Search Results (53)

Respiratory syncytial virus (RSV) infections have a significant impact on global health. Despite of recent advancements, the current treatment options for managing severe RSV infections remain primarily limited to supportive care, emphasizing the high priority for the development of effective antiviral therapies. Antiviral activity of 3,3′,4,4′,5,5′-hexahydroxy-trans-stilbene (HHS), a synthetic polyhydroxyphenol, has previously been demonstrated against SARS-CoV-2. In this study, we provide evidence for a direct virucidal effect of HHS against RSV infection in permissive HEp-2 cells in vitro. HHS, with an IC50 of 3.44 μM, efficiently inhibited HEp-2 cell infection with no sign of toxicity at least up to 25 μM. Interestingly, resveratrol, a polyhydroxyphenol analogue, was less efficient. Mode of action experiments revealed that HHS directly interacts with RSV particles, indicating that its virucidal activity is based on this interaction rather than affecting HEp-2 cells or post-infection processes. Together with previous data, our results suggest a broad antiviral activity of HHS against different respiratory viruses. Further studies are necessary to unveil the exact mechanism and evaluate the potential of HHS in the treatment of severe respiratory virus infections. Full article

Naturally occurring antioxidants have attracted significant research interest, owing to their radical scavenging ability that can be improved via structural modifications. In this study, aromaticity-extended resveratrol analogues (3–5) containing chalcogens were designed and synthesized using ring closure and Horner–Wadsworth–Emmons reactions. The antioxidant activities of the derivatives were evaluated using 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABST) assay. All resveratrol derivatives (3–5) exhibited higher radical scavenging activities than resveratrol 1 and analogue 2, with benzoselenophene-conjugated derivative 5 demonstrating the highest activity. The improved antioxidant performance of the resveratrol derivatives was attributed to the extended π conjugation resulting from the incorporation of fused rings, benzoheteroles. Additionally, the integration of benzoheteroles into resveratrol contributed to an efficient reduction in HOMO-LUMO gaps. This study demonstrates that aromaticity extension by introducing benzofuran, benzothiophene, and benzoselenophene is a feasible strategy for improving the antioxidant activity of naturally occurring oxidants. Full article

Vascular endothelial growth factor (VEGF), also known as VEGF-A, has been reported to mediate various diseases, including cancer and wet age-related macular degeneration (wAMD). Despite the fact that VEGF inhibitors are commercially available and appear to be effective in clinical applications, adverse effects have been caused by these treatments. There is an unmet need for developing novel VEGF-targeted treatments against these diseases. Resveratrol, a phytochemical derived from fruits and vegetables, has shown promising potency in suppressing VEGF-mediated bioactivities through a series of in vitro and in vivo testing models. Herein, we report that RE-1, a synthetic resveratrol-type analog, displays robust inhibitory activities against VEGF and its downstream signaling pathways, surpassing its parental molecule, resveratrol. In addition, the drug capabilities of RE-1 were evaluated. As a newly synthesized chemical, RE-1 could be considered for subsequent pharmacological development targeting VEGF-related diseases. Full article

Resveratrol is a natural polyphenol (stilbenoid), which can be found in grape skin, red wine, blueberries, peanuts and others. The biological properties of resveratrol, in particular antioxidant, anti-inflammatory, anticancer, estrogenic, vasorelaxant and cardioprotective activity, are the main reason for its importance in medicine and pharmacy. Despite all of its advantages, however, there are many problems related to this polyphenolic substance, such as low stability, water insolubility, poor bioavailability and fast metabolism. For this reason, scientists are currently searching for different approaches to dealing with these problematic properties and improving the therapeutic usage of resveratrol. This review summarizes the mechanisms of the biological effects of resveratrol, determined in vitro and in vivo, and the main limitations of the drug. The article emphasizes new approaches for the improvement of resveratrol delivery, in particular nanoencapsulation, formation of nanocrystals, prodrugs and structure analogues. Full article

Acetylcholinesterase and butyrylcholinesterase are two related enzymes that represent pharmacologically suitable targets in neurodegenerative disorders, given their physiological roles in the body. The treatment of neurodegenerative disorders currently includes common reversible cholinesterase inhibitors. Resveratrol analogues, as the molecules in focus, have shown the very strong inhibition potential of cholinesterases. In this research, experimental and DFT approaches for their pK_a value determination were carried out knowing that pK_a is very important for predicting the ADMET properties of the potentially bioactive molecules and their behavior in the environment. An in silico study was used to calculate more indicators about the absorption and distribution in the human body. Among the investigated compounds, the weakest acid was experimentally detected and confirmed using three computational models. Additionally performed calculations provided access to the potential of each resveratrol analogue to engage in both π-π stacking and hydrogen bond interactions in the active site of the enzyme crucial for the stability of the ligand–enzyme complex. Full article

Background and Objectives: Expansion of white adipose tissue causes systemic inflammation and increased risk of metabolic diseases due to its endocrine function. Resveratrol was suggested to be able to prevent obesity-related disorders by mimicking caloric restriction; however, its structure–activity relationships and molecular targets are still unknown. We aimed to compare the effects of resveratrol and its analogues on adipocyte metabolism and lipid accumulation in vitro. Methods: Mouse embryonic fibroblasts were differentiated to adipocytes in the absence or presence of resveratrol or its derivatives (oxyresveratrol, monomethylated resveratrol, or trimethylated resveratrol). Intracellular lipid content was assessed by Oil Red O staining. Glucose uptake and its response to insulin were estimated by 2-NBDG, and mitochondrial activity was assayed via resazurin reduction. Involvement of potential molecular pathways was investigated by concurrent treatment with their inhibitors. Results: Although lipid accumulation was significantly reduced by all analogues without altering protein content, oxyresveratrol was the most potent (IC50 = 4.2 μM), while the lowest potency was observed with trimethylated resveratrol (IC50 = 27.4 μM). Increased insulin-stimulated glucose uptake was restored by each analogue with comparable efficiency. The enhanced mitochondrial activity was normalized by resveratrol and its methylated derivatives, while oxyresveratrol had a minor impact on it. Among the examined pathways, inhibition of SIRT1, PGC-1α, and JNK diminished the lipid-reducing effect of the compounds. Autophagy appeared to play a key role in the effect of all compounds but oxyresveratrol. Conclusions: Resveratrol and its analogues can mimic caloric restriction with complex mechanisms, including activation of SIRT1, PGC-1α, and JNK, making them possible drug candidates to treat obesity-related diseases. Full article

Inhibitors of NQO2 (NRH: quinone oxidoreductase) have potential application in several areas of medicine and pharmacology, including cancer, neurodegeneration (PD and AD), stroke, and diabetes. Here, resveratrol, a known inhibitor of NQO2, was used as the lead by replacing the double bond in resveratrol with a benzothiazole scaffold. Fifty-five benzothiazoles were designed as NQO2 inhibitors and synthesized, comprising five benzothiazole series with 3,5-dimethoxy, 2,4-dimethoxy, 2,5-dimethoxy, 3,4-dimethoxy, and 3,4,5-trimethoxy substituents, the key synthetic step being a Jacobson cyclisation with the appropriate thiobenzamide. All compounds were evaluated in an NQO2 enzyme inhibition assay, with four compounds having IC₅₀ values of <100 nM. The most active (IC₅₀ 25 nM) was 6-hydroxy-2-(3’,5’-dihydroxyphenyl)benzo[d]thiazole (15), a good mimetic of resveratrol. Three of the 3’,4’,5’-trimethoxybenzothiazole analogues, with 6-methoxy (40, IC₅₀ 51 nM), 6-amino (48, IC₅₀ 79 nM), and 6-acetamide (49, IC₅₀ 31 nM) substituents, were also potent inhibitors of NQO2. Computational modelling indicated the most active compounds exhibited good shape complementarity and polar interactions with the NQO2 active site. Through the inhibition of NQO2, benzothiazole-based compounds may have the potential to enhance the efficiency of cancer therapies or minimise oxidative damage in neuroinflammation. Full article

Lung cancer is among the most clinically challenging tumors because of its aggressive proliferation, metastasis, and the presence of cancer stem cells (CSCs). Natural bioactive substances have been used for cancer prevention, and, in particular, resveratrol (RSV), a stilbene-based compound with wide biological properties, has been proposed for chemoprevention. Its lesser-known analogue 4,4’-dihydroxy-trans-stilbene (DHS) has demonstrated superior activity both in cell-based assays and in mouse and zebrafish in vivo models. The present study analyzed the effects of DHS and RSV on A549 lung cancer cells, with a particular focus on stemness features and CSCs, isolated by sorting of the side population (SP). The results show that both stilbenes, especially DHS, strongly inhibited cell cycle progression. A reduction in the S phase was induced by DHS, whereas an increase in this phase was obtained with RSV. In addition, 50% reductions in the clonogenicity and soft agar colony formation were observed with the DHS treatment only. Finally, both stilbenes, especially DHS, reduced stemness marker expression in A549 cells and their sorted SP fraction. Spheroid formation, higher in SP cells than in the main population (MP), was significantly reduced after pretreatment with DHS, which was found to decrease SOX2 levels more than RSV. These findings indicate that stilbenes, and particularly DHS, affect stemness features of A549 cells and the SP fraction, suggesting their potential utility as anticancer agents, either alone or combined with chemotherapeutic drugs. Full article

Piceatannol is a naturally occurring hydroxylated analogue of the stilbene phytoalexin resveratrol that can be found in grape fruit and derived products. Piceatannol has aroused great interest as it has been shown to surpass some human health-beneficial properties of resveratrol including antioxidant activity, several pharmacological activities and also bioavailability. The plant biosynthetic pathway of piceatannol is still poorly understood, which is a bottleneck for the development of both plant defence and bioproduction strategies. Cell cultures of Vitis vinifera cv. Gamay, when elicited with dimethyl-β-cyclodextrin (MBCD) and methyl jasmonate (MeJA), lead to large increases in the accumulation of resveratrol, and after 120 h of elicitation, piceatannol is also detected due to the regiospecific hydroxylation of resveratrol. Therefore, an ortho-hydroxylase must participate in the biosynthesis of piceatannol. Herein, three possible types of resveratrol hydroxylation enzymatic reactions have been tested, specifically, a reaction catalyzed by an NADPH-dependent cytochrome, P450 hydroxylase, a 2-oxoglutarate-dependent dioxygenase and ortho-hydroxylation, similar to polyphenol oxidase (PPO) cresolase activity. Compared with P450 hydoxylase and the dioxygenase activities, PPO displayed the highest specific activity detected either in the crude extract, the particulate or the soluble fraction obtained from cell cultures elicited with MBCD and MeJA for 120 h. The overall yield of PPO activity present in the crude extract (107.42 EU) was distributed mostly in the soluble fraction (66.15 EU) rather than in the particulate fraction (3.71 EU). Thus, partial purification of the soluble fraction by precipitation with ammonium sulphate, dialysis and ion exchange chromatography was carried out. The soluble fraction precipitated with 80% ammonium sulphate and the chromatographic fractions also showed high levels of PPO activity, and the presence of the PPO protein was confirmed by Western blot and LC-MS/MS. In addition, a kinetic characterization of the cresolase activity of partially purified PPO was carried out for the resveratrol substrate, including Vmax and Km parameters. The Km value was 118.35 ± 49.84 µM, and the Vmax value was 2.18 ± 0.46 µmol min⁻¹ mg⁻¹. Full article

Within the huge class of plant secondary metabolites, resveratrol-derived stilbenoids show wide structural diversity and mediate a great number of biological responses relevant for human health, including cancer prevention and cytotoxicity. Resveratrol is known to modulate several pathways directly linked to cancer progression, as well as its analogue pterostilbene, characterized by an increased metabolic stability and significant pharmacological activities. To study the potential anticancer activity of other stilbenoids, a home-made collection of resveratrol dimers and simplified analogues was tested on melanoma A375, non-small cell lung cancer H460 and PC3 prostate cancer cell lines. The structural determinants responsible for the antiproliferative activity have been highlighted. Moreover, to investigate the DNA damage ability of the selected molecules, the expression of the γ-H2AX after compound exposure was evaluated. Full article

Naturally occurring stilbenoids, such as the (E)-stilbenoid resveratrol and the (Z)-stilbenoid combretastatin A4, have been considered as promising lead compounds for the development of anticancer drugs. The antitumour properties of stilbenoids are known to be modulated by cytochrome P450 enzymes CYP1A1 and CYP1B1, which contribute to extrahepatic phase I xenobiotic and drug metabolism. Thirty-four methyl ether analogues of resveratrol were synthesised, and their anticancer properties were assessed, using the MTT cell proliferation assay on a panel of human breast cell lines. Breast tumour cell lines that express CYP1 were significantly more strongly affected by the resveratrol analogues than the cell lines that did not have CYP1 activity. Metabolism studies using isolated CYP1 enzymes provided further evidence that (E)-stilbenoids can be substrates for these enzymes. Structures of metabolic products were confirmed by comparison with synthetic standards and LC-MS co-elution studies. The most promising stilbenoid was (E)-4,3′,4′,5′-tetramethoxystilbene (DMU212). The compound itself showed low to moderate cytotoxicity, but upon CYP1-catalysed dealkylation, some highly cytotoxic metabolites were formed. Thus, DMU212 selectively affects proliferation of cells that express CYP1 enzymes. Full article

It has been argued that methoxylated stilbenes are better candidates for oral administration than hydroxylated stilbenes, including resveratrol, as they share many biological activities but have better bioavailability. By contrast, they have a disadvantage to consider, i.e., their lower hydrophilic character that leads to precipitation issues in the final product. In this work, we analysed and compared the growth inhibition of colorectal cancer cells of the methoxylated stilbene rhapontigenin and some analogues and overcame potential problems in the development of fortified products by designing inclusion complexes. Among several cyclodextrins, we found the one that best fit the molecule by physicochemical and bioinformatics assays. The stoichiometry and the encapsulation constants with natural and modified cyclodextrins were determined by fluorescence spectroscopy. The most promising complexes were analysed at different temperature and pH conditions, determining the thermodynamic parameters, to discover the optimal conditions for the preparation and storage of the products. The results showed that rhapontigenin solubility and stability were significantly improved, achieving a sevenfold increase in water solubility and maintaining more than 73% of the stilbene after three months. These findings could be of great interest for industries that aim to deliver novel bioactive compounds with higher solubility and lower degradation. Full article

Stilbenoids, a group of phytoalexin polyphenols produced by plants as a defence mechanism in response to stress conditions, are known for their anti-inflammatory potential. Pinosylvin, a naturally occurring molecule traditionally found in pinus trees, was here identified in Pinus nigra subsp. laricio var. calabrica from Southern Italy through HPLC analysis. Both this molecule and its well-known analogue resveratrol, the most famous wine polyphenol, were compared for their in vitro potential anti-inflammatory activity. Pinosylvin significantly inhibited the release of pro-inflammatory cytokines (TNF-α and IL-6) and NO mediator in LPS-stimulated RAW 264.7 cells. Moreover, its ability to inhibit the JAK/STAT signaling pathway was assessed: Western blot analyses showed a downregulation of both phosphorylated JAK2 and STAT3 proteins. Finally, in order to verify whether this biological activity could be attributed to a direct interaction of pinosylvin with JAK2, a molecular docking study was performed, confirming the capability of pinosylvin to bind the active site of the protein. Full article

3,4,5,4’-Trans-tetramethoxystilbene (Synonyms: DMU-212) is a resveratrol analogue with stronger antiproliferative activity and more bioavailability. However, the metabolite characterization of this component remains insufficient. An efficient strategy was proposed for the comprehensive in vivo metabolite profiling of DMU-212 after oral administration in Apc^Min/+ mice based on the effectiveness of the medicine. Ultra-high performance liquid chromatography-quadrupole/orbitrap/linear ion trap mass spectrometry (UHPLC-Q/Orbitrap/LTQ MS) in the AcquireX^TM intelligent data acquisition mode, combining the exact mass and structural information, was established for the profiling and identification of the metabolites of DMU-212 in vivo, and the possible metabolic pathways were subsequently proposed after the oral dose of 240mg/kg for 3 weeks in the colorectal adenoma (CRA) spontaneous model Apc^Min/+ mice. A total of 63 metabolites of DMU-212 were tentatively identified, including 48, 48, 34 and 28 metabolites in the Apc^Min/+ mice’s intestinal contents, liver, serum, and colorectal tissues, respectively. The metabolic pathways, including demethylation, oxidation, desaturation, methylation, acetylation, glucuronide and cysteine conjugation were involved in the metabolism. Additionally, further verification of the representative active metabolites was employed using molecular docking analysis. This study provides important information for the further investigation of the active constituents of DMU-212 and its action mechanisms for CRA prevention. Full article

The quality of wine grapes and wine depends on their content of phenolic compounds. Under commercial conditions, the phenolic maturity of grapes is mostly achieved by applying abscisic acid analogues. Some Ca forms represent a cost-effective alternative for these compounds. In this study, ‘Shiraz’ vines (veraison of 90%) were sprayed with CaCO₃-rich residues from the cement industry (4.26 g of Ca per L). Fruit from treated and untreated vines was harvested 45 days after CaCO₃ spraying and evaluated for quality. The fruit was vinified, and the obtained wines were bottled and stored in darkness for 15 months at 20 °C. Wines were evaluated for quality after storage. The evaluation of grape and wine quality included the content of phenolic compounds and antioxidant capacity. The treatment with CaCO₃ did not affect the ripening rate of grapes. However, the treatment improved the fruit yield as well as the color development, the content of phenolic compounds, and antioxidant capacity of grapes and wine. The treatment favored especially the accumulation of malvidin-3-O-glucoside, pelargonidin-3-O-glucoside, caftaric acid, caffeic acid, trans-cinnamic acid, quercetin, catechin, epicatechin, resveratrol, and the procyanidins B1 and B2. Wine made with treated fruit was of higher quality than that of control fruit. Full article