Resveratrol Oligomers Research Articles

The anti-biofilm and anti-virulence activities of trans-resveratrol and oxyresveratrol against uropathogenic Escherichia coli

Uropathogenic Escherichia coli (UPEC) is the primary causative agent of urinary tract infections, which are one of the most common infectious disease types in humans. UPEC infections involve bacterial cell adhesion to bladder epithelial cells, and UPEC can also form biofilms on indwelling catheters that are often tolerant to common antibiotics. In this study, the anti-biofilm activities of t-stilbene, stilbestrol, t-resveratrol, oxyresveratrol, ε-viniferin, suffruticosol A, and vitisin A were investigated against UPEC. t-Resveratrol, oxyresveratrol, and ε-viniferin, suffruticosol A, and vitisin A significantly inhibited UPEC biofilm formation at subinhibitory concentrations (10–50 μg ml−1). These findings were supported by observations that t-resveratrol and oxyresveratrol reduced fimbriae production and the swarming motility in UPEC. Furthermore, t-resveratrol and oxyresveratrol markedly diminished the hemagglutinating ability of UPEC, and enhanced UPEC killing by human whole blood. The findings show that t-resveratrol, oxyresveratrol, and resveratrol oligomers warrant further attention as antivirulence strategies against persistent UPEC infections.

Antioxidant Capacity and Cytotoxic Effects of Catechins and Resveratrol Oligomers Produced by Enzymatic Oxidation against T24 Human Urinary Bladder Cancer Cells.

In this work the polymerization of catechin, epicatechin, and resveratrol was carried out through a peroxidase oxidation process in order to improve the biological activity of these phenolic compounds. The antioxidant activity of the oligomers was evaluated by their ability to scavenge reactive oxygen species (ROS) and their capacity to chelate metal ions Fe2+ and Cu2+. The antitumor effect of the oligomers was determined by their ability to induce toxicity in the T24 human bladder cancer cell line. By enzymatic peroxidase oxidation, it was possible to produce oligomers of catechin, epicatechin, and resveratrol with antioxidant capacity significantly higher than their preceding monomers. The ROS scavenging capacity of the oligomers was 20 times higher than that of the monomers, while the ability of the oligomers to chelate metal ions increased up to about 1000 times. Our data show the antitumor effect of the oligomers of catechin, epicatechin, and resveratrol in the T24 cell line, which was similar to that observed with cisplatin. Oligomers of catechin, epicatechin, and resveratrol have great potential to be used as therapeutic agents for the treatment of oxidative stress-related diseases and bladder cancer.

Design, synthesis and biological evaluation of novel indone derivatives as selective ERβ modulators

To reduce the endometrial toxicity and improve the efficacy of current selective estrogen receptor modulators used in breast cancer treatment by enhancing ERβ selectivity, inspired by active resveratrol oligomer, a series of analogs (5a–f, 6a–b, 7a–d, 8a–d) were designed, synthesized and biologically evaluated. Among them, the chiral indone analog (2R,3R)-8a exhibited best antiproliferative activity against both breast cancer cell lines (MDA-MB-231 and MCF-7) and better safety profile on uterus than tamoxifen. Analog (2R,3R)-8a demonstrated good binding affinity and selectivity toward ERβ, which was further proved by both molecular docking and radiometric competitive binding assay. Other studies for (2R,3R)-8a also have been explored including cell cycle and apoptosis evaluation and in vitro metabolic stability studies. These results demonstrated that (2R,3R)-8a could be a promising lead compound for future exploration of selective ERβ anti-breast cancer agents.

Isolation and characterization of resveratrol oligomers from the stem bark of Hopea ponga (Dennst.) Mabb. And their antidiabetic effect by modulation of digestive enzymes, protein glycation and glucose uptake in L6 myocytes

Ethnopharmacological relevanceHopea ponga (Dennst.) Mabb. Is used in traditional herbal formulations for diabetes complications. The aim of this study is to evaluate the antidiabetic effect of extracts and compounds from H. ponga. Materials and methodsSilica gel column chromatography was performed to identify various chemical components of the plant extract. Different extracts of H. ponga and isolated compounds were screened for their antidiabetic effect by modulation of digestive enzymes and protein glycation. The effect of glucose uptake by the compounds and the pathways through which the compounds mediate the glucose uptake potential were confirmed by fluorescent microscopy, flow cytometry and western blot analysis. ResultsAcetone and ethanol extracts of the stem bark of Hopea ponga (Dennst.) Mabb. Afforded six resveratrol oligomers namely, E-resveratrol (1), (−)-ε-viniferin (2), (−)-α-viniferin (3), trihydroxyphenanthrene glucoside (THPG) (4), vaticaphenol A (5), (−)-hopeaphenol (6), along with four phytosterols. The structures were determined on the basis of spectroscopic analyses including nuclear magnetic resonance (NMR) spectroscopy and high resolution mass spectrometry (HRMS) data. Compounds 1–5 and 7–10 were tested for their α-glucosidase, α-amylase and glycation inhibitiory activities. All the resveratrol oligomers (1–5) showed prominent α-glucosidase inhibition with IC50 values, 12.56 ± 1.00, 23.98 ± 1.11, 7.17 ± 1.10, 31.74 ± 0.42 and 16.95 ± 0.39 μM, respectively. Molecular docking studies also supported the observed α-glucosidase inhibition. Compound 3 displayed IC50 values of 4.85 ± 0.06 and 27.10 ± 0.04 μM in α-amylase and glycation inhibitory assays activity. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay revealed that the compounds 3 and 4 were found to be less toxic at a concentration of 100 μM (<10%) and 25 μM (<20%), respectively. The effect of glucose uptake performed by 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG) in L6 myoblast were measured by fluorescent microscopy and flow cytometry. The compounds 3 and 4 showed 2-NBDG uptake of 49.6% and 38.8% respectively. By examining the molecular pathway through which the compounds elicit their glucose uptake potential, it was observed that both the compounds mainly act via AMPK pathway. ConclusionThis is the first report on the isolation of compounds from H. ponga. Altogether, the results of this study reveal the antidiabetic effects of H. ponga extracts and isolated compounds promoting traditional use of this plant in the treatment of diabetes.

Synthetic approaches to natural products containing 2,3-dihydrobenzofuran skeleton.

Covering: 2000 to 2018 Natural products containing the 2,3-dihydrobenzofuran (2,3-DHB) skeleton have been the focus of a substantial number of synthetic studies since 2000. Herein, we review the total syntheses of decursivine, serotobenine, lithospermic acid, linderol A, bisabosqual A, pterocarpans, conocarpan, heliannuols, and some resveratrol oligomers, with emphasis on the synthetic strategies employed.

Effect of Resveratrol Dimers and Tetramers Isolated from Vitaceous and Dipterocarpaceous Plants on Human SIRT1 Enzyme Activity

SIRT1 is a mammalian ortholog of the yeast enzyme Sir2, which is an NAD+-dependent deacetylase of histones, p53, FOXO, NF-κB, PGC-1α, and other transcription factors. The Sir2 protein is reported as a longevity protein in yeast. Resveratrol, a polyphenol isolated from various types of plant families, particularly the Vitaceae family, is a known naturally occurring SIRT1 activator. In this study, we evaluated the effects of four types of resveratrol dimers and four types of tetramers isolated from vitaceous plants, and one type of resveratrol tetramer isolated from a dipterocarpaceous plant on purified human SIRT1 enzyme activity. Of the resveratrol dimers examined, (+)-ε-viniferin and pallidol exhibited no effect on SIRT1 enzyme activity, whereas (+)-ampelopsin B and (-)-ampelopsin F showed inhibitory activity on SIRT1. However, all the resveratrol tetramers examined, i.e., (+)-vitisin A, (-)-vitisin B, (+)-hopeaphenol, (-)-hopeaphenol, and (-)-isohopeaphenol markedly inhibited the human SIRT1 enzyme activity. (+)-Hopeaphenol exhibited the most potent inhibitory activity, which was comparable with that exhibited by a known SIRT1 inhibitor suramin. Since SIRT1 inhibitors reportedly possess anticancer activity, (+)-hopeaphenol and other resveratrol oligomers can be used as a seed compound for anticancer drugs.

Using the relative abundance of characteristic product ions in UHPLC-ESI-QTOF-MS2 methods to identify isomers of resveratrol oligomers in extracts of Xinjiang winegrape stems

Stilbenoids, particularly resveratrol and its oligomer, are abundantly present in grapes, and their antioxidant activities have been widely reported. A quick and simple method based on UHPLC-ESI-QTOF-MS2 was established for the fragmentation pathways analysis of trans-ε-Viniferin, cis-ε-Viniferin, trans-δ-Viniferin and (−)-Hopeaphenol. MS/MS experiments on the [M-H]− ions provided abundant structural information, especially regarding the relative abundance of the key product ion at m/z 347. The product ion was used to further identify structures in isomers of resveratrol dimers and its analogues. Based on the fragmentation pathways, we tentatively determined two compounds from the crude extracts of Xinjiang winegrape stems as Gnetin C and cis-Scirpusin A. Results from these experiments contribute to a more complete understanding of the stilbene compounds found in grape stems. The UHPLC-QTOF-MS2 method can be used for the rapid analysis of stilbenes compounds in plant materials, foods and wine.

Resveratrol oligomer C-glucosides and anti-viral resveratrol tetramers isolated from the stem bark of Shorea uliginosa

A new resveratrol dimer C-glucoside [uliginosides D (1)] was isolated from the stem bark of Shorea uliginosa, along with 21 resveratrol derivatives (2–22). Eight of these compounds (1, 3–9) comprised the building block, 4-C-glucosylresveratrol (10). The absolute configurations of six compounds (1 and 3–7) were determined using NMR and circular dichroism. The antiviral effects of the main oligostilbenoid compounds in this plant and representative oligostilbenoids from other Dipterocarpaceaeous plants were evaluated. Five resveratrol derivatives (13, 15, 17, and vaticanols B and G) were found to inhibit the replication of the herpes simplex virus types 1 and 2 with selectivity indices (SIs) ranging from 31 to 290. Two resveratrol tetramers (13 and 15) also showed an inhibitory effect on influenza A virus replication with SIs ranging from 21 to 66.

Field-Based Metabolomics of Vitis vinifera L. Stems Provides New Insights for Genotype Discrimination and Polyphenol Metabolism Structuring.

Grape accumulates numerous polyphenols with abundant health benefit and organoleptic properties that in planta act as key components of the plant defense system against diseases. Considerable advances have been made in the chemical characterization of wine metabolites particularly volatile and polyphenolic compounds. However, the metabotyping (metabolite-phenotype characterization) of grape varieties, from polyphenolic-rich vineyard by-product is unprecedented. As this composition might result from the complex interaction between genotype, environment and viticultural practices, a field experiment was setting up with uniform pedo-climatic factors and viticultural practices of growing vines to favor the genetic determinism of polyphenol expression. As a result, UPLC-MS-based targeted metabolomic analyses of grape stems from 8 Vitis vinifera L. cultivars allowed the determination of 42 polyphenols related to phenolic acids, flavonoids, procyanidins, and stilbenoids as resveratrol oligomers (degree of oligomerization 1–4). Using a partial least-square discriminant analysis approach, grape stem chemical profiles were discriminated according to their genotypic origin showing that polyphenol profile express a varietal signature. Furthermore, hierarchical clustering highlights various degree of polyphenol similarity between grape varieties that were in agreement with the genetic distance using clustering analyses of 22 microsatellite DNA markers. Metabolite correlation network suggested that several polyphenol subclasses were differently controlled. The present polyphenol metabotyping approach coupled to multivariate statistical analyses might assist grape selection programs to improve metabolites with both health-benefit potential and plant defense traits.

Effects of a Grapevine Shoot Extract Containing Resveratrol and Resveratrol Oligomers on Intestinal Adenoma Development in Mice: In Vitro and In Vivo Studies.

Evidence suggests that the dietary consumption of plant extracts containing polyphenols might help prevent the onset of cancers of the gastrointestinal tract. In the present study, the chemopreventive and antiproliferative efficacy of a grapevine shoot extract (Vineatrol®30) containing resveratrol and resveratrol oligomers is investigated in vivo and in vitro. The in vivo study is performed using ApcMin mice on a high-fat diet, which represents a model of human adenomatous polyposis, while the potential of the extract as well as some of its isolated constituents to inhibit intestinal adenoma cell proliferation in vitro is investigated using APC10.1 cells derived from an ApcMin mouse. Vineatrol®30 at a low (2.3mgkg-1 diet) or high dose (476mgkg-1 diet) reduces the adenoma number in male and adenoma volume in female animals. Furthermore, Vineatrol®30 as well as resveratrol and two resveratrol tetramers compromise the expansion of APC10.1 cells by reducing cell number, inducing cell cycle arrest, cellular senescence, and apoptosis. However, except for the extract, none of the isolated resveratrol oligomers is more efficacious than resveratrol in these cells. Vineatrol®30 may merit further investigation as a potential dietary gastrointestinal cancer chemopreventive agent in humans.

Front cover: Effects of a Grapevine Shoot Extract Containing Resveratrol and Resveratrol Oligomers on Intestinal Adenoma Development in Mice: In Vitro and In Vivo Studies

Front cover: Effects of a Grapevine Shoot Extract Containing Resveratrol and Resveratrol Oligomers on Intestinal Adenoma Development in Mice: In Vitro and In Vivo Studies

Update on Phytochemistry and Pharmacology of Naturally Occurring Resveratrol Oligomers.

Resveratrol oligomers (REVs), a major class of stilbenoids, are biosynthesized by regioselective oxidative coupling of two to eight units of resveratrol monomer. Due to their unique structures and pleiotropic biological activities, natural product chemists are increasingly focusing on REVs in the last few decades. This study presents a detailed and thorough examination of REVs, including chemical structures, natural resources, and biological activities, during the period of 2010–2017. Ninety-two new REVs compounds, including 39 dimers, 23 trimers, 13 tetramers, six resveratrol monomers, six hexamers, four pentamers, and one octamer, have been reported from the families of Dipterocarpaceae, Paeoniaceae, Vitaceae, Leguminosae, Gnetaceae, Cyperaceae, Polygonaceae Gramineae, and Poaceae. Amongst these families, Dipterocarpaceae, with 50 REVs, accounts for the majority, and seven genera of Dipterocarpaceae are involved, including Vatica, Vateria, Shorea, Hopea, Neobalanocarpus, Dipterocarpus, and Dryobalanops. These REVs have shown a wide range of bioactivities. Pharmacological studies have mainly focused on potential efficacy on tumors, bacteria, Alzheimer’s disease, cardiovascular diseases, and others. The information updated in this review might assist further research and development of novel REVs as potential therapeutic agents.

Insights on the stilbenes in Raboso Piave grape (Vitis vinifera L.) as a consequence of postharvest vs on-vine dehydration.

Grape withering is a process used to produce reinforced wines and raisins. Dehydration is usually carried out postharvest by keeping ripe grapes in special warehouses in controlled conditions of temperature, relative humidity (RH) and air flow. Alternatively, grape clusters can be left on the vines after the canes have been pruned. In general, dehydration increases stilbenes in grape, but there are few studies on the effects of on-vine withering. The stilbene profiles of Raboso Piave grape during postharvest and on-vine dehydration were studied here. High-resolution mass spectrometry (MS) was used to identify 19 stilbenes, including resveratrol monomers, dimers (viniferins), oligomers and glucoside derivatives. The two dehydration methods generally had different effects on the above nutraceuticals in grape. The samples kept in warehouses revealed significant increases in Z-ω-viniferin, E-ϵ-viniferin, δ-viniferin and another resveratrol dimer which were not observed in the plants. Trans-Resveratrol increased significantly only in samples dehydrated in the warehouse at 21 °C and 60-70% RH. The findings increase knowledge of stilbene composition in grapes subjected to withering on-vine. The choice of dehydration method affects the contents of these nutraceuticals in the grape and consequently in wines. Reasonably, it could also affect other secondary metabolites important for wine quality. © 2017 Society of Chemical Industry.

Resveratrol dimer trans-ε-viniferin prevents rotaviral diarrhea in mice by inhibition of the intestinal calcium-activated chloride channel

We previously identified, by a natural-product screen, resveratrol oligomers as inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Here, we report the resveratrol dimer trans-ε-viniferin (TV) and tetramer r-2-viniferin (RV) as inhibitors of the intestinal calcium-activated chloride channel (CaCC) and demonstrate their antisecretory efficacy in a neonatal mouse model of rotaviral diarrhea. Short-circuit measurements show inhibition of CaCC current in the human colonic cell line HT-29 by TV and RV with IC50∼1 and 20μM, respectively. TV primarily inhibited the physiologically relevant, long-term CaCC current following agonist stimulation, without effect on cytoplasmic Ca2+ signaling. TV and RV inhibited short-circuit current in mouse colon as well. In a neonatal mouse model of rotaviral secretory diarrhea produced by oral inoculation with rotavirus, 2μg TV or 11μg RV inhibited secretory diarrhea by >50%, without effect on the rotaviral infection. Our results support the antisecretory efficacy of non-toxic, natural-product resveratrol oligomers for diarrheas produced by CaCC activation. Because these compounds also inhibit the CFTR chloride channel, they may be useful for antisecretory therapy of a wide range of diarrheas.

Gnetin-C and other resveratrol oligomers with cancer chemopreventive potential.

Resveratrol has been extensively studied to investigate its biological effects, including its chemopreventive potential against cancer. Over the past decade, various resveratrol oligomers, both naturally occurring and synthetic, have been described. These resveratrol oligomers result from the polymerization of two or more resveratrol units to form dimers, trimers, tetramers, or even more complex derivatives. Some oligomers appear to have antitumor activities that are similar or superior to monomeric resveratrol. In this review, we discuss resveratrol oligomers with anticancer potential, with emphasis on well-characterized compounds, such as the dimer gnetin-C and other oligomers from Gnetum gnemon, whose safety, pharmacokinetic, and biological activities have been studied in humans.

Biomimetic Synthesis of Resveratrol Trimers Catalyzed by Horseradish Peroxidase.

Biotransformation of trans-resveratrol and synthetic (±)-ε-viniferin in aqueous acetone using horseradish peroxidase and hydrogen peroxide as oxidants resulted in the isolation of two new resveratrol trimers (3 and 4), one new resveratrol derivative (5) with a dihydrobenzofuran skeleton, together with two known stilbene trimers (6 and 7), and six known stilbene dimers (8–13). Their structures and relative configurations were identified through spectral analysis and possible formation mechanisms were also discussed. Among these oligomers, trimers 6 and 7 were obtained for the first time through direct transformation from resveratrol. Results indicated that this reaction is suitable for the preparation of resveratrol oligomers with a complex structure.

Trans-scirpusin A showed antitumor effects via autophagy activation and apoptosis induction of colorectal cancer cells.

Trans-Scirpusin A (TSA) is a resveratrol oligomer found in Borassus flabellifer L. We found that TSA inhibited the growth of colorectal cancer Her2/CT26 cells in vivo in mice. Although some cytotoxic T lymphocytes (CTLs) were induced against the tumor-associated antigen Her2, TSA treatment did not significantly increase the level of Her2-specific CTL response compared to that with vehicle treatment. However, there was a significant increase in the level of TNF-α mRNA in tumor tissue and Her2-specific Ab (antibody) production. More importantly, we found that TSA overcomes the tumor-associated immunosuppressive microenvironment by reducing the number of CD25+FoxP3+ regulatory T cells and myeloid-derived suppressor cells (MDSCs). We detected the induction of autophagy in TSA-treated Her2/CT26 cells, based on the increased level of the mammalian autophagy protein LC3 puncta, and increased conversion of LC3-I to LC3-II. Further, TSA induced 5' AMP-activated protein kinase (p-AMPK) (T172) and inhibited mammalian target of rapamycin complex 1 (mTORC1) activity as estimated by phosphorylated ribosomal protein S6 kinase beta-1 (p-p70S6K) levels, thereby suggesting that TSA-mediated AMPK activation and inhibition of mTORC1 pathway might be associated with autophagy induction. TSA also induced apoptosis of Her2/CT26 cells, as inferred by the increased sub-G1 mitotic phases in these cells, Annexin V/PI-double positive results, and TUNEL-positive cells. Finally, we found that the combined treatment of mice with docetaxel and TSA successfully inhibited tumor growth to a greater extent than docetaxel alone. Therefore, we propose the use of TSA for supplementary anticancer therapy to support anti-neoplastic drugs, such as docetaxel, by inducing apoptosis in cancer cells and resulting in the induction of neighborhood anti-cancer immunity.

Absolute configuration of resveratrol oligomer glucosides isolated from the leaves of Upuna borneensis

A comprehensive investigation of the chemical constituents of the leaves of Upuna borneensis (Dipterocarpaceae) was performed. Three new glucosides of resveratrol oligomers having a pentameric aglycone [upunoside E (1)] and dimeric aglycones [upunosides F (3) and G (4)], as well as 14 resveratrol derivatives (2, 5–17), were isolated. The absolute configurations of the new compounds were elucidated by spectroscopic analysis, including two-dimensional NMR and CD spectra.

Radical route to resveratrol oligomers

Resveratrol—made famous by its presence in red wine—has been touted for its health benefits. Oligomers of the compound may have even more promising medicinal properties, as they exhibit anti-inflammatory, immunomodulatory, and cytotoxic activities in cell studies. But getting enough of these complex polyphenols to study their mechanisms of action has been challenging. Chemists led by the University of Michigan’s Corey Stephenson and the University of Ottawa’s Derek Pratt now report a stereoconvergent synthesis of the resveratrol tetramers nepalensinol B and vateriaphenol C in 13 steps (Science 2016, DOI: 10.1126/science.aaj1597). Their strategy makes use of a persistent radical (shown) that’s derived from the resveratrol dimer, e-viniferin. “Persistent free radicals have become indispensable in the synthesis of organic materials through living radical polymerization,” the chemists point out in the report. “However, examples of their use in the synthesis of small molecules are rare.” Stephenson and Pratt n...

Stilbenoids from Hopea acuminata

Two resveratrol oligomers, a dimer (1) and a tetramer (2), were isolated from the ethyl acetate extracts of the leaves of Hopea acuminata along with vaticanol B, vaticaphenol A, vateriaphenol B, hopeaphenol, ε-viniferindiol, balanocarpol, and ampelopsin A. The structures of these compounds were established on the basis of spectroscopic data including two-dimentional nuclear magnetic resonance experiments. Compound 2, vaticanol B, vaticaphenol A, vateriaphenol B, hopeaphenol were found to inhibit protein splicing mediated by the Mycobacterium tuberculosis RecA intein in a nonspecific manner.