantly lower IC50 values of 0.96 ± 0.10 and 0.57 ± 0.04 µM, respectively. The evaluation of enzyme kinetics unveiled that the isolated xanthones manifested inhibition of ß-glucuronidase through a mixed inhibition mode, whereas azaleatin exhibited a noncompetitive inhibition mechanism. The findings from molecular docking analysis unveiled that the compounds under investigation, particularly azaleatin, displayed comparatively diminished binding affinities towards ß-glucuronidase. Furthermore, the tested drugs were shown to occupy a common binding site as the employed reference drug. Our comprehensive Molecular Dynamics (MD) simulations analysis revealed consistent trajectories for the investigated drugs, wherein azaleatin and gentisin demonstrated notable stabilization of energy levels. Analysis of various MD parameters revealed that drugs with the lowest IC50 values maintained relatively stable interactions with ß-glucuronidase. These drugs were shown to exert notable alterations in their conformation or flexibility upon complexation with the target enzyme. Conversely, the flexibility and accessibility of ß-glucuronidase was reduced upon drug binding, particularly with azaleatin and gentisin, underscoring the stability of the drug-enzyme complexes. Analysis of Coul-SR and LJ-SR interaction energies unveiled consistent and stable interactions between certain isolated drugs and ß-glucuronidase. Azaleatin notably displayed the lowest average Coul-SR interaction energy, suggesting strong electrostatic interactions with the enzyme's active site and significant conformational variability during simulation. Remarkably, LJ-SR interaction energies across different xanthones complexes were more negative than their Coul-SR counterparts, emphasizing the predominant role of van der Waals interactions, encompassing attractive dispersion and repulsive forces, in stabilizing the drug-enzyme complexes rather than electrostatic interactions.

Antiplasmodial potential of isolated xanthones from Mesua ferrea Linn. roots: an in vitro and in silico molecular docking and pharmacokinetics study.

BACKGROUND: Malaria is a major global health concern, particularly in tropical and subtropical countries. With growing resistance to first-line treatment with artemisinin, there is an urgent need to discover novel antimalarial drugs. Mesua ferrea Linn., a plant used in traditional medicine for various purposes, has previously been investigated by our research group for its cytotoxic properties. The objective of this study was to explore the compounds isolated from M. ferrea with regards to their potential antiplasmodial activity, their interaction with Plasmodium falciparum lactate dehydrogenase (PfLDH), a crucial enzyme for parasite survival, and their pharmacokinetic and toxicity profiles. METHODS: The isolated compounds were assessed for in vitro antiplasmodial activity against a multidrug-resistant strain of P. falciparum K1 using a parasite lactate dehydrogenase (pLDH) assay. In vitro cytotoxicity against Vero cells was determined using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The interactions between the isolated compounds and the target enzyme PfLDH were investigated using molecular docking. Additionally, pharmacokinetic and toxicity properties were estimated using online web tools SwissADME and ProTox-II, respectively. RESULTS: Among the seven compounds isolated from M. ferrea roots, rheediachromenoxanthone (5), which belongs to the pyranoxanthone class, demonstrated good in vitro antiplasmodial activity, with the IC50 being 19.93 µM. Additionally, there was no toxicity towards Vero cells (CC50 = 112.34 µM) and a selectivity index (SI) of 5.64. Molecular docking analysis revealed that compound (5) exhibited a strong binding affinity of - 8.6 kcal/mol towards PfLDH and was stabilized by forming hydrogen bonds with key amino acid residues, including ASP53, TYR85, and GLU122. Pharmacokinetic predictions indicated that compound (5) possessed favorable drug-like properties and desired pharmacokinetic characteristics. These include high absorption in the gastrointestinal tract, classification as a non-substrate of permeability glycoprotein (P-gp), non-inhibition of CYP2C19, ease of synthesis, a high predicted LD50 value of 4,000 mg/kg, and importantly, non-hepatotoxic, non-carcinogenic, and non-cytotoxic effects. CONCLUSIONS: This study demonstrated that compounds isolated from M. ferrea exhibit activity against P. falciparum. Rheediachromenoxanthone has significant potential as a scaffold for the development of potent antimalarial drugs.

New α-glucosidase inhibitory xanthones from the fruits of Garcinia schomburgkiana.

Two previously unreported xanthones, xanthoschomes A and B (1 and 2), along with six known xanthones, α-mangostin (3), ß-mangostin (4), γ-mangostin (5), garcinone C (6), 2-(γ,γ-dimethylallyl)-1,7-dihydroxy-3-methoxyxanthone (7), and dulxanthone D (8), have been isolated from the fruits of Vietnamese Garcinia schomburgkiana. The structures of all isolated compounds were fully characterised using spectroscopic data and comparison with the previous literature. All isolated compounds were evaluated for their in vitro α-glucosidase inhibitory activity. Compounds 1-8 demonstrated effective α-glucosidase inhibition, with the IC50 ranging from 2.91 to 26.0 µM, outperforming the standard acarbose (IC50 179 µM). Among these isolated compounds, compound 8 exhibited the highest inhibitory activity against α-glucosidase, with an IC50 value of 2.91 µM.

The total xanthones extracted from Gentianella acuta alleviates HFpEF by activating the IRE1α/Xbp1s pathway.

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by pulmonary and systemic congestion resulting from left ventricular diastolic dysfunction and increased filling pressure. Currently, however, there is no evidence on effective pharmacotherapy for HFpEF. In this study, we aimed to investigate the therapeutic effect of total xanthones extracted from Gentianella acuta (TXG) on HFpEF by establishing an high-fat diet (HFD) + L-NAME-induced mouse model. Echocardiography was employed to assess the impact of TXG on the cardiac function in HFpEF mice. Haematoxylin and eosin staining, wheat germ agglutinin staining, and Masson's trichrome staining were utilized to observe the histopathological changes following TXG treatment. The results demonstrated that TXG alleviated HFpEF by reducing the expressions of genes associated with myocardial hypertrophy, fibrosis and apoptosis. Furthermore, TXG improved cardiomyocyte apoptosis by inhibiting the expression of apoptosis-related proteins. Mechanistic investigations revealed that TXG could activate the inositol-requiring enzyme 1α (IRE1α)/X-box-binding protein 1 (Xbp1s) signalling pathway, but the knockdown of IRE1α using the IRE1α inhibitor STF083010 or siRNA-IRE1α impaired the ability of TXG to ameliorate cardiac remodelling in HFpEF models. In conclusion, TXG alleviates myocardial hypertrophy, fibrosis and apoptosis through the activation of the IRE1α/Xbp1s signalling pathway, suggesting its potential beneficial effects on HFpEF patients.

A new xanthone isolated from Garcinia bracteata and its important effect on NO levels.

A new xanthone, allanxanthone F (1), and 10 known compounds were isolated from the ethanol extract of Garcinia bracteata. The structure of compound 1 was elucidated based on spectroscopic methods (UV, IR, HR-ESI-MS, and NMR). In addition, compounds 1-9 were assessed for their anti-inflammatory activities based on the expression of nitric oxide (NO) levels on lipopolysaccharide (LPS)-induced RAW264.7 macrophages, and compounds 1-3, 4 and 6-9 suggested potential anti-inflammatory activities.

A Mechanistic Review on Protective Effects of Mangosteen and its Xanthones Against Hazardous Materials and Toxins.

Due to its pharmacological properties, α-Mangostin, mainly found in Garcinia mangostana (G. mangostana) L. (Mangosteen, queen of fruits), treats wounds, skin infections, and many other disorders. In fact, α-Mangostin and other xanthonoid, including ß-Mangostin and γ-Mangostin, are found in G. mangostana, which have various advantages, namely neuroprotective, anti-proliferative, antinociceptive, antioxidant, pro-apoptotic, anti-obesity, anti-inflammatory, and hypoglycemic through multiple signaling mechanisms, for instance, extracellular signal-regulated kinase1/2 (ERK 1/2), mitogenactivated Protein kinase (MAPK), nuclear factor-kappa B (NF-kB), transforming growth factor beta1 (TGF-ß1) and AMP-activated protein kinase (AMPK). This review presents comprehensive information on Mangosteen's pharmacological and antitoxic aspects and its xanthones against various natural and chemical toxins. Because of the insufficient clinical study, we hope the current research can benefit from performing clinical and preclinical studies against different toxic agents.

Xanthones with multiple roles against diabetes: their synthesis, structure-activity relationship, and mechanism studies.

A four-step synthetic process has been developed to prepare 1,3,5,8-tetrahydroxyxanthone (2a) and its isomer 1,3,7,8-tetrahydroxyxanthone (2b). 25 more xanthones were also synthesized by a modified scheme. Xanthone 2a was identified as the most active inhibitor against both α-glucosidase and aldose reductase (ALR2), with IC50 values of 7.8 ± 0.5 µM and 63.2 ± 0.6 nM, respectively, which was far active than acarbose (35.0 ± 0.1 µM), and a little more active than epalrestat (67.0 ± 3.0 nM). 2a was also confirmed as the most active antioxidant in vitro with EC50 value of 8.9 ± 0.1 µM. Any structural modification including methylation, deletion, and position change of hydroxyl group in 2a will cause an activity loss in inhibitory and antioxidation. By applying a H2 O2 -induced oxidative stress nematode model, it was confirmed that xanthone 2a can be absorbed by Caenorhabditis elegans and is bioavailable to attenuate in vivo oxidative stress, including the effects on lifespan, superoxide dismutase, Catalase, and malondialdehyde. 2a was verified with in vivo hypoglycemic effect and mitigation of embryo malformations in high glucose. All our data support that xanthone 2a behaves triple roles and is a potential agent to treat diabetic mellitus, gestational diabetes mellitus, and diabetic complications.

Photoactivatable Xanthone (PaX) Dyes Enable Quantitative, Dual Color, and Live-Cell MINFLUX Nanoscopy.

The single-molecule localization concept MINFLUX has triggered a reevaluation of the features of fluorophores for attaining nanometer-scale resolution. MINFLUX nanoscopy benefits from temporally controlled fluorescence ("on"/"off") photoswitching. Combined with an irreversible switching behavior, the localization process is expected to turn highly efficient and quantitative data analysis simple. The potential in the recently reported photoactivable xanthone (PaX) dyes is recognized to extend the list of molecular switches used for MINFLUX with 561 nm excitation beyond the fluorescent protein mMaple. The MINFLUX localization success rates of PaX560 , PaX+560, and mMaple are quantitatively compared by analyzing the effective labeling efficiency of endogenously tagged nuclear pore complexes. The PaX dyes prove to be superior to mMaple and on par with the best reversible molecular switches routinely used in single-molecule localization microscopy. Moreover, the rationally designed PaX595 is introduced for complementing PaX560 in dual color 561 nm MINFLUX imaging based on spectral classification and the deterministic, irreversible, and additive-independent nature of PaX photoactivation is showcased in fast live-cell MINFLUX imaging. The PaX dyes meet the demands of MINFLUX for a robust readout of each label position and fill the void of reliable fluorophores dedicated to 561 nm MINFLUX imaging.

In silico studies on the anti-acne potential of Garcinia mangostana xanthones and benzophenones.

Garcinia mangostana fruits are used traditionally for inflammatory skin conditions, including acne. In this study, an in silico approach was employed to predict the interactions of G. mangostana xanthones and benzophenones with three proteins involved in the pathogenicity of acne, namely the human JNK1, Cutibacterium acnes KAS III and exo-ß-1,4-mannosidase. Molecular docking analysis was performed using Autodock Vina. The highest docking scores and size-independent ligand efficiency values towards JNK1, C. acnes KAS III and exo-ß-1,4-mannosidase were obtained for garcinoxanthone T, gentisein/2,4,6,3',5'-pentahydroxybenzophenone and mangostanaxanthone VI, respectively. To the best of our knowledge, this is the first report of the potential of xanthones and benzophenones to interact with C. acnes KAS III. Molecular dynamics simulations using GROMACS indicated that the JNK1-garcinoxanthone T complex had the highest stability of all ligand-protein complexes, with a high number of hydrogen bonds predicted to form between this ligand and its target. Petra/Osiris/Molinspiration (POM) analysis was also conducted to determine pharmacophore sites and predict the molecular properties of ligands influencing ADMET. All ligands, except for mangostanaxanthone VI, showed good membrane permeability. Garcinoxanthone T, gentisein and 2,4,6,3',5'-pentahydroxybenzophenone were identified as the most promising compounds to explore further, including in experimental studies, for their anti-acne potential.

Two rearranged acylphloroglucinols with moderate neuroprotective effects from Hypericum ascyron Linn.

Phytochemical studies on the leaves and twigs of Hypericum ascyron Linn. led to the isolation of two previously undescribed rearranged polycyclic polyprenylated acylphloroglucinols (PPAP) with a 4,5-seco-3(2H)-furanone skeleton, named hyperascone A and B (1-2). Additionally, a known PPAP tomoeone A (3) and two known xanthones 1,3,5 -trihydroxy-6-O-prenylxanthone (4) and 3,7-dihydroxy-1,6-dimethoxyxanthone (5) were also isolated. The structures of the compounds were determined by the analysis of their spectroscopic data including HRMS, NMR and ECD. All of the five isolated compounds exhibited neuroprotective effects against MPP+ and microglia activation induced damage of SH-SY5Y cells.

Evaluation of Antitumor Activity of Xanthones Conjugated with Amino Acids.

Cancer is a complex disease characterized by several alterations, which confer, to the cells, the capacity to proliferate uncontrollably and to resist cellular death. Multiresistance to conventional chemotherapy drugs is often the cause of treatment failure; thus, the search for natural products or their derivatives with therapeutic action is essential. Chiral derivatives of xanthones (CDXs) have shown potential inhibitory activity against the growth of some human tumor cell lines. This work reports the screening of a library of CDXs, through viability assays, in different cancer cell lines: A375-C5, MCF-7, NCI-H460, and HCT-15. CDXs' effect was analyzed based on several parameters of cancer cells, and it was also verified if these compounds were substrates of glycoprotein-P (Pgp), one of the main mechanisms of resistance in cancer therapy. Pgp expression was evaluated in all cell lines, but no expression was observed, except for HCT-15. Also, when a humanized yeast expressing the human gene MDR1 was used, no conclusions could be drawn about CDXs as Pgp substrates. The selected CDXs did not induce significant differences in the metabolic parameters analyzed. These results show that some CDXs present promising antitumor activity, but other mechanisms should be triggered by these compounds.

Antibacterial Potential of Symmetrical Twin-Drug 3,6-Diaminoxanthones.

Global health faces a significant issue with the rise of infectious diseases caused by bacteria, fungi, viruses, and parasites. The increasing number of multi-drug resistant microbial pathogens severely threatens public health worldwide. Antibiotic-resistant pathogenic bacteria, in particular, present a significant challenge. Therefore, there is an urgent need to identify new potential antimicrobial targets and discover new chemical entities that can potentially reverse bacterial resistance. The main goal of this research work was to create and develop a library of 3,6-disubstituted xanthones based on twin drugs and molecular extension approaches to inhibit the activity of efflux pumps. The process involved synthesizing 3,6-diaminoxanthones through the reaction of 9-oxo-9H-xanthene-3,6-diyl bis(trifluoromethanesulfonate) with various primary and secondary amines. The resulting 3,6-disubstituted xanthone derivatives were then tested for their in vitro antimicrobial properties against a range of pathogenic strains and their efficacy in inhibiting the activity of efflux pumps, biofilm formation, and quorum-sensing. Several compounds have exhibited effective antibacterial properties against the Gram-positive bacterial species tested. Xanthone 16, in particular, has demonstrated exceptional efficacy with a remarkable MIC of 11 µM (4 µg/mL) against reference strains Staphylococcus aureus ATCC 25923 and Enterococcus faecalis ATCC 29212, and 25 µM (9 µg/mL) against methicillin-resistant S. aureus 272123. Furthermore, some derivatives have shown potential as antibiofilm agents in a crystal violet assay. The ethidium bromide accumulation assay pinpointed certain compounds inhibiting bacterial efflux pumps. The cytotoxic effect of the most promising compounds was examined in mouse fibroblast cell line NIH/3T3, and two monoamine substituted xanthone derivatives with a hydroxyl substituent did not exhibit any cytotoxicity. Overall, the nature of the substituent was critical in determining the antimicrobial spectra of aminated xanthones.

Terricoxanthones A-E, unprecedented dihydropyran-containing dimeric xanthones from the endophytic fungus Neurospora terricola HDF-Br-2 associated with the vulnerable conifer Pseudotsuga gaussenii.

An investigation on the secondary metabolites from a rice culture broth of the endophytic fungus Neurospora terricola HDF-Br-2 derived from the vulnerable conifer Pseudotsuga gaussenii led to the isolation and characterization of 34 structurally diverse polyketides (1-34). Seven of them are previously undescribed, including five unprecedented dihydropyran-containing (terricoxanthones A-E, 1-5, resp.) and one rare tetrahydrofuran-containing (terricoxanthone F, 6) dimeric xanthones. The structures were elucidated by spectroscopic methods and single-crystal X-ray diffraction analyses. Terricoxanthones each were obtained as a racemic mixture. Their plausible biosynthetic relationships were briefly proposed. Compounds 6, aspergillusone A (8), and alatinone (27) displayed considerable inhibition against Candida albicans with MIC values of 8-16 µg/mL. 4-Hydroxyvertixanthone (12) and 27 exhibited significant inhibitory activities against Staphylococcus aureus, with MIC values of 4-8 µg/mL. Furthermore, compounds 8 and 27 could disrupt biofilm of S. aureus and C. albicans at 128 µg/mL. The findings not only extend the skeletons of xanthone dimers and contribute to the diversity of metabolites of endophytes associated with the endangered Chinese conifer P. gaussenii, but could further reveal the important role of protecting plant species diversity in support of chemical diversity and potential sources of new therapeutics.

Inhibition of Seizure-Like Paroxysms and Toxicity Effects of Securidaca longepedunculata Extracts and Constituents in Zebrafish Danio rerio.

Plants used in traditional medicine in the management of epilepsy could potentially yield novel drug compounds with antiepileptic properties. The medicinal plant Securidaca longepedunculata is widely used in traditional medicine in the African continent, and epilepsy is among several indications. Limited knowledge is available on its toxicity and medicinal effects, such as anticonvulsant activities. This study explores the potential in vivo inhibition of seizure-like paroxysms and toxicity effects of dichloromethane (DCM) and ethanol (EtOH) extracts, as well as isolated xanthones and benzoates of S. longepedunculata. Ten phenolic compounds were isolated from the DCM extract. All of the substances were identified by nuclear magnetic resonance spectroscopy. Assays for toxicity and inhibition of pentylenetetrazole (PTZ)-induced seizure-like paroxysms were performed in zebrafish larvae. Among the compounds assessed in the assay for maximum tolerated concentration (MTC), benzyl-2-hydroxy-6-methoxy-benzoate (MTC 12.5 µM), 4,8-dihydroxy-1,2,3,5,6-pentamethoxyxanthone (MTC 25 µM), and 1,7-dihydroxy-4-methoxyxanthone (MTC 6.25 µM) were the most toxic. The DCM extract, 1,7-dihydroxy-4-methoxyxanthone and 2-hydroxy-1,7-dimethoxyxanthone displayed the most significant inhibition of paroxysms by altering the locomotor behavior in GABAA receptor antagonist, PTZ, which induced seizures in larval zebrafish. The EtOH extract, benzyl benzoate, and benzyl-2-hydroxy-6-methoxy-benzoate unexpectedly increased locomotor activity in treated larval zebrafish and decreased locomotor activity in nontreated larval zebrafish, seemingly due to paradoxical excitation. The results reveal promising medicinal activities of this plant, contributing to our understanding of its use as an antiepileptic drug. It also shows us the presence of potentially new lead compounds for future drug development.

Phenolics and triterpenoids from stem bark of Calophyllum lanigerum var. austrocoriaceum (Whitmore) P. F. Stevens and their cytotoxic activities.

Genus Calophyllum is well-known for its phenolic constituents, especially coumarins, which have shown to have a wide range of significant biological activities. In this study, four known phenolic constituents and two triterpenoids have been isolated from the stem bark of Calophyllum lanigerum. The compounds were two pyranochromanone acids are known as caloteysmannic acid (1), isocalolongic acid (2), a simple dihydroxyxanthone, namely euxanthone (3), one coumarin named calanone (4), and two common triterpenoids, friedelin (5), and stigmasterol (6). Chromanone acids were reported for the first time in this Calophyllum species. Cytotoxic evaluations were carried out on n-hexane extract (87.14 ± 2.04 µg/mL; 81.46 ± 2.42 µg/mL) followed by the chromanone acids (1 [79.96 ± 2.39 µM; 83.41 ± 3.39 µM] & 2 [57.88 ± 2.34; 53.04 ± 3.18 µM]) against two cancerous cell lines, MDA-MB-231 and MG-63 cell lines, respectively. The results showed that all tested samples exhibited moderate cytotoxicity.

Cytotoxic xanthones from Garcinia pedunculata fruits.

Eight previously undescribed and seven known xanthones were isolated from the fruits of Garcinia pedunculata Roxb. The structures were identified by a variety of spectroscopic methods as well as by comparison with the literature. The isolates showed appreciable cytotoxicity against three human tumor cell lines (HepG2, A549, and MCF-7). Pedunculaxanthone G exhibited inhibitory activities with IC50 values of 12.41, 16.51, and 15.45 µM against the cancer cell lines and induced cell apoptosis in HepG2 cells.

Caged Polyprenylated Xanthones in Garcinia hanburyi and the Biological Activities of Them.

The previous phytochemical analyses of Garcinia hanburyi revealed that the main structural characteristic associated with its biological activity is the caged polyprenylated xanthones with a unique 4-oxatricyclo [4.3.1.03,7] dec-2-one scaffold, which contains a highly substituted tetrahydrofuran ring with three quaternary carbons. Based on the progress in research of the chemical constituents, pharmacological effects and modification methods of the caged polyprenylated xanthones, this paper presents a preliminary predictive analysis of their drug-like properties based on the absorption, distribution, metabolism, excretion and toxicity (ADME/T) properties. It was found out that these compounds have very similar pharmacokinetic properties because they possess the same caged xanthone structure, the 9,10-double bond in a,b-unsaturated ketones are critical for the antitumor activity. The author believes that there is an urgent need to seek new breakthroughs in the study of these caged polyprenylated xanthones. Thus, the research on the route of administration, therapeutic effect, structural modification and development of such active ingredients is of great interest. It is hoped that this paper will provide ideas for researchers to develop and utilize the active ingredients derived from natural products.

Demethylcalabaxanthone from Garcinia mangostana Exerts Antioxidant Effects through the Activation of the Nrf2 Pathway as Assessed via Molecular Docking and Biological Evaluation.

Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway activation promotes the expression of antioxidant enzymes in response to rising oxidative stress, resulting in reactive oxygen species (ROS) detoxification and playing a central role in the maintenance of intracellular redox homeostasis and regulation of inflammation. Moreover, the biological effects of Nrf2 pathway activation contribute to reducing apoptosis and enhancing cell survival. The activity of Nrf2 is negatively regulated by Kelch-like ECH-associated protein 1 (Keap1). Prompted by the recent results reporting the impact of xanthone metabolites on oxidative stress, cancer, and inflammation, the antioxidant properties of xanthones isolated from Garcinia mangostana (γ-mangostin, α-mangostin, 8-deoxygartanin, demethylcalabaxanthone, garcinone D) were assessed. In particular, the capability of these natural products to disrupt the interaction between Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2), triggering the activation of the Nrf2-mediated pathway, was evaluated using molecular docking experiments and in vitro tests. The modulation of some key Nrf2-related mediators like glutathione (GSH) and lactate dehydrogenase (LDH) to highlight a possible direct antioxidant effect was investigated. Among the tested compounds, demethylcalabaxanthone showed an indirect antioxidant effect, as corroborated by a Western blot assay, displaying a significant increase in the translocated protein upon its administration.

Potent halogenated xanthone derivatives: synthesis, molecular docking and study on antityrosinase activity.

Tyrosinase inhibitors can reduce melanin production for skin whitening, but some existing products may harm the skin. This study discovered six compounds that inhibit tyrosinase in the mushroom Agaricus bisporus by over 50%. Compound 11 displayed strong inhibition (92.2% and 86.7%) for L-tyrosine and L-DOPA substrates, while compound 13 showed high inhibition (96.0% and 62.0%) for both substrates. Molecular docking simulations revealed compounds 11 and 13 bind at the allosteric site of the enzyme. Xanthone derivatives, based on these findings, hold potential as safe skin whitening agents and for pigmentation-related diseases in the cosmetic industry.