Vaticanol B

Inhibitory Effects of Oligostilbenoids from the Bark of Shorea roxburghii on Malignant Melanoma Cell Growth: Implications for Novel Topical Anticancer Candidates.[Pubmed:27725445]

Biol Pharm Bull. 2016;39(10):1675-1682.

Human malignant melanomas remain associated with dismal prognosis due to their resistance to apoptosis and chemotherapy. There is growing interest in plant oligostilbenoids owing to their pleiotropic biological activities, including anti-inflammatory, antioxidant, and anticancer effects. Recent studies have demonstrated that resveratrol, a well-known stilbenoid from red wine, exhibits cell cycle-disrupting and apoptosis-inducing activities on melanoma cells. The objective of our study was to evaluate the anti-melanoma effect of oligostilbenoids isolated from the bark of Shorea roxburghii. Among the isolates, four resveratrol oligomers, i.e., (-)-hopeaphenol, Vaticanol B, hemsleyanol D, and (+)-alpha-viniferin, possessed more potent antiproliferative action than did resveratrol against SK-MEL-28 melanoma cells. Cell cycle analysis revealed that (-)-hopeaphenol, hemsleyanol D, and (+)-alpha-viniferin arrested cell division cycle at the G1 phase, whereas Vaticanol B had little effect on the cell cycle. In addition, cell proliferation assay also revealed that (+)-alpha-viniferin induced DNA damage followed by induction of apoptosis in SK-MEL-28 cells, which was confirmed by an increased expression of gamma-H2AX and cleaved caspase-3, respectively. The compounds Vaticanol B, hemsleyanol D, and resveratrol significantly increased the expression of p21, suggesting that they are able to block cell cycle progression. Moreover, these oligostilbenoids downmodulated cylin D1 expression and extracellular signal-regulated kinase (ERK) activation. Furthermore, hemsleyanol D, (+)-alpha-viniferin, and resveratrol significantly decreased the expression of cyclin B1, which could also suppress cell cycle progression. The present study thus suggests that these plant oligostilbenoids are effective as therapeutic or chemopreventive agents against melanoma.

Solving the supply of resveratrol tetramers from Papua New Guinean rainforest anisoptera species that inhibit bacterial type III secretion systems.[Pubmed:25405587]

J Nat Prod. 2014 Dec 26;77(12):2633-40.

The supply of (-)-hopeaphenol (1) was achieved via enzymatic biotransformation in order to provide material for preclinical investigation. High-throughput screening of a prefractionated natural product library aimed to identify compounds that inhibit the bacterial virulence type III secretion system (T3SS) identified several fractions derived from two Papua New Guinean Anisoptera species, showing activity against Yersinia pseudotuberculosis outer proteins E and H (YopE and YopH). Bioassay-directed isolation from the leaves of A. thurifera, and similarly A. polyandra, resulted in three known resveratrol tetramers, (-)-hopeaphenol (1), vatalbinoside A (2), and Vaticanol B (3). Compounds 1-3 displayed IC50 values of 8.8, 12.5, and 9.9 muM in a luminescent reporter-gene assay (YopE) and IC50 values of 2.9, 4.5, and 3.3 muM in an enzyme-based YopH assay, respectively, which suggested that they could potentially act against the T3SS in Yersinia. The structures of 1-3 were confirmed through a combination of spectrometric, chemical methods, and single-crystal X-ray structure determinations of the natural product 1 and the permethyl ether analogue of 3. The enzymatic hydrolysis of the beta-glycoside 2 to the aglycone 1 was achieved through biotransformation using the endogenous leaf enzymes. This significantly enhanced the yield of the target bioactive natural product from 0.08% to 1.3% and facilitates ADMET studies of (-)-hopeaphenol (1).

Malaysianol B, an oligostilbenoid derivative from Dryobalanops lanceolata.[Pubmed:22982329]

Fitoterapia. 2012 Dec;83(8):1569-75.

A new oligostilbenoid tetramer, malaysianol B (1), was isolated from the acetone extract of the stem bark of Dryobalanops lanceolata along with seven oligostilbenoids tetramers; hopeaphenol (2), stenophyllol A (3), nepalensinol B (4), Vaticanol B (5) and C (6), upunaphenol D (7), and flexuosol A (8). The structures of the isolated compounds were established on the basis of their spectroscopic data evidence. The antibacterial activity of the isolated compounds was evaluated using resazurin microtitre-plate assay.

Resveratrol derivatives from Vatica albiramis.[Pubmed:21467673]

Chem Pharm Bull (Tokyo). 2011;59(4):452-7.

Three new stilbene derivatives, albiraminols A (1) (resveratrol hexamer), B (2) (resveratrol dimer), and vatalbinoside F (3) (mono-glucoside of resveratrol dimer), along with malibatol were isolated from acetone soluble portions of the stem of Vatica albiramis. The structures of the isolates were established on the basis of spectroscopic analyses, including a detailed NMR spectroscopic investigation. The biosynthetic aspects of the isolates are discussed in this paper. Compound 1 is composed of tetrameric resveratrol (Vaticanol B (1A)) and dimeric resveratrol (1B) and is the first instance of the resveratrol derivative bearing a 5,6,11,12-tetrahydro-5,11-epoxydibenzo[a,e][8]annulene ring system. Compound 2 possesses a novel 4,5-dihydro-13-oxabenzo[3,4]azuleno[7,8,1-jkl]phenanthrene skeleton in the framework.

[Structures of oligostilbenoids in dipterocarpaceaeous plants and their biological activities].[Pubmed:21212619]

Yakugaku Zasshi. 2011 Jan;131(1):93-100.

Stilbenoids such as resveratrol (3,5,4'-trihydroxystilbene) have drawn much attention due to the diversity of structures and biological activities. These compounds are typically found as oligomers in a few plant families, such as Dipterocarpaceae, Vitaceae, Leguminosae, Cyperaceae, and Gnetaceae. The rich structural variation and multifunctional bioactivity make stilbenoid oligomers interesting targets for detailed phytochemical investigations. The oligomeric stilbenoids in Dipterocarpaceaeous plants have been my main focus of extensive structural investigation for the past decade. The tetramers of a resveratrol such as (-)-hopeaphenol, Vaticanol B, and vaticanol C are widespread and present in large quantities in Dipterocarpaceaeous plants. These are of special interest due to the large number of stereoisomers resulting from many asymmetric carbons and the various frameworks when a resveratrol is homogeneously oligomerized. The structural variations in Vatica, Vateria, Upuna, Cotylelobium, Dipterocarpus, Shorea, and Hopea genera have been examined and about 120 new resveratrol oligomers isolated to date. A detailed structural determination based on comprehensive spectral study has solved the difficulties in elucidation caused by the complicated stereochemistry that comprises diastereomers, epimers, enantiomers, and rotamers. The isolates bear a structural variation of fused cyclic frameworks including heterocyclic and bicyclo ring systems, and have been developed as a chemical library for drug discovery and chemical biology probes for the first time.

A high throughput live transparent animal bioassay to identify non-toxic small molecules or genes that regulate vertebrate fat metabolism for obesity drug development.[Pubmed:18752667]

Nutr Metab (Lond). 2008 Aug 27;5:23.

BACKGROUND: The alarming rise in the obesity epidemic and growing concern for the pathologic consequences of the metabolic syndrome warrant great need for development of obesity-related pharmacotherapeutics. The search for such therapeutics is severely limited by the slow throughput of animal models of obesity. Amenable to placement into a 96 well plate, zebrafish larvae have emerged as one of the highest throughput vertebrate model organisms for performing small molecule screens. A method for visually identifying non-toxic molecular effectors of fat metabolism using a live transparent vertebrate was developed. Given that increased levels of nicotinamide adenine dinucleotide (NAD) via deletion of CD38 have been shown to prevent high fat diet induced obesity in mice in a SIRT-1 dependent fashion we explored the possibility of directly applying NAD to zebrafish. METHODS: Zebrafish larvae were incubated with daily refreshing of nile red containing media starting from a developmental stage of equivalent fat content among siblings (3 days post-fertilization, dpf) and continuing with daily refreshing until 7 dpf. RESULTS: PPAR activators, beta-adrenergic agonists, SIRT-1 activators, and nicotinic acid treatment all caused predicted changes in fat, cholesterol, and gene expression consistent with a high degree of evolutionary conservation of fat metabolism signal transduction extending from man to zebrafish larvae. All changes in fat content were visually quantifiable in a relative fashion using live zebrafish larvae nile red fluorescence microscopy. Resveratrol treatment caused the greatest and most consistent loss of fat content. The resveratrol tetramer Vaticanol B caused loss of fat equivalent in potency to resveratrol alone. Significantly, the direct administration of NAD decreased fat content in zebrafish. Results from knockdown of a zebrafish G-PCR ortholog previously determined to decrease fat content in C. elegans support that future GPR142 antagonists may be effective non-toxic anti-obesity therapeutics. CONCLUSION: Owing to the apparently high level of evolutionary conservation of signal transduction pathways regulating lipid metabolism, the zebrafish can be useful for identifying non-toxic small molecules or pharmacological target gene products for developing molecular therapeutics for treating clinical obesity. Our results support the promising potential in applying NAD or resveratrol where the underlying target protein likely involves Sirtuin family member proteins. Furthermore data supports future studies focused on determining whether there is a high concentration window for resveratrol that is effective and non-toxic in high fat obesity murine models.

Oligostilbenoids from Shorea gibbosa and their cytotoxic properties against P-388 cells.[Pubmed:18404322]

J Nat Med. 2008 Apr;62(2):195-8.

A new oligostilbenoid derivative, diptoindonesin F (1), along with five known oligostilbenoids, (-)-ampelopsin A (2), (-)-alpha-viniferin (3), ampelopsin E (4), (-)-Vaticanol B (5), and (-)-hemsleyanol D (6), were isolated from the methanol extract of the tree bark of Shorea gibbosa. The structure of the new compound was determined based on the analysis of spectroscopic data, including UV, IR, NMR 1-D and 2-D, and mass spectra. Cytotoxic properties of the isolated oligostilbenoids were evaluated against murine leukemia P-388 cells with the result that compounds 2 and 4 showed the highest cytotoxicity.

Resveratrol tetramers with a C6-C3 or a C1 unit from Upuna borneensis.[Pubmed:17917303]

Chem Pharm Bull (Tokyo). 2007 Oct;55(10):1535-9.

Investigation of the chemical constituents in the stem of Upuna borneensis (Dipterocarpaceae) resulted in the isolation of three new resveratrol derivatives, upunaphenols L (1), M (2) (resveratrol tetramers with a C(6)-C(3) unit) and N (3) (resveratrol tetramer with a C(1) unit). The structures have the same partial structure as Vaticanol B (4). Upunaphenols L and M are new complex polyphenol compounds, lignostilbene. Their structures were determined by spectroscopic analysis including two dimensional NMR. Upunaphenol M was found to be an artifact generated by silica gel catalyzed methanolysis of 1.

Vaticanol B, a resveratrol tetramer, regulates endoplasmic reticulum stress and inflammation.[Pubmed:17475668]

Am J Physiol Cell Physiol. 2007 Jul;293(1):C411-8.

Enhanced endoplasmic reticulum (ER) stress has been implicated in various pathological situations including inflammation. During a search for compounds that regulate ER stress, we identified Vaticanol B, a tetramer of resveratrol, as an agent that protects against ER stress-induced cell death. Vaticanol B suppressed the induction of unfolded protein response-targeted genes such as glucose-regulated protein 78 (GRP78) and C/EBP-homologous protein (CHOP) after cells were treated with ER stressors. Analysis in the mouse macrophage cell line RAW 264.7 revealed that Vaticanol B also possesses a strong anti-inflammatory activity. Production of a variety of inflammatory modulators such as tumor necrosis factor-alpha, nitric oxide, and prostaglandin E(2) was inhibited by Vaticanol B to a much greater extent than by monomeric or dimeric resveratrol after exposure of cells to lipopolysaccharide. Further investigations to determine the common mechanisms underlying the regulation of ER stress and inflammation by Vaticanol B disclosed an important role for Vaticanol B in regulation of basic gene expression and in prevention of the protein leakage from the ER into the cytosol in both conditions. These results suggest that Vaticanol B is a novel anti-inflammatory agent that improves the ER environment by reducing the protein load on the ER and by maintaining the membrane integrity of the ER.

Cytotoxic resveratrol oligomers from the tree bark of Dipterocarpus hasseltii.[Pubmed:17071016]

Fitoterapia. 2006 Dec;77(7-8):550-5.

A new resveratrol tetramer, named diptoindonesin E, was isolated from the acetone extract of the tree bark of Dipterocarpus hasseltii, together with five known resveratrol oligomers (-)-epsilon-viniferin, laevifonol, (-)-alpha-viniferin, Vaticanol B, (-)-hopeaphenol, and a coumarin, scopoletin. The structures of these compounds were determined from spectroscopic evidence. Cytotoxicity test of the isolated compounds showed that hopeaphenol strongly inhibited murine leukemia P-388 cells.

Cytotoxic properties of oligostilbenoids from the tree barks of Hopea dryobalanoides.[Pubmed:16320615]

Z Naturforsch C J Biosci. 2005 Sep-Oct;60(9-10):723-7.

A new modified stilbene dimer, diptoindonesin D (1), was isolated from the acetone extract of the tree bark of Hopea dryobalanoides, together with seven known compounds, parviflorol (2), (-)-balanocarpol (3), heimiol A (4), hopeafuran (5), (+)-alpha-viniferin (6), Vaticanol B (7) and (-)-hopeaphenol (8). Cytotoxic properties of compounds 1-8 were evaluated against murine leukemia P-388 cells. Compound 8 was found to be the most active with IC50 of 5.7 microM.

Antitumor effect of stilbenoids from Vateria indica against allografted sarcoma S-180 in animal model.[Pubmed:14696625]

J Exp Ther Oncol. 2003 Sep-Oct;3(5):283-88.

Dipterocarpaceous plants contain various resveratrol oligomers that exhibit a variety of biological activities, such as antibacterial and antitumor effects. Previously, we found that vaticanol C, a resveratrol tetramer, exhibits strong cytotoxicity against various tumor cell lines. In the present study, we examined the antitumor activity of the ethanol extract from the stem bark of Vateria indica, which has been traditionally used for health and healing diseases as Ayurveda in India. High-performance liquid chromatography analysis showed that the extract contains bergenin, hopeaphenol, Vaticanol B, vaticanol C, and epsilon-viniferin. The in vitro assay displayed the extract's anti-cancer activity against mouse sarcoma 180 cells (IC50=29.5 microM). In the animal study, the tumor growth of sarcoma S-180 cells subcutaneously allografted in DDY mice was significantly retarded by oral administration of the extract (30 or 100 mg/kg body weight: P < 0.001). The extract did not show significant toxicity to mice even at a dosage of 1000 mg/kg body weight by daily oral administration for 28 days. These results demonstrated that the ethanol extract containing various stilbenoids from the stem bark of V. indica has the potent antitumor activity.