benzofurans and ampelopsin

Bacterial infections continue to threaten humankind and the rapid spread of antibiotic resistant bacteria is alarming. Current antibiotics target essential bacterial processes and thereby apply a strong selective pressure on pathogenic and non-pathogenic bacteria alike. One alternative strategy is to block bacterial virulence systems that are essential for the ability to cause disease but not for general bacterial viability. We have previously show that the plant natural product (-)-hopeaphenol blocks the type III secretion system (T3SS) in the Gram-negative pathogens Yersinia pseudotuberculosis and Pseudomonas aeruginosa. (-)-Hopeaphenol is a resveratrol tetramer and in the present study we explore various resveratrol dimers, including partial structures of (-)-hopeaphenol, as T3SS inhibitors. To allow rapid and efficient assessment of T3SS inhibition in P. aeruginosa, we developed a new screening method by using a green fluorescent protein reporter under the control of the ExoS promoter. Using a panel of assays we showed that compounds with a benzofuran core structure i.e. viniferifuran, dehydroampelopsin B, anigopreissin A, dehydro-δ-viniferin and resveratrol-piceatannol hybrid displayed significant to moderate activities towards the T3SS in Y. pseudotuberculosis and P. aeruginosa.

Topics: Anti-Bacterial Agents; Benzofurans; Drug Discovery; Flavonoids; Genes, Reporter; Green Fluorescent Proteins; Phenols; Pseudomonas aeruginosa; Resveratrol; Stilbenes; Type III Secretion Systems; Virulence; Yersinia pseudotuberculosis

Resveratrol was shown to exert anti-inflammatory effects in experimental models of psoriasis. Several natural oligomers of resveratrol have been extracted from plants. We investigated the antipsoriatic activity of topical administration of resveratrol oligomers and explored the effect of the number of resveratrol subunits on skin absorption to establish the structure-permeation relationship (SPR). Three oligomers, ε-viniferin (dimer), ampelopsin C (trimer) and vitisin A (tetramer), extracted from Vitis thunbergii root were compared to the resveratrol glycoside polydatin. Delivery to porcine skin was assessed in vitro using the Franz cell. Keratinocytes activated with imiquimod (IMQ) were utilized to evaluate cytokine/chemokine inhibition. Topical application of resveratrol and oligomers was characterized in vivo by assessing cutaneous absorption, skin physiology, proinflammatory mediator expression, and histopathology in IMQ-treated mice. Skin deposition decreased as the molecular size and lipophilicity of the permeants increased. Resveratrol exhibited highest absorption, followed by ε-viniferin. The monomers resveratrol and polydatin exhibited higher flux across skin than the larger oligomers. In silico modeling revealed the permeants that strongly interacted with stratum corneum (SC) lipids exhibited lower transport to viable skin and the receptor compartment. In vitro, resveratrol and its derivatives had comparable ability to inhibit IMQ-induced IL-1β, IL-6, and CXCL8 secretion in activated keratinocytes. In vivo, topically applied ε-viniferin accumulated at higher levels than resveratrol (0.067 versus 0.029 nmol/mg) in psoriasis-like mouse skin with impaired barrier capacity. Topical ε-viniferin alleviated psoriasiform symptoms and reduced IL-23 secretion (by 58% vs. 37%) more effectively than resveratrol. ε-Viniferin has potential as an anti-inflammatory agent to prevent or treat psoriasis.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Benzofurans; Chemistry, Pharmaceutical; Chemokines; Cytokines; Flavonoids; Glucosides; Inflammation Mediators; Keratinocytes; Mice; Phenols; Plant Extracts; Psoriasis; Resveratrol; Skin Absorption; Stilbenes; Swine

Hepatitis C virus (HCV) infection is responsible for various chronic inflammatory liver diseases. Here, we have identified a naturally occurring compound with anti-HCV activity and have elucidated its mode of antiviral action.. Luciferase reporter and real-time RT-PCR assays were used to measure HCV replication. Western blot, fluorescence-labelled HCV replicons and infectious clones were employed to quantitate expression levels of viral proteins. Resistant HCV mutant mapping, in vitro NS3 protease, helicase, NS5B polymerase and drug affinity responsive target stability assays were also used to study the antiviral mechanism.. A resveratrol tetramer, vitisin B from grapevine root extract showed high potency against HCV replication (EC50 = 6 nM) with relatively low cytotoxicity (EC50 >10 μM). Combined treatment of vitisin B with an NS5B polymerase inhibitor (sofosbuvir) exhibited a synergistic or at least additive antiviral activity. Analysis of a number of vitisin B-resistant HCV variants suggested an NS3 helicase as its potential target. We confirmed a direct binding between vitisin B and a purified NS3 helicase in vitro. Vitisin B was a potent inhibitor of a HCV NS3 helicase (IC50 = 3 nM). In vivo, Finally, we observed a preferred tissue distribution of vitisin B in the liver after i.p. injection in rats, at clinically attainable concentrations. Conclusion and Implications Vitisin B is one of the most potent HCV helicase inhibitors identified so far. Vitisin B is thus a prime candidate to be developed as the first HCV drug derived from natural products.

Topics: Animals; Benzofurans; Biological Products; Cell Line; Cell Survival; Dose-Response Relationship, Drug; Drug Synergism; Flavonoids; Hepacivirus; Humans; Phenols; Protein Binding; Rats; Resveratrol; RNA Helicases; Sofosbuvir; Stilbenes; Tissue Distribution; Viral Nonstructural Proteins; Virus Replication

A new tetramer oligostilbenoid possessing tetrahydrofuran ring, malaysianol C (1), was isolated from the acetone extract of the stem bark of Dryobalanops lanceolata, together with four known oligostilbenoids nepalensinol E (2), ϵ-viniferin (3), laevifonol (4), and ampelopsin F (5). The structures of isolated compounds were elucidated on the basis of spectral evidence. The antibacterial activity of the isolated compounds was evaluated using resazurin microtitre-plate assay, whereas the cytotoxic activity was tested using MTT assay. The plausible biogenetic routes of the isolated compounds are also discussed.

Topics: Anti-Bacterial Agents; Antineoplastic Agents, Phytogenic; Benzofurans; Dipterocarpaceae; Flavonoids; Furans; Humans; Malaysia; Molecular Structure; Plant Bark; Plant Extracts; Plant Stems; Stereoisomerism; Stilbenes

We present stilbenoid profiles of canes from 16 grapevines. Fifteen stilbenoids were obtained through isolation and structure identification using MS, NMR, and [α](D) or as commercial standards. An HPLC-UV method for the simultaneous quantification of nine of these stilbenoids was developed and applied to canes of Vitis amurensis, Vitis arizonica, Vitis berlandieri, Vitis betulifolia, Vitis cinerea, Vitis × champini, Vitis × doaniana, Vitis labrusca, Vitis candicans (syn. Vitis mustangensis), Vitis riparia, Vitis rupestris, Vitis vinifera, Muscadinia rotundifolia, and a V. vinifera × M. rotundifolia hybrid. In these species, E-ampelopsin E, E-amurensin B, E-piceid, E-piceatannol, E-resveratrol, E-resveratroloside, E-ε-viniferin, E-ω-viniferin, and E-vitisin B were quantified, when found in sufficient amounts. Total concentrations ranged from ~2.2 to 19.5 g/kg of dry weight. Additional stilbenoids, E-3,5,4'-trihydroxystilbene 2-C-glucoside, Z-ampelopsin E, Z-trans-miyabenol C, E-trans-miyabenol C, scirpusin A, and Z-vitisin B, were identified but not quantified. Our results indicate that canes, particularly those of non-vinifera species, have substantial quantities of valuable, health-promoting stilbenoids.

Topics: Benzofurans; Chromatography, High Pressure Liquid; Flavonoids; Glucosides; Magnetic Resonance Spectroscopy; Phenols; Resveratrol; Stilbenes; Vitis

This study aimed to investigate the antihypertensive effects of ethanolic extracts (EE) and compounds isolated from the small-leaf grape (Vitis thunbergii var. taiwaniana, VTT). The highest antiangiotensin-converting enzyme (anti-ACE) was found in stem-EE (IC50 was 69.5 μg/mL). In spontaneously hypertensive rats (SHRs), stem-EE effectively reduced blood pressure 24 h after administration of a single oral dose or when administered daily for 4 weeks. The isolated compounds, including (+)-vitisin A, ampelopsin C, and (+)-ε-viniferin, were shown to have anti-ACE and vasodilating effects against phenylephrine-induced tensions in an endothelium-intact aortic ring, with (+)-vitisin A being the most effective compound. Compared to control rats, SHRs showed significantly reduced systolic and diastolic blood pressures 24 h after a single oral dose of (+)-vitisin A (10 mg/kg) or captopril (2 mg/kg). These results suggest that the development of functional foods with VTT extracts may be beneficial for regulating blood pressure.

Topics: Administration, Oral; Angiotensins; Animals; Antihypertensive Agents; Benzofurans; Blood Pressure; Captopril; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Ethanol; Flavonoids; Male; Phenols; Plant Extracts; Plant Leaves; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Stilbenes; Vitis

Bioassay-guided high-performance liquid chromatography analysis of a MeOH extract of Iris clarkei seeds yielded the resveratrol-type oligomeric stilbenes, ampelopsin B and alpha-viniferin, which antagonize the action of 20-hydroxyecdysone; with a 20-hydroxyecdysone concentration of 50 nM, the ED50 values were 33 microM and 10 microM, respectively. The structures of these compounds were determined by spectroscopic analysis, notably ultraviolet, liquid secondary ion mass spectrometry and modern one- and two-dimensional nuclear magnetic resonance techniques.

Topics: Animals; Benzofurans; Cell Line; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Drosophila melanogaster; Ecdysterone; Flavonoids; Magnetic Resonance Spectroscopy; Mass Spectrometry; Plants; Radioimmunoassay; Resveratrol; Seeds; Stilbenes