Resveratrol Dimer Research Articles

Regio‐ and Diastereoselective Organo‐Zinc‐Promoted Arylation of trans‐2,3‐Diaryloxiranes by Arylboronic Acids: Stereoselective Access to trans‐2,3‐Diphenyl‐2,3‐dihydrobenzofuran

ortho‐Oxo substituted trans 2,3‐diaryloxiranes were regio‐ and stereoselectively arylated by arylzinc reagents, obtained from the corresponding boronic acids by B–Zn exchange. The reaction was quite general, irrespective to the aryl nucleophile and proceeded via a ring opening at the α‐carbon with respect to the substituted aryl ring. The stereoselectivity was from high to complete toward the alcohol resulted from retention of configuration at the electrophilic carbon. The method allowed a direct and high yielding access to trans 2,3‐diphenyl‐2,3‐dihydrobenzofuran, which is a key structural motif in resveratrol dimers as viniferins. The use of enantioenriched starting diaryloxiranes resulted in no loss of stereochemical integrity in the final trans 2,3‐dihydrobenzofuran, which was characterized for the first time in enantioenriched form.

Theoretical studies on the antioxidant activity of viniferifuran

DFT studies reveal the thermodynamics and kinetics of radical scavenging reactions of a resveratrol dimer derivative – viniferifuran.

Synthesis and evaluation of isoprenylation-resveratrol dimer derivatives against Alzheimer's disease

A series of resveratrol dimer derivatives against Alzheimer's disease (AD) was obtained by structural modification and transformation using resveratrol as substrate. Biological analysis revealed that these derivatives had moderate inhibitory activity against human monoamine oxidase B (hMAO-B). In particular, 3 and 7 showed the better inhibitory activity for hMAO-B (IC50 = 3.91 ± 0.23 μM, 0.90 ± 0.01 μM) respectively. Compound 3 (IC50 = 46.95 ± 0.21 μM for DPPH, 1.43 and 1.74 trolox equivalent by ABTS and FRAP method respectively), and 7 (IC50 = 35.33 ± 0.15 μM for DPPH, 1.70 and 1.97 trolox equivalent by ABTS method and FRAP method respectively) have excellent antioxidant effects. Cellular assay shown that 3 and 7 had lower toxicity and were resistant to neurotoxicity induced by oxidative toxins (H2O2, rotenone and oligomycin-A). More importantly, the selected compounds have neuroprotective effects against ROS generation, H2O2-induced apoptosis and a significant in vitro anti-inflammatory activity. The results of the parallel artificial membrane permeability assay for blood-brain barrier indicated that 3 and 7 would be predominant to cross the blood-brain barrier. In this study, mouse microglia BV2 cells were used to establish cell oxidative stress injury model with H2O2 and to explore the protective effect and mechanism of 3 and 7. In general, 3 and 7 can be considered candidates for potential treatment of AD.

Cyclopropylmethyl Protection of Phenols: Total Synthesis of the Resveratrol Dimers Anigopreissin A and Resveratrol-Piceatannol Hybrid.

We demonstrate the versatile use of the cyclopropylmethyl group to protect phenols through the total synthesis of two benzofuran‐based natural products, that is, anigopreissin A and the resveratrol–piceatannol hybrid. This protecting group is a good alternative to the conventional methyl group, owing to the feasibility of introduction, stability under a variety of conditions, and its relative ease of removal under different acidic conditions.

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.

Gnetin C suppresses double-stranded RNA-induced C-C motif chemokine ligand 2 (CCL2) and CCL5 production by inhibiting Toll-like receptor 3 signaling pathway.

The innate immune system is a prerequisite for biophylactic ability, but its dysregulation can cause inflammatory and autoimmune diseases. To determine a safe method of controlling inflammatory reactions in the brain, we examined the effects of gnetin C, a natural resveratrol dimer, on C-C motif chemokine ligand 2 (CCL2) and CCL5 (pro-inflammatory chemokines) production observed after treatment with polyinosinic-polycytidylic acid [poly IC; a synthetic analog of dsRNA as a Toll-like receptor 3 (TRL3) ligand, 30 μg/mL] in cultured human astrocytoma U373MG and neuroblastoma SH-SY5Y cells. The addition of gnetin C (10 μM) to the media moderately reduced the CCL2 production and markedly suppressed CCL5 production in both cells. In the TLR3-interferon (IFN)-β-phosphorylated-STAT1 (signal transducer and activator of transcription protein 1)RIG-I (retinoic acid-inducible gene-I) pathway that mediates CCL2 and CCL5 production, gnetin C first inhibits IFN-β expression in SH-SY5Y cells and primarily inhibits STAT1 phosphorylation in U373MG cells. In any case, gnetin C attenuated the dsRNA-activated TLR3 signaling resulting in CCL2 and CCL5 production, thus, may be useful for controlling TLR3-mediated inflammation in the brain.

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.

Abstract 253: Gnetin C as a candidate for targeted chemopreventive and therapeutic measures in prostate cancer

Abstract Overexpression of chromatin modifier protein, metastasis-associated protein 1 (MTA1) in prostate cancer contributes to tumor aggressiveness and metastasis. MTA1 ChiP-Seq analysis identified downstream targets that are transcriptionally regulated by MTA1 and suggested a link between MTA1 and ETS2. The effects of ETS2 in cancer are context-dependent and both oncogenic and tumor suppressive functions have been described. We have shown that there is a positive correlation between MTA1 and ETS2 using loss of function studies and various preclinical models of prostate cancer. Our conclusion that MTA1 functions as a co-activator for regulating ETS2 expression in prostate cancer leading to promotion of prostate cancer progression, prompted us to look for pharmacological inhibitors of MTA1/ETS2 axis. In our previous studies, we reported inhibition of MTA1 by resveratrol and its potent analog pterostilbene in vitro and in vivo. We have demonstrated that pterostilbene treatment blocks the progression of PIN and adenocarcinoma in xenografts and transgenic mouse models by inhibiting MTA1 expression and signaling. Here, we found that Gnetin C, double-resveratrol, has more potent inhibition of MTA1/ETS2 axis than other stilbenes. Gnetin C, a resveratrol dimer, is found abundantly in melinjo plant widely cultivated in Southeast Asia; its seeds and fruits are common ingredients in Indonesian culinary. As resveratrol and pterostilbene, Gnetin C has been reported to possess anti-inflammatory and anticancer activity, however it has not been considered as chemopreventive agent in prostate cancer. Using two prostate cancer cell lines, namely DU145 and PC3M cells, we found that Gnetin C shows significant inhibitory effect on cell proliferation, more potent effects in colony formation and wound healing assays than resveratrol or pterostilbene. Importantly, Gnetin C specifically and strongly downregulates MTA1 and ETS2 expression in prostate cancer cells. Taken together, our findings implicate the potential of Gnetin C in MTA1/ETS2-mediated chemoprevention and therapy in prostate cancer. Citation Format: Urvi Kolhatkar, Kshiti Dholakia, Gabriela Sikorska, Avinash Kumar, Luis A. Martinez, Anait S. Levenson. Gnetin C as a candidate for targeted chemopreventive and therapeutic measures in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 253.

Gnetin C, a resveratrol dimer, reduces amyloid-β 1-42 (Aβ42) production and ameliorates Aβ42-lowered cell viability in cultured SH-SY5Y human neuroblastoma cells.

Accumulation and oligomerization of amyloid-beta (Aβ) peptides have been known to be a potent cause of neurodegenerative diseases such as Alzheimer's disease (AD). To expand the possibilities of preventing AD, we investigated the effects of resveratrol dimers, gnetin C and ε-viniferin, on Aβ 1-42 (Aβ42) production and the reduced cell viability observed after Aβ42 treatment (monomers, 10 μM) in cultured SH-SY5Y human neuroblastoma cells. Among them, addition of gnetin C (20 μM) into the media reduced Aβ42 production most efficiently. Gnetin C suppressed the expression of β-site amyloid precursor protein-cleaving enzyme-1 (BACE1, β-secretase). Furthermore, gnetin C ameliorated the Aβ42-reduced cell viability most significantly. Concomitantly, gnetin C reduced intracellular Aβ oligomers (ca. 15 and 130 kDa) and elevated both levels of intracellular and extracellular Aβ monomers. Under the treatment with or without Aβ42, gnetin C upregulated the expression of matrix metalloproteinase-14 (MMP-14) which is assumed to be an Aβ-decomposing enzyme. Gnetin C may thereby prevent Aβ toxicity by suppressing BACE1 and enhancing MMP-14, together with reducing both internalization and oligomerization of exogenous Aβ monomers. The use of gnetin C may lead to the prevention of Aβ-mediated diseases, particularly AD.

Isolation and purification of five phenolic compounds from the Xinjiang wine grape (Vitis Vinifera) and determination of their antioxidant mechanism at cellular level

Xinjiang wine grapes (Vitis Vinifera) are extraordinarily rich sources of stilbenes. In this study, two pair of isomers of resveratrol dimers trans-e-viniferin (1) and (+)-cis-e-viniferin (2), astilbin (4) and isoastilbin (5), and resveratrol tetramer (−)-hopeaphenol (3) were isolated and purified. Their structures were determined by means of nuclear magnetic resonance and mass spectrometry analysis. Then, cellular antioxidant activity of the five phenolic compounds was evaluated in human hepatoma (Hep G2) cells. Results indicated that (4) has the strongest antioxidant activity (10 µg/mL), while (5) is the weakest one. Mechanism process of antioxidant at genes expression was elaborated by real-time quantitative PCR, which showed that the five stilbenes could down-regulation of oxidative stress genes and apoptosis genes. Therefore, this study provides the useful evidence for these compounds to develop the functional foods and nutritional supplements. Five phenolic compounds, trans-e-viniferin (1) and (+)-cis-e-viniferin (2), astilbin (4) and isoastilbin (5), resveratrol tetramer (−)-hopeaphenol (3) were isolated and purified. These five compounds have a significantly reduced effect on oxidative stress genes at cellular level by real-time quantitative PCR

Apoptotic effects of ε-viniferin in combination with cis-platin in C6 cells.

Glioblastoma (GBM) is one of the most common and lethal forms of primary brain tumors in human adults. Treatment options are limited, and in most cases ineffective. Natural products are sources of novel compounds endowed with therapeutic properties in many human diseases like cancer. ε-viniferin is a resveratrol dimer and well known for having antiproliferative and apoptotic effects on cancer cells. Cisplatin is a platinumcontaining anti-cancer drug. In this study, we aimed to investigate antiproliferative and apoptotic effects of using cis-platin and ε-viniferin alone or in combined treatment of C6 cells. Cell proliferation was detected by WST-1. Mitochondrial membrane potential changes in the cells (ΔΨm) were evaluated using cationic dye JC1. Apoptotic index which is a hallmark of late apoptosis was detected by using Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) method and apoptotic alterations were observed by transmission electron microscope (TEM). Activation of caspase-8,-9, -3 in C6 cells at various incubation periods was measured by flow cytometer. Apoptotic index increased at highest level in only combined treatment cells (91.6%) after 48h incubation. These results were supported by TEM images. Caspase-8 activation in C6 cells increased to a maximum (12.5%) after 6h by using combined cis-platin/ε-viniferintreatment (13.25/95μM). Caspase-9 was activated at 44.5% after combined treatment for 24h. This rate is higher than using cis-platin (14.2%) or ε-viniferin (43.3%) alone. The combined 13.25μM/cisplatin and 95μM ε-viniferintreatment caused maximum caspase-3 activation in C6 cells (15.5%) at the end of the 72hincubation. In conclusion, it was observed that caspase-8, -9, -3 activation which was determined in vitro, trigerred apoptotic mechanism in C6 cells by using low concentrations of combined cis-platin and ε-viniferin.

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.

Cytotoxicity of Labruscol, a New Resveratrol Dimer Produced by Grapevine Cell Suspensions, on Human Skin Melanoma Cancer Cell Line HT-144.

A new resveratrol dimer (1) called labruscol, has been purified by centrifugal partition chromatography of a crude ethyl acetate stilbene extract obtained from elicited grapevine cell suspensions of Vitis labrusca L. cultured in a 14-liter stirred bioreactor. One dimensional (1D) and two dimensional (2D) nuclear magnetic resonance (NMR) analyses including 1H, 13C, heteronuclear single-quantum correlation (HSQC), heteronuclear multiple bond correlation (HMBC), and correlation spectroscopy (COSY) as well as high-resolution electrospray ionisation mass spectrometry (HR-ESI-MS) were used to characterize this compound and to unambiguously identify it as a new stilbene dimer, though its relative stereochemistry remained unsolved. Labruscol was recovered as a pure compound (>93%) in sufficient amounts (41 mg) to allow assessment of its biological activity (cell viability, cell invasion and apoptotic activity) on two different cell lines, including one human skin melanoma cancer cell line HT-144 and a healthy human dermal fibroblast (HDF) line. This compound induced almost 100% of cell viability inhibition in the cancer line at a dose of 100 μM within 72 h of treatment. However, at all tested concentrations and treatment times, resveratrol displayed an inhibition of the cancer line viability higher than that of labruscol in the presence of fetal bovine serum. Both compounds also showed differential activities on healthy and cancer cell lines. Finally, labruscol at a concentration of 1.2 μM was shown to reduce cell invasion by 40%, although no similar activity was observed with resveratrol. The cytotoxic activity of this newly-identified dimer is discussed.

HMG-CoA Reductase Inhibitory Activity of Gnetum gnemon Seed Extract and Identification of Potential Inhibitors for Lowering Cholesterol Level

Objectives: Melinjo (Gnetum gnemon) seeds have been known to have some biological properties. One of them is ant hypercholesterolemia. The present study investigated in vitro and in silico methods to predict potential antihypercholesterolemic of the Melinjo seed extracts of through HMG-CoA reductase inhibitory activity. Methods: Melinjo seed powders were successively extracted by reflux method using five solvents with gradient polarity including: n-hexane, dichloromethane, ethyl acetate and methanol. All extracts were evaluated in vitro using HMG-CoA Reductase assay kit, to analyze the inhibitory activity. Molecular docking of the phytochemical content of the seeds were carried out using Auto Dock Vina, and also Ligand Scout to analyses interaction between ligand and receptor. Results: Dichloromethane extract demonstrated the highest inhibitory activity against HMG-CoA reductase with IC50 value is 0.40 μg/mL, followed by that of ethyl acetate extract. UPLC-MS analyses showed that dichloromethane extract contained trans-resveratrol, piceid, gnetin C, gnetol, isorhapontigenin, ɛ-viniferin, gnemonol L, and gnemonol M. Molecular docking studies demonstrated that dimer of resveratrol such as gnemonol L, gnemosida, and ɛ-viniferin have better free binding energy than that of monomer. piceid, gnetin C, gnemonol L, and gnemonol M could be considered as HMG-CoA reductase inhibitor. Conclusion: Gnetum gnemon seed extract showed strong HMG-CoA reductase activity. Resveratrol dimer promises as a potential lead compound to design/synthesize anti-cholesterol. Key words: Gnetum gnemon, Melinjo, HMG-CoA Reductase, Resveratrol, Stilbene, Molecular Docking.

Inhibitory effects of 17β-estradiol or a resveratrol dimer on hypoxia-inducible factor-1α in genioglossus myoblasts: Involvement of ERα and its downstream p38MAPK pathways.

Deficiency in the functioning of the genioglossus, which is one of the upper airway dilator muscles, is an important cause of obstructive sleep apnea/hypopnea syndrome (OSAHS). Estrogens have been reported to inhibit hypoxia-inducible factor-1α (HIF-1α) expression in hypoxia, regulating its target genes and exerting protective effects on the genioglossus in chronic intermittent hypoxia (CIH). This study aimed to investigate the role of 17β-estradiol (E2) and a resveratrol dimer (RD) on HIF-1α and the underlying mechanism. Mouse genioglossus myoblasts were isolated and cultured, and the estrogen receptor α (ERα) shRNA lentivirus was used for gene knockdown. Then MTT assay was used to determine the effects of E2 and RD on the viability of the cells. Cells in different groups were treated with different agents (E2, or RD, or E2 and SB203580), incubated under normoxia or hypoxia for 24 h, and then expression levels of HIF-1α, ERα, ERβ, total-p38 MAPK and phospho-p38 MAPK were detected. We observed that both E2 and RD inhibited the overexpression of HIF-1α induced by hypoxia at the mRNA and protein levels, and these effects were eliminated by genetic silencing of ERα by RNAi. In addition, we found that E2 activated p38 MAPK pathways to inhibit HIF-1α expression. On the whole, ERα may be responsible for downregulation of HIF-1α by E2 or RD via activation of downstream p38 MAPK pathways.

Synthesis of 4‐Formyl‐2‐arylbenzofuran Derivatives by PdCl(C3H5)dppb‐Catalyzed Tandem Sonogashira Coupling‐Cyclization under Microwave Irradiation ‐ Application to the Synthesis of Viniferifuran Analogues

AbstractHerein we present the use of low catalyst loading of PdCl(C3H5)dppb (1 mol%) to directly prepare 4‐CHO‐2‐arylbenzofurans by copper‐free tandem Sonogashira coupling‐cyclization under microwave irradiation. The method was utilized to prepare highly substituted analogues of viniferifuran, a biologically active resveratrol dimer. Key transformations included the application of PdCl(C3H5)dppb (5 mol%) catalyzed direct arylation of C‐3 sterically congested C‐2 and C‐4 substituted benzofuran substrates. Finally, we demonstrated that BCl3/TBAI is superior to BBr3 for final demethylation.

Mechanism of isomers and analogues of resveratrol dimers selectively quenching singlet oxygen by UHPLC-ESI-MS2

Stilbenoids, in particular, resveratrol and its dimers are abundantly present in Vitis vinifera and proved to be quenchers with selective singlet oxygen. However, only a few mechanisms are reported for their complex molecular architectures. Hence, UHPLC combined with accurate MS is employed to investigate the photo-radiation mechanism of resveratrol dimers systematically. Ⅰ: Resorcinol ring exists in Scirpusin A 1, Trans-ε-viniferin 2 and Trans-σ-viniferin 3. The photochemical products were 14Da or 16Da higher than reagents and underwent an endoperoxide intermediate to quinones; Ⅱ: [2+2] cyclization of intra-molecular trans-double bond. The products were 18Da greater than substrates thereby cycloaddited to oxygen heterocyclic; Ⅲ : [4+1], [4+2] cyclization of oxetane formed products were 28Da and 44Da higher than 3, 2 and 1. Ⅳ : 5-phenol-2,3-dihydrobenzofuran ring exists in 2 been oxidized, causing the products at 16Da, 32Da higher than 2. This is the first to reveal the generally regular mechanism of stilbenoids quenching singlet oxygen.

In Vitro Glucuronidation and Sulfation of ε-Viniferin, a Resveratrol Dimer, in Humans and Rats.

ε-Viniferin is a resveratrol dimer that possesses antioxidant or anti-inflammatory activities. However little is known about the metabolism of this oligostilbene. This study was thus undertaken as a first approach to identify and characterize the metabolites of ε-viniferin and to describe the kinetic profile of their appearance in humans and rats. The glucuronides and sulfates of ε-viniferin were first obtained by chemical hemi-synthesis and were fully characterized by UPLC-MS and NMR spectroscopy. Then, ε-viniferin was incubated with human or rat S9 liver fractions that led to the formation of four glucuronoconjugates and four sulfoconjugates. In both species, ε-viniferin was subjected to an intense metabolism as 70 to 80% of the molecule was converted to glucuronides and sulfates. In humans, the hepatic clearance of ε-viniferin (Vmax/Km) for glucuronidation and sulfation were 4.98 and 6.35 µL/min/mg protein, respectively, whereas, in rats, the hepatic clearance for glucuronidation was 20.08 vs. 2.59 µL/min/mg protein for sulfation. In humans, three major metabolites were observed: two glucuronides and one sulfate. By contrast, only one major glucuronide was observed in rats. This strong hepatic clearance of ε-viniferin in human and rat could explain its poor bioavailability and could help to characterize its active metabolites.