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At least 865 records · Page 48Linked to original sources
PubMed2003

Stilbenecarboxylate biosynthesis: a new function in the family of chalcone synthase-related proteins.

Chalcone (CHS), stilbene (STS) synthases, and related proteins are key enzymes in the biosynthesis of many secondary plant products. Precursor feeding studies and mechanistic rationalization suggest that stilbenecarboxylates might also be synthesized by plant type III polyketide synthases; however, the enzyme activity leading to retention of the carboxyl moiety in a stilbene backbone has not yet been demonstrated. Hydrangea macrophylla L. (Garden Hortensia) contains stilbenecarboxylates (hydrangeic acid and lunularic acid) that are derived from 4-coumaroyl and dihydro-4-coumaroyl starter residues, respectively. We used homology-based techniques to clone CHS-related sequences, and the enzyme functions were investigated with recombinant proteins. Sequences for two proteins were obtained. One was identified as CHS. The other shared 65-70% identity with CHSs and other family members. The purified recombinant protein had stilbenecarboxylate synthase (STCS) activity with dihydro-4-coumaroyl-CoA, but not with 4-coumaroyl-CoA or other substrates. We propose that the enzyme is involved in the biosynthesis of lunularic acid. It is the first example of a STS-type reaction that does not lose the terminal carboxyl group during the ring folding to the end product. Comparisons with CHS, STS, and a pyrone synthase showed that it is the only enzyme exerting a tight control over decarboxylation reactions. The protein contains unusual residues in positions highly conserved in other CHS-related proteins, and mutagenesis studies suggest that they are important for the structure or/and the catalytic activity. The formation of the natural products in vivo requires a reducing step, and we discuss the possibility that the absence of a reductase in the in vitro reactions may be responsible for the failure to obtain stilbenecarboxylates from substrates like 4-coumaroyl-CoA.

Acyltransferases↗
PubMed2003

Differentiation-dependent levels of benzofuran-type resveratrol dimers in root cultures of Anigozanthos preissii.

The level of secondary compounds formed by sterile root cultures of Anigozanthos preissii depends on the differentiation state. Cultures showing shoot formation and accelerated growth are depleted in stilbenes, stilbene glucosides, and phenylphenalenones. Three glucosides of anigopreissin A, a benzofuran-type resveratrol dimer, were isolated from slow-growing cultures and their structures elucidated by spectrometric methods.

Benzofurans↗
PubMed1989

Antimitotic natural products combretastatin A-4 and combretastatin A-2: studies on the mechanism of their inhibition of the binding of colchicine to tubulin.

Combretastatin A-4 (CS-A4), 3,4,5-trimethoxy-3'-hydroxy-4'-methoxy-(Z)-stilbene, and combretastatin A-2 (CS-A2), 3,4-(methylenedioxy)-5-methoxy-3'-hydroxy-4'-methoxy-(Z)-stilbene, are structurally simple natural products isolated from the South African tree Combretum caffrum. They inhibit mitosis and microtubule assembly and are competitive inhibitors of the binding of colchicine to tubulin [Lin et al. (1988) Mol. Pharmacol. 34, 200-208]. In contrast to colchicine, drug effects on tubulin were not enhanced by preincubating CS-A4 or CS-A2 with the protein. The mechanism of their binding to tubulin was examined indirectly by evaluating their effects on the binding of radiolabeled colchicine to the protein. These studies demonstrated rapid binding of both compounds to tubulin even at 0 degrees C (binding was complete at the earliest times examined), in contrast to the relatively slow and temperature-dependent binding of colchicine. Although the binding of the C. caffrum compounds to tubulin was quite tight, permitting ready isolation of near-stoichiometric amounts of drug-tubulin complex even in the absence of free drug, both CS-A4 and CS-A2 dissociated rapidly from tubulin in the presence of high concentrations of radiolabeled colchicine. Apparent rate constants for drug dissociation from tubulin at 37 degrees C were 3.2 x 10(-3) s-1 for CS-A4, 4.8 x 10(-3) s-1 for CS-A2, and 2.9 x 10(-5) s-1 for colchicine (half-lives of 3.6, 2.4, and 405 min, respectively). Thus, the effectiveness of the C. caffrum compounds as antimitotic agents appears to derive primarily from the rapidity of their binding to tubulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

How much pi-stacking do DNA termini seek? Solution structure of a self-complementary DNA hexamer with trimethoxystilbenes capping the terminal base pairs.

The exposed terminal base pairs of DNA duplexes are nonclassical binding sites for small molecules. Instead, small molecules usually prefer intercalation or minor groove binding. Here we report the solution structure of the DNA duplex (TMS-TGCGCA)(2), where TMS denotes trimethoxystilbene carboxamides that are 5'-tethered to the DNA. The stilbenes, for which intercalation is conformationally accessible, stack on the terminal T:A base pairs of an undisturbed B-form duplex. Two conformations, differing by the orientation of the stilbene relative to the terminal base pair, are observed, indicating that the flip rate is slow for the pi-stacked aromatic ring system. The trimethoxystilbene is known to greatly increase base pairing fidelity at the terminus. Here we show that it gauges the size of the T:A base pair by embracing the 2'-methylene group of the terminal dA residue of the unmodified terminus with its methoxy "arms", but that it does not engage the entire base pair in pi-stacking. Mismatched base pairs with their altered geometry will not allow for the same embracing interaction. On the basis of the current structure, a trimethoxychrysene carboxamide is proposed as a ligand with increased pi-stacking surface and possible applications as improved fidelity-enhancing element.

Base Pairing↗
PubMed1996

Incorporation of a non-nucleotide bridge into hairpin oligonucleotides capable of high-affinity binding to the Rev protein of HIV-1.

A bridge containing a rigid trans-stilbene group, -P(O)(O-)O(CH2)3NHC(O)- C6H4-CH=CHC6H4C(O)NH(CH2)3OP(O)(O-)-, has been incorporated into several oligonucleotide sequences based on the minimal Rev Binding Element (RBE) of HIV-1. This bridge was found to be effective as a UUCG tetraloop in stabilizing short RNA duplex structures containing mismatched bases and bulged out nucleotide residues and to be more effective than either a TTTT loop or a triethyleneglycol linker in stabilizing similar DNA structures. Evaluation of stilbene-containing RNA RBE sequences of varying length for their ability to bind the Rev protein of HIV-1 showed that a 22-nucleotide stilbenedicarboxamide conjugate bound Rev almost as well as a 94-base fragment of the Rev Responsive Element (RRE). A DNA hairpin mimetic with the same sequence was incapable of Rev binding. Taken together, these experiments serve as an example for how in vitro selection and chemical modification can be combined to generate high-affinity mimetics of nucleic acid sequence and structure.

Base Sequence↗
PubMed1997

Plant polyketide synthases leading to stilbenoids have a domain catalyzing malonyl-CoA:CO2 exchange, malonyl-CoA decarboxylation, and covalent enzyme modification and a site for chain lengthening.

Stilbene synthases and the related bibenzyl synthases are plant polyketide synthases whose biological functions lie in the formation of antimicrobial phytoalexins. The formation of hydroxystilbenes from one molecule of acyl-CoA and three molecules of malonyl-CoA is catalyzed by a homodimeric 90 kDa protein and includes Claisen condensations and cleavage of a thioester followed by decarboxylation. Combining inhibitor studies, protein modifications, and site-directed mutagenesis, we were able to differentiate between the binding sites for malonyl-CoA and the regions responsible for the selection of the primer, p-coumaroyl-CoA or m-hydroxyphenylpropionyl-CoA, respectively. Mutations in the C-terminal part of the molecule or modification by photolabeling with p-azidocinnamoyl-CoA influence the overall reaction, the formation of hydroxystilbenes, but leave partial reactions, such as the malonyl-CoA:CO2 exchange and the malonyl-CoA-dependent modification of the enzyme, unaffected. Data obtained with several kinds of stilbene synthase and mutant forms suggest that the malonyl-CoA-dependent covalent modification takes place at a cysteine residue in the N-terminal part of the enzyme. Mutations in the C-terminal half of the enzyme molecule do not interfere with the malonyl-CoA-dependent reactions.

Acyl Coenzyme A↗
PubMed2003

Stepwise evolution of the structure and electronic properties of DNA.

The optical properties of a family of duplex DNA conjugates possessing from 1 to 11 A:T base pairs and covalently attached stilbene chromophores at both ends have been investigated. As few as from two to four base bairs are needed to establish base-pair absorption and circular dichroism spectra similar to those of longer oligomers. The stilbene chromophores exhibit exciton-coupled circular dichroism, which can be observed even with 11 intervening base pairs, a distance of ca. 40 A. The dependence of the sign and amplitude of these spectra reveals the ability of B-DNA to serve as a helical ruler.

Circular Dichroism↗
PubMed2001

Resveratrol and other phenolics from the bark of Yucca schidigera roezl.

Five phenolic constituents have been identified in Yucca schidigera bark, and their structures were established by spectral (FABMS and NMR) experiments. These included two known stilbenes, trans-3,4',5-trihydroxystilbene (resveratrol) and trans-3,3',5,5'-tetrahydroxy-4'-methoxystilbene, as well as three novel compounds, yuccaols A, B, and C, with spiro-structures rarely occurring in the plant kingdom. It is suggested that yuccaols A-C are biosynthethized via attachment of a stilbenic derivative to the carbocationic intermediate of the oxidative flavanone-flavonol conversion.

Flavonoids↗
PubMed2002

Plant foods and herbal sources of resveratrol.

Stilbenes, in particular trans-resveratrol and its glucoside, are widely reported to be beneficial to health, having been shown to possess antioxidative, anticarcinogenic, and antitumor properties. Major dietary sources include grapes, wine, peanuts, and soy; however, they can also be introduced into the diet through Itadori tea, which has long been used in Japan and China as a traditional herbal remedy for heart disease and strokes. Analysis of grapes, peanuts, and Itadori tea shows that they contain mainly trans-resveratrol glucoside. In contrast, red wines are primarily a source of the aglycones cis- and trans-resveratrol. While peanuts and grapes contain low levels of the stilbenes, Itadori tea and red wine both supply relatively high concentrations of resveratrol. For people who do not consume alcohol, Itadori tea may be a suitable substitute for red wine. However, further study on the potential biological effects of other endogenous compounds in Itadori tea is required and there is also a need for more information on the absorption and in vivo biomedical actions of free and conjugated resveratrol.

Animals↗
PubMed2002

Phytoalexins from the Vitaceae: biosynthesis, phytoalexin gene expression in transgenic plants, antifungal activity, and metabolism.

Resistance of plants to infection by phytopathogenic microorganisms is the result of multiple defense reactions comprising both constitutive and inducible barriers. In grapevine, the most frequently observed and best characterized defense mechanisms are the accumulation of phytoalexins and the synthesis of PR-proteins. Particular attention has been given here to stilbene phytoalexins produced by Vitaceae, specifically, their pathway of biosynthesis (including stilbene phytoalexin gene transfer experiments to other plants) and their biological activity together with fungal metabolism.

Acyltransferases↗
PubMed2005

Cellular uptake and efflux of trans-piceid and its aglycone trans-resveratrol on the apical membrane of human intestinal Caco-2 cells.

Two stilbenes (trans-piceid and its aglycone trans-resveratrol) were investigated in the uptake across the apical membrane of the human intestinal cell line Caco-2 in order to determine their mechanisms of transport. The uptake was quantified using a reverse phase high-performance liquid chromatography method with fluorescence detection. The rate of cellular accumulation in the cells was found to be higher for trans-resveratrol than for trans-piceid. In addition, trans-resveratrol uses passive transport to cross the apical membrane of the cells, whereas the transport of trans-piceid is likely active. With regard to the mechanisms of transport, the involvement of the active transporter SGLT1 in the absorption of trans-piceid was deduced using various inhibitors directly or indirectly exploiting the activity of this transporter (glucose, phlorizin, and ouabain). Moreover, we investigated the involvement of the multidrug-related protein 2 (MRP2), an efflux pump present on the apical membrane, in stilbene efflux by Caco-2 cells. The effect of MK-571 (an MRP inhibitor) seems to implicate MRP2 as responsible for apical efflux of trans-piceid and trans-resveratrol.

Biological Transport↗
PubMed2004

Determination of piceid and resveratrol in Spanish wines deriving from Monastrell (Vitis vinifera L.) grape variety.

The presence of stilbenes in wine is becoming an important issue due to their claimed relation to a low incidence in coronary diseases and their increasing implication as cancer chemopreventive and neuroprotective agents. Total resveratrol content, quantified as glucoside and aglycone forms of resveratrol, has been determined in a survey of 45 Monastrell monovarietal Spanish red wine types (around 135 wine samples), belonging to Alicante and Bullas appellations. The average between ratio glucoside/aglycone forms of resveratrol in these wines was considerably high, ranging from 82 to 91% of resveratrol in its glycosidic form. This characteristic was observed in a high percentage of the studied wines, which were made under different winemaking procedures, and from different vintages (1995-2002). In addition, wines made using macerative fermentations with double amount of solid parts ("doble pasta") reached the highest levels of total stilbene content expressed as resveratrol equivalent, i.e., 30 mg/L (average of 18.8 mg/L). It can be concluded that high resveratrol glucoside concentration and low free isomer content can be considered characteristics of the Monastrell variety, as it happens to red wines deriving from other varieties grown at warm climates. This fact, also observed for other French and Portuguese red varieties, might play an important role in food habits involving these types of wines.

Chromatography, High Pressure Liquid↗
PubMed2006

Detection and quantitation of resveratrol in tomato fruit (Lycopersicon esculentum Mill.).

Resveratrol is a stilbene phytoalexin well-known for its presence in grape, wine, and peanut. As a result of its antioxidant and chemopreventative properties, it has gained much attention as a functional food ingredient. A gas chromatography-mass spectrometry method for the detection of resveratrol, its 3-glucopyranoside piceid, and the cis isomers of both compounds has been developed and used to quantitate the levels of these compounds in the skin of commercially available tomato fruit (Lycopersicon esculentum Mill.). The resveratrol concentration remains relatively stable during fruit maturation, reaching a maximum concentration in the skin of 18.4 +/- 1.6 microg/g dry weight at 4 weeks postbreaker. No stilbenes were detected in the flesh of tomato fruit.

Anticarcinogenic Agents↗
PubMed2000

Antineoplastic agents 440. Asymmetric synthesis and evaluation of the combretastatin A-1 SAR probes (1S,2S)- and (1R,2R)-1, 2-dihydroxy- 1-(2',3'-dihydroxy-4'-methoxyphenyl)-2-(3' ',4' ',5' '-trimethoxyphenyl)-ethane.

The synthetic (E)-isomer (3b) of natural combretastatin A-1 (1a) isolated from the African bushwillow Combretum caffrum was the focus of chiral hydroxylation (Sharpless) reactions as part of a structure-activity relationship study. The resulting (R,R)- and (S,S, )-diols (6 and 7) and synthetic intermediates were evaluated against a series of cancer cell lines, microorganisms, and tubulin. Chiral diols 6 and 7 showed increased activity against the P-388 murine lymphocytic leukemia cell line with ED(50) values of 3.9 and 2.9 microg/mL, respectively, when compared to the precursor (E)-stilbene 3b. In contrast, (E)-stilbene 3b exhibited more potent antibiotic activity than the chiral diols (6 and 7). Both diols, (R,R)-6 and (S, S)-7, displayed less cancer cell growth inhibition and less antibiotic activity than did natural combretastatin A-1 (1a) (P-388 ED(50) 0.25 microg/mL).

Animals↗
PubMed2005

Bioactive constituents from Boswellia papyrifera.

Phytochemical investigation of the stem bark extract of Boswellia papyrifera afforded two new stilbene glycosides, trans-4',5-dihydroxy-3-methoxystilbene-5-O-{alpha-L-rhamnopyranosyl-(1-->2)-[alpha-L-rhamnopyranosyl-(1-->6)]-beta-D-glucopyranoside (1), trans-4',5-dihydroxy-3-methoxystilbene-5-O-[alpha-L-rhamnopyranosyl-(1-->6)]-beta-D-glucopyranoside (2), and a new triterpene, 3alpha-acetoxy-27-hydroxylup-20(29)-en-24-oic acid (3), along with five known compounds, 11-keto-beta-boswellic acid (4), beta-elemonic acid (7), 3alpha-acetoxy-11-keto-beta-boswellic acid (8), beta-boswellic acid (9), and beta-sitosterol (10). The stilbene glycosides exhibited significant inhibition of phosphodiesterase I and xanthine oxidase. The triterpenes (3-9) exhibited prolyl endopeptidase inhibitory activities.

Boswellia↗
PubMed1995

Development of chloride channel modulators.

Chloride channels are ubiquitously distributed, biophysically varied and functionally diverse. Despite the known contribution of chloride channels to the physiology of various cell types and the pathology of several diseases, high affinity ligands are not available to study these channels. Here we report the iterative and integrated use of ion channel kinetic analysis and computational chemical methods in the development of high affinity blockers of the outwardly rectifying chloride channel (ORCC). Kinetic analysis, with emphasis on estimation of the block time constant as determined from critical closed time plots, was used to guide the synthesis of new disulfonic stilbene derivatives. Computational chemical methods were used to deduce the important features of the disulfonic stilbene molecule necessary for potent blockade of ORCC and ultimately led to the discovery of the calixarenes. Para-sulfonated calixarenes were found to be potent blockers of ORCC with subnanomolar inhibition constants and exceptionally long block times.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗
PubMed2005

Alpha- and beta-stilbenosides as base-pair surrogates in DNA hairpins.

The synthesis, structure, and optical spectroscopy of hairpin oligonucleotide conjugates possessing synthetic stilbene C-nucleosides (stilbenosides) are reported. Synthetic methods for selective preparation of both the alpha- and beta-stilbenosides have been developed. Both anomers are effective in stabilizing hairpin structures when used as capping groups at the open end of the hairpin base-pair domain. However, only the beta-anomer effectively stabilizes the hairpin structure when located in the interior of the base-pair domain opposite an abasic site. Similar results are obtained for hairpins possessing two stilbenosides, either adjacent to each other or with one intervening base-pair. Molecular dynamics simulations are employed to obtain averaged structures for these conjugates. The calculated structures for the capped hairpins formed with either anomer show effective pi-stacking with the adjacent base-pair. The calculated structures for the internal stilbenosides show that the alpha- and beta-anomers form extrahelical and intrahelical structures, respectively. The relative orientations of the two stilbenes in the bis-stilbenosides have been studied using a combination of exciton-coupled circular dichroism spectroscopy and molecular modeling.

Base Pairing↗
PubMed1995

Sulfate transport mediated by the mammalian anion exchangers in reconstituted proteoliposomes.

The kinetic properties of sulfate transport mediated by the anion exchangers AE1 and AE2 have been examined. Microsomes isolated from HEK cells transiently overexpressing either protein were reconstituted in unilamellar, 200-600-nm diameter proteoliposomes. Transport mediated by the exchangers was monitored by loading the reconstituted proteoliposomes with the slowly transportable anion SO4(2-) using [35S]SO4(2-) as a tracer and performing [35S]SO4(2-)/SO4(2-) exchange. The following data suggest that AE1 and AE2 have been functionally reconstituted: (i) the rate of SO4(2-) transport in AE1 and AE2 containing proteoliposomes was 10-20 times higher than in proteoliposomes derived from control microsomes; (ii) the transport of SO4(2-) was strongly dependent on the presence of a trans anion; and (iii) the anion exchanger inhibitors, 4,4'-diisothiocyanostilbene-2,2'-disulfonate (DIDS) and 4,4'-dinitrostilbene-2,2'-di-sulfonate (DIDS) totally abolished SO4(2-) transport. furthermore, DIDS inhibits SO4(2-) transport only when occluded inside the vesicles, indicating a uniform, asymmetrical, inside-out orientation of the reconstituted exchangers. The Ki values of the stilbene disulfonate compound DNDS were 2.5 and 4 microM for AE1 and AE2, respectively, suggesting that the two exchangers possess similar high affinity sites for stilbene compounds. Both AE1 and AE2 showed the same steep pH dependence of sulfate transport, which was maximal at pH 5.5 and reduced to less than 10% (of the value at pH 5.5) at pH 8.5, suggesting that an acidic residue shared by AE1 and AE2 participates in the pH regulation of sulfate transport.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗