Iodonium Ion-Induced Cyclization and Aryl Migration of ortho-Hydroxystilbenes for the Synthesis of 3-Aryl-2,3-dihydrobenzofuran.

A facile and versatile protocol for the efficient synthesis of 3-aryl-2,3-dihydrobenzofuran (ADB) has been reported first. This reaction features the cyclization and aryl migration reaction of ortho-hydroxystilbene in ethanol, which is mediated by an iodonium ion, under ambient conditions. A class of ADB was prepared efficiently in good to excellent yields. Mechanism investigation revealed that acids and alcohols facilitated aryl migration, but alkaline and non-alcohol solvents promoted ß elimination. The practicality of this strategy was further substantiated by two scale-up reactions and demonstrated in efficient synthetic elaboration.

Chondroprotective and anti-inflammatory effects of amurensin H by regulating TLR4/Syk/NF-κB signals.

The low-grade, chronic inflammation initiated by TLR4-triggered innate immune responses has a central role on early osteoarthritis. Amurensin H is a resveratrol dimer with anti-inflammatory and anti-apoptotic effects, while its effects on TLR-4 signals to inhibit osteoarthritis are still unclear. In the present study, treatment with amurensin H for 2 weeks in monosodium iodoacetate-induced mice significantly slows down cartilage degeneration and inflammation using macroscopic evaluation, haematoxylin and eosin (HE) staining and micro-magnetic resonance imaging. In IL-1ß-stimulated rat chondrocytes, amurensin H suppresses the production of inflammatory mediators including nitric oxide, IL-6, IL-17, PGE2 and TNF-α using Greiss and ELISA assay. Amurensin H inhibits matrix degradation via decreasing levels of MMP-9 and MMP-13 using Western blot assay, promotes synthesis of type II collagen and glycosaminoglycan using immunostaining and safranin O staining, respectively. Amurensin H inhibits intracellular and mitochondrial reactive oxygen species (ROS) generation, and mitochondrial membrane depolarization using DCFH-DA, MitoSOX Red and JC-1 assay as well. IL-1ß stimulates TLR4 activation and Syk phosphorylation in chondrocytes, while amurensin H inhibits TLR4/Syk signals and downstream p65 phosphorylation and translocation in a time and dose-dependent manner. Together, these results suggest that amurensin H exerts chondroprotective effects by attenuating oxidative stress, inflammation and matrix degradation via the TLR4/Syk/NF-κB pathway.

Total synthesis of the active resveratrol dimer dehydro-δ-viniferin.

A new approach for the total synthesis of the active stilbene dimer dehydro-δ-viniferin has been achieved in 9 steps with methyl 4-hydroxybenzoate and 3,5-dihydroxyacetophenone as starting materials. The key feature of the method is the amberlyst 15-mediated cyclodehydration of α-aryloxyketone. [Formula: see text].

Discovery of a semi-synthesized cyclolignan as a potent HIV-1 non-nucleoside reverse transcriptase inhibitor.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are essential components of highly active antiretroviral therapy (HAART) for human immunodeficiency virus type 1 (HIV-1) infection. In this study, we identified (+)-(7'S,8S,8'S)-3',4,4',5,5'-pentamethoxy-2,7'-cyclolignan (SG-1), a cyclolignan semi-synthesized from Machilus robusta and M. wangchiana extracts, as a potent NNRTI. SG-1 displayed anti-HIV-1 activity with an IC50 of 0.77 µmol/L by inhibiting reverse transcriptase (RT) RNA-dependent DNA polymerase activity through a direct binding. It had synergistic effects when combined with tenofovir/lamivudine or zidovudine/lamivudine. The pharmacodynamics properties of SG-1 render it a valuable lead for the development of novel NNRTIs.

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.

Naturally active oligostilbenes.

Many naturally occurring oligostilbenes have drawn considerable attention because of their intricate structures and diverse biological activities. In recent years, oligostilbene bioactivities have become a popular research topic worldwide. Although these bioactivities are known to be extensive and several summaries on the activities of the compounds have been published, a comprehensive and systematic summary on active oligostilbenes is unavailable. From January 2005 to December 2013, a large number of active oligostilbenes and corresponding new bioactivities were reported in the literature. This review mainly focuses on the diverse bioactivities of oligostilbenes with various backbones.

Potassium Hexacyanoferrate (III)-Catalyzed Dimerization of Hydroxystilbene: Biomimetic Synthesis of Indane Stilbene Dimers.

Using potassium hexacyanoferrate (III)-sodium acetate as oxidant, the oxidative coupling reaction of isorhapontigenin and resveratrol in aqueous acetone resulted in the isolation of three new indane dimers 4, 6, and 7, together with six known stilbene dimers. Indane dimer 5 was obtained for the first time by direct transformation from isorhapontigenin. The structures and relative configurations of the dimers were elucidated using spectral analysis, and their possible formation mechanisms were discussed. The results indicate that this reaction could be used as a convenient method for the semi-synthesis of indane dimers because of the mild conditions and simple reaction products.

[Analysis of porphyrin photosensitizers using HPLC method].

Photodynamic therapy (PDT), because of its good targeting, minimal invasion, and safety, is becoming a very active area in cancer prevention and treatment, in which the photosensitizers have proved to be the core element for PDT. We developed a new HPLC method for analyzing porphyrin photosensitizers using Shiseido Capcell PAK C18 (150 mm x 4.6 mm, 5 µm) as the column at 30 °C, methanol-1% aqueous solution of acetic acid as the mobile phase in a flow rate of 1.0 mL · min(-1) in a gradient elution mode, and the detection wavelength at 380 nm. This method, showing good specificity, precision, accuracy and robusty via methodology validations, can be applied to the purity test and assay of porphyrin photosensitizers, and has played a key guide role in the R&D of the new porphyrin photosensitizer--sinoporphyrin sodium.

Vam3, a resveratrol dimer, inhibits cigarette smoke-induced cell apoptosis in lungs by improving mitochondrial function.

AIM: To investigate the effects of Vam3 (a resveratrol dimer extracted from Vitis amurensis Rupr) on cigarette smoke (CS)-induced cell apoptosis in lungs in vitro and in vivo and the underlying mechanisms of action. METHODS: Human bronchial epithelial cell line BEAS-2B was exposed to cigarette smoke condensate (CSC, 300 mg/L), and cell apoptosis was determined using flow cytometry and Hoechst staining. Mitochondrial membrane potential was examined with TMRE staining. ROS and ceramide levels were detected with DCFH-DA fluorescence and HPLC-MS/MS, respectively. Cytochrome c release was detected using immunofluorescence. Caspase-9 and neutral sphingomyelinase 2 expression was measured with Western blotting. The breast carcinoma cell line MCF7 stably expressing GFP-tagged Bax was used to elucidate the role of mitochondria in CS-induced apoptosis. For in vivo study, male mice were exposed to CS for 5 min twice a day for 4 weeks. The mice were orally administered Vam3 (50 mg·kg(-1)·d(-1)) or resveratrol (30 mg·kg(-1)·d(-1)) each day 1 h before the first CS exposure. RESULTS: Pretreatment of BEAS-2B cells with Vam3 (5 µmol/L) or resveratrol (5 µmol/L) significantly suppressed CSC-induced apoptosis, and prevented CSC-induced Bax level increase in the mitochondria, mitochondrial membrane potential loss, cytochrome c release and caspase-9 activation. Furthermore, pretreatment of BEAS-2B cells with Vam3 or resveratrol significantly suppressed CSC-stimulated intracellular ceramide production, and CSC-induced upregulation of neutral sphingomyelinase 2, the enzyme responsible for ceramide production in bronchial epithelial cells. Similar results were obtained in C6-pyridinium ceramide-induced apoptosis of GFP-Bax-stable MCF7 cells in vitro, and in the lungs of CS-exposed mice that were treated with oral administration of Vam3 or resveratrol. CONCLUSION: Vam3 protects bronchial epithelial cells from CS-induced apoptosis in vitro and in vivo by preventing mitochondrial dysfunction.

Biomimetic synthesis of active isorhapontigenin dimers.

Synthetic isorhapontigenin was treated with several kinds of inorganic reagents and peroxidase so as to prepare active stilbene dimers. Among them, silver acetate in methanol gave two new isorhapontigenin dimers 4 and 5, together with four known natural stilbene dimers 2, 3, 6, and 7. Their structures and relative configurations were determined on the basis of spectral analysis, and their possible formation mechanisms were discussed, respectively. Compounds 2, 6, and 7 were artificially synthesized for the first time. All the products were evaluated for anti-inflammatory activities.

[Effects of Vam3 on sodium nitroprusside-induced apoptosis and SIRT1 and p53 expression in rat articular chondrocytes].

This study is to investigate the effect of Vam3, a dimeric derivative of resveratrol, on SNP-induced apoptosis and its potential mechanism in rat articular chondrocytes. Isolated rat articular chondrocytes were treated with sodium nitroprusside (SNP), a NO donor, to induce apoptosis. Apoptosis percentage was evaluated by Annexin V-PI and nucleus fracture was examined by DAPI staining. Level of intracellular reactive oxygen species (ROS) was detected using 2, 7'-dichlorofluorescin diacetate (DCFH-DA) as a fluorescence probe by fluorescence microplate reader. The change in mitochondrial membrane potential was detected by TMRE staining. Expressions of SIRT1, acetylated p53 (ac-p53), cleaved caspase 9 and cleaved caspase 3 were determined by Western blotting. It showed that Vam3 up to 10 micromol x L(-1) could significantly reduce SNP-induced rat articular chondrocytes apoptosis (P < 0.01) and nucleus fracture, inhibit the increase of intracellular ROS level (P < 0.01) and reverse the decrease in mitochondrial membrane potential (P < 0.01). Simultaneously, Vam3 could upregulate the expression of SIRT1, deacetylate p53, and inhibit the cleavage of caspase 9 and caspase 3 (P < 0.01) of rat articular chondrocytes exposed to SNP. This study indicates Vam3 could protect rat articular chondrocytes against SNP-induced apoptosis, perhaps through the upregulation of SIRT1 and deacetylation of p53.

A new stilbene dimer from Vitis amurensis.

One new stilbene dimer named amurensin O (1), together with one known resveratrol trimer melapinol B (2), was isolated from Vitis amurensis, and their structures were identified on the basis of spectral analysis, especially 2D NMR spectral analysis.

[Chemical constituents from the linseed meal].

Ten compounds were isolated from the 70% ethanol extract of linseed meal (Linum usitatissimum L) through a combination of various chromatographic techniques, including silica gel, macroporous adsorbent resin, Sephadex LH-20, and preparative HPLC. On the basis of spectroscopic data analysis, they were elucidated as 1-methylethyl-2-O-beta-D-glucopyranosyl-(1" --> 6')-beta-D-glucopyanoside (1), linustatin (2), neolinustatin (3), lotaustralin (4), linamarin (5), deoxyguanosine (6), deoxyadenosine (7), (+)-pinoresinol-4'-O-beta-D-glucopyranoside (8), 4-O-beta-D-glucopyranosylvanillyl alcohol (9) and tachioside (10), separately. Among them, compound 1 is a new compound, and compounds 6, 8 and 10 were isolated from the linseed meal for the first time.

Vam3, a derivative of resveratrol, attenuates cigarette smoke-induced autophagy.

AIM: To appraise the efficacy of Vam3 (Amurensis H), a dimeric derivative of resveratrol, at inhibiting cigarette smoke-induced autophagy. METHODS: Human bronchial epithelial cells were treated with cigarette smoke condensates, and a chronic obstructive pulmonary disease (COPD) model was established by exposing male BALB/c mice to cigarette smoke. The protein levels of the autophagic marker microtubule-associated protein 1A/1B-light chain 3 (LC3), Sirtuin 1 (Sirt1), and foxhead box O 3a (FoxO3a) were examined using Western blotting and Immunohistochemistry. LC3 punctae were detected by immunofluorescence. The levels of FoxO3a acetylation were examined by immunoprecipitation. The level of intracellular oxidation was assessed by detecting ROS and GSH-Px. RESULTS: Vam3 attenuated cigarette smoke condensate-induced autophagy in human bronchial epithelial cells, and restored the expression levels of Sirt1 and FoxO3a that had been reduced by cigarette smoke condensates. Similar protective effects of Vam3, reducing autophagy and restoring the levels of Sirt1 and FoxO3a, were observed in the COPD animal model. Additionally, Vam3 also diminished the oxidative stress that was induced by the cigarette smoke condensates. CONCLUSION: Vam3 decreases cigarette smoke-induced autophagy via up-regulating/restoring the levels of Sirt1 and FoxO3a and inhibiting the induced oxidative stress.

A new resveratrol trimer derivative from Gnetum brunonianum.

A new resveratrol trimer derivative, named as gnetubrunol A (1), together with five known stilbene derivatives, shegansu B (2), resveratrol (3), isorhapontigenin (4), gnetifolin E (5), and isorhapontigenin-11-O-ß-d-glucopyranoside (6) were isolated from the lianas of Gnetum brunonianum Griff. Their structures were elucidated on the basis of spectral analysis (UV, IR, MS, (1)H NMR, (13)C NMR, and 2D NMR). The anti-inflammatory activities of 1, 5, and 6 have also been assayed.

A concise and efficient total synthetic route of active stilbene dimer (±)-ε-viniferin.

A concise and efficient procedure for the total synthesis of natural stilbene dimer (±)-ε-viniferin was accomplished with high overall yield. Demethylation of the key intermediate methyl 3-arylbenzofuran-4-carboxylate was achieved successfully through bromination followed by BBr3-or BCl3/TBAI-mediated ether cleavage reaction. Pd/C and bromobenzene-catalyzed MOM ether cleavage was successfully carried out to aquire (±)-ε-viniferin.

Bioactive neolignans and lignans from the bark of Machilus robusta.

Sixteen new neolignans and lignans (1-16), together with 12 known analogues, have been isolated from an ethanol extract of the bark of Machilus robusta. Compounds 1 and 2 showed activity against HIV-1 replication in vitro, with IC(50) values of 2.52 and 2.01 µM, respectively. At 10 µM, 6, 8, and 9 reduced dl-galactosamine-induced hepatocyte (WB-F344 cells) damage, and 9 could additionally attenuate rotenone-induced PC12 cell damage. The known compounds (-)-pinoresinol (17) and (+)-lyoniresinol (18) were active against serum deprivation induced PC12 cell damage.

[Effects of dihydroxy-stilbene compound Vam3 on airway inflammation, expression of ICAM-1, activities of NF-kappaB and MMP-9 in asthmatic mice].

The aim of the present study is to investigate the effects of Vam3 which is one of the dihydroxystilbene compounds on expressions of ICAM-1 in the lungs of OVA-induced asthmatic mice and the mechanisms of anti-airway inflammation. Balb/c mice were challenged with OVA inhalation. Lung tissues were stained with Mayer's hematoxylin and eosin for histopathologic examination. The expression of ICAM-1 in the lungs of mice was analyzed by Western blotting and immunohistochemistry method. The NF-kappaB activities were detected by NF-kappaB-luc reporter genetic transient transfection method. The activities of MMP-9 induced by LPS, TNF-alpha and PMA in THP-1 cells were determined by gelatin zymography method. The results showed that Vam3 could inhibit the expression of ICAM-1 in the OVA-induced mouse model. In addition, Vam3 could significantly suppress the activities of NF-kappaB in A549 cells and MMP-9 in THP-1 cells induced by LPS, TNF-alpha and PMA. These results suggested that Vam3 could alleviate the asthmatic inflammation by decreasing ICAM-1 expression in asthmatic mice, down regulating NF-kappaB and MMP-9 activities. Compound Vam3 showed inhibitory effects on inflammatory signal pathways involved in asthma.

Multiple Components Rapidly Screened from Perilla Leaves Attenuate Asthma Airway Inflammation by Synergistic Targeting on Syk.

BACKGROUND: Perilla frutescens (L.) Britt., a classic medicinal plant, has been demonstrated to have anti-inflammatory and anti-allergic effects in asthma. Perilla leaves extract (PLE) exerted significant therapeutic effect against allergic asthma inflammation through Syk inhibition. But the active chemical ingredients from PLE are complex and unclear, it is difficult to fully elucidate its pharmacological mechanisms. METHODS: A method was established for rapid screening and characterization of active ingredients from PLE that targeted Syk, with which three potential active ingredients were identified. By using OVA-induced allergic asthma mouse model in vivo, OVA-induced human PBMCs inflammation model and DNP-IgE/BSA-induced RBL-2H3 cells model in vitro, the effects and mechanisms of PLE and its active components were evaluated. RESULTS: Using Syk-affinity screening method, roseoside (RosS), vicenin-2 (Vic-2) and rosmarinic acid (RosA) were identified from PLE. In vitro, PLE and its ingredients showed significant inhibitory activities against Syk, with their mixture (Mix, prepared by RosS, Vic-2 and RosA in accordance with their ratio in Syk-conjugated beads bound fraction) showing a stronger inhibitory activity. RosS, Vic-2 and RosA also showed significant effects on allergic asthma, and a synergistic effect of Mix was observed. Moreover, treatment with PLE, RosS, Vic-2, RosA, and Mix significantly inhibited the expression and phosphorylation of Syk, PKC, NF-κB p65, and cPLA2 in allergic mice lung tissue and in RBL-2H3 cells. CONCLUSION: PLE may alleviate allergic airway inflammation partly through the multiple components synergistic targeting on Syk and its downstream inflammatory pathway.

Amurensin H, a Derivative From Resveratrol, Ameliorates Lipopolysaccharide/Cigarette Smoke-Induced Airway Inflammation by Blocking the Syk/NF-κB Pathway.

Amurensin H, a resveratrol dimer derived from Vitis amurensis Rupr, has several biological effects, including anti-inflammatory and antioxidant activities. Studies have found that amurensin H attenuated asthma-like allergic airway inflammation. However, its protective activity on chronic obstructive pulmonary disease (COPD) airway inflammation is not fully explored. The present study used a lipopolysaccharide (LPS)/cigarette smoke-induced mice model and an LPS-stimulated THP-1-derived macrophages model to measure the lung tissue's morphology changes. The results showed that amurensin H ameliorated the histological inflammatory alterations in the lung tissues, leading to a decrease in the expression of interleukin 6 (IL-6), IL-17A, tumor necrosis factor α (TNF-α), and interferon γ in bronchoalveolar lavage fluid. Amurensin H also significantly inhibited the release of IL-1ß, IL-6, IL-8, and TNF-α in LPS-stimulated THP-1-derived macrophages. Furthermore, amurensin H markedly inhibited the expressions of p-Syk, nuclear factor κB (NF-κB), and p-NF-κB both in vivo and in vitro. Results from cotreatment with Syk inhibitor BAY61-3606 and NF-κB inhibitor BAY11-7082 in vitro revealed that amurensin H's protective effect against airway inflammation could be due partly to the inhibition of the Syk/NF-κB pathway. These findings suggest that amurensin H shows therapeutic effects on COPD airway inflammation, and inhibiting the Syk/NF-κB pathway might be part of its underlying mechanisms.