Resveratrols

A short and efficient synthetic approach to hydroxy-substituted ( )-stil-benoids, as exemplified by the natural compound resveratrol (371b) via solid-phase CM, was reported by a Korean group (Scheme 71) [154]. When two different stilbenes were allowed to couple by catalyst C, all three kinds of possible stilbenes were obtained as an inseparable mixture. Anchoring 4-vinylphenol to Merrifield resin, followed by exposing the supported styrenyl ether 368 and diacetoxy styrene 369 (10 equiv) to the catalyst, inhibited self-metathesis of the supported substrate. Sequential separation of the homodimer formed from 369 by washing and subsequent cleavage of the resin 370 with acid provided (E)-stilbene 371a with complete stereocontrol in 61% yield. 

Other topical bleaching agents include arbu-tin, licorice, unsaturated fatty acids, soy extracts, serine protease inhibitors, ellagic acid and resveratrol. 

Along with these well-defined complexes, other protocols have been developed to directly involve imidazolinm salts with Pd sonrces and form the active catalysts in situ. One of the most popnlar consists of the nse of carbene precursors such as IMes HCl or IPr HCl with PdCOAc) or PdCdba) and a base [40]. A mixture of SIPr HCl and PdCOAc) in a 1 1 ratio was nsed for the synthesis of resveratrol analogues (MOM protected MOM = methoxymethylether) through decarbonylative Mizoroki-Heck coupling [41] (Scheme 6.9). 

Scheme 6.9 An in situ protocol applied to the synthesis of resveratrol analogues...

Andrus and Liu exploited a Pd(NHC) decarbonylative Heck coupling reaction in the total synthesis of resveratrol [59], The catalyst was formed in situ with Pd(OAc), and IPr HCl. 

Baur, JA and Sinclair, DA, 2006. Therapeutic potential of resveratrol The in vivo evidence. Nat Rev Drug Discov 5,493-506. 

Owing to the fact that ethyl ethers are especially effective substrates for CYP1A1 [184], the probe possesses an ethyl group on the phenolic oxygen of the trimethyl lock. In vitro, fluorescence was manifested by CYP1A1 isozyme with Kcat/KM 8.8 x 103 M-1s 1 and KM 0.09 pM. In cellulo, the probe revealed the induction of cytochrome P450 activity by the carcinogen 2,3,7,8-tetrachlorodi-benzo-p-dioxin (TCDD), and its repression by the chemoprotectant resveratrol. 

Levite D, Adrian M and Tamm L (2000), Preliminary results of resveratrol in wine of organic and conventional vineyards , in Wilier H and Meier U, Proceedings 6th International Congress on Organic Viticulture, 25-26 August 2000, Ackerstrasse, Germany, 256-257. 

This protocol could be extended to a range of different ,/i-unsaturated carbonyl compounds and either activated or deactivated aryl iodides [22], An application of related Heck chemistry to the synthesis of methylated resveratrol (3,4, 5-trihydroxy-( )-stilbene) is shown in Scheme 6.4 [23]. The phytoalexin resveratrol exhibits a variety of interesting biological and therapeutic properties, among them activity against several human cancer cell lines. Botella and Najera have shown that the trimethyl ether of resveratrol (Scheme 6.4) can be rapidly prepared by microwave-assisted Heck reaction of the appropriate aryl iodide and styrene derivatives, using the same oxime-derived palladacycle as indicated in Scheme 6.3. 

Scheme 6.4 Synthesis of resveratrol trimethyl ether via Heck arylation.

Frankel EN, Waterhouse AL and Kinsella JE. 1993. Inhibition of human LDL oxidation by resveratrol. Lancet 341 1103-1104. 

Stilbenes have a 1,2-diphenylethylene as their basic structure (C6-C2-C6). Resve-ratrol, the most widely known compound, contains three hydroxyl groups in the basic structure and is called 3,4, 5-trihydroxystilbene. In plants, piceid, the glucoside of resveratrol, is the major derivative of resveratrol. Stilbenes are present in plants as cis or trans isomers. Trans forms can be isomerized to cis forms by UV radiation (Lamuela-Raventos and others 1995). 

Mattivi F, Reniero F and Korhammer S. 1995. Isolation, characterization, and evolution in red wine vinification of resveratrol monomers. J Agric Food Chem 43(7)1820-1823. 

Romero-Perez AI, Ibern-Gomez M, Lamuela-Raventos RM and de la Torre-Boronat MC. 1999. Piceid, the major resveratrol derivative in grape juices. J Agric Food Chem 47(4) 1533—1536. 

Romero-Perez AI, Lamuela-Raventos RM, Andres-Lacueva C and Torre-Boronat MC. 2001. Method for the quantitative extraction of resveratrol and piceid isomers in grape berry skins. Effect of powdery mildew on the stilbene content. J Agric Food Chem 49(1) 210-215. 

Urpi-Sarda M, Jauregui O, Lamuela-Raventos RM, Jaeger W, Miksits M, Covas MI and Andres-Lacueva C. 2005. Uptake of diet resveratrol into the human low-density lipoprotein. Identification and quantification of resveratrol metabolites by liquid chromatography coupled with tandem mass spectrometry. Anal Chem 77(10) 3149—3155. 

Urpi-Sarda M, Zamora-Ros R, Lamuela-Raventos R, Cherubini A, Jauregui O, de la Torre R, Covas MI, Estruch R, Jaeger W and Andres-Lacueva C. 2007. HPLC-tandem mass spectrometric method to characterize resveratrol metabolism in humans. Clin Chem 53(2) 292-299. 

Zamora-Ros R, Andres-Lacueva C, Lamuela-Raventos RM, Berenguer T, Jakszyn P, Martinez C, Sanchez MJ, Navarro C, Chirlaque MD, Tormo MJ, Quiros JR, Amiano P, Dorronsoro M, Larranaga N, Barricarte A, Ardanaz E and Gonzalez CA. 2007. Concentrations of resveratrol and derivatives in foods and estimation of dietary intake in a Spanish population European Prospective Investigation into Cancer and Nutrition (EPIC)-Spain cohort. Br J Nutr 100(1) 188-196. 

Condensation of coumaric acid with malonic acid yields the basic chalcone and stilbane skeletons (see Fig. 3.6). Stilbenes are found in most vascular plants, where they exhibit fungicidal and to a lesser extent antibiotic properties. They function as both constitutive and inducible defense substances. Some stilbenes inhibit fungal spore germination and hyphal growth, whereas others are toxic to insects and parasitic nematodes (round-worms). They also possess antifeeding and nematicide properties in mammals. For example, resveratrol (a stilbene in red wine) suppresses tumor formation in mammals. 

Lopez-Nicolas JM and Garcia-CarmonaF. 2008. Aggregation state and pKa values of (E)-resveratrol as determined by fluorescence spectroscopy and UV-visible absorption. J Agric Food Chem 56(17) 7600-7605. 

Lopez-Nicolas JM, Nunez-Delicado E, Perez-Lopez AJ, Carbonell A and Cuadra-Crespo P. 2006. Determination of stoichiometric coefficients and apparent formation constants for (3-cyclodextrin complexes of trans-resveratrol using reversed-phase liquid chromatography. J Chromatogr A 1135 158—165. 

Olas and Wachowicz (2002) investigated the effects of tranx-resveratrol and vitamin C on oxidative stress in blood platelets. The level of 02 in control blood platelets and platelets incubated with resveratrol or vitamin C was recorded using a chemiluminescence method. On the other hand, Oh and others (2006) reported the x02 quenching activities of various freshly squeezed fruit and vegetable juices by measuring their inhibitory effects on the rubrene oxidation induced by x02 from disproportionation of hydrogen peroxide by sodium molybdate in a microemulsion system. 

Olas B and Wachowicz B. 2002. Resveratrol and vitamin C as antioxidants in blood platelets. Thromb Res 106(2) 143-148. 

A similar effect was observed in other fruits and vegetables, where UV-C treated strawberries showed a higher increment of phenols and PAL activity 12 hours after treatment than unirradiated (control)(Pan and others 2004), which could be the reason for the increment in total phenol constituents (Lancaster and others 2000). UV-C and UV-B caused a two- and threefold increase in content of resveratrol (a grape phenol constituent). Thus, mature Napoleon grapes that had been irradiated with UV-C light can provide up to 3 mg of resveratrol per serving (Cantos and others 2001). Therefore, UV-C treatments clearly cause a benefit effect, increasing total phenol content, which can be mainly attributed to the increment of PAL activity. 

Cantos E, Espin JC and Tomas-Barberan FA. 2001. Postharvest induction modeling method using UV irradiation pulses for obtaining resveratrol-enriched table grapes A new functional fruit J Agric Food Chem 49(10) 5052-5058. 

People in France eat a lot of fatty foods but suffer less from fatal heart strokes than people in the northern regions of Europe or in North America, where wine is not consumed on a regular basis ( French paradox ). There is an increased favorable effect from red wine. The unique cardioprotective properties of red wine are due to the action of flavonoids, which are minimal in white wine. The best-researched flavonoids are resveratrol and quercetin, which confer antioxidant properties more potent than a-tocopherol. 

Classic antioxidants, vitamin E, vitamin C, and others can suppress the activation of apoptosis. For example, ascorbic acid prevented cytochrome c release and caspase activation in human leukemia cells exposed to hydrogen peroxide [128], Pretreatment with A -acctylcystcinc, ascorbate, and vitamin E decreased homocysteine thiolactone-induced apoptosis in human promyelocytic leukemia HL-60 cells [129]. Resveratrol protected rat brain mitochondria from anoxia-reoxygenation damage by the inhibition of cytochrome c release and the reduction of superoxide production [130]. However, it should be mentioned that the proapoptotic effect of ascorbate, gallic acid, or epigallocatechin gallate has been shown in the same human promyelocytic leukemia cells [131]. 

There are numerous other polyphenolic compounds possessing in vitro and in vivo antioxidative activity. Several examples of these compounds are cited below. One of nonflavonoid polyphenols of particular interest is resveratrol (3,5,4 -trihydroxy-Znmv-stilbcne, Figure 29.8), which has been identified as a potential cancer chemopreventive agent and an antimutagen [182]. It has been found that resveratrol is the efficient inhibitor of cyclooxygenase and the inhibitor of free radical-mediated cellular processes. For example, resveratrol is a better free radical scavenger than a-tocopherol or ascorbic acid but has nearly the same activity as... 

A comparison with its different derivatives shows that 4 -OH is not a sole reactive group responsible for the antioxidant activity of resveratrol, while the trans-conformation is absolutely necessary for the inhibition of cell proliferation [187], However, similar to flavonoids resveratrol may exhibit prooxidant properties, for example to promote DNA fragmentation, although its prooxidant activity seems to be unimportant under physiological conditions [188],... 

In addition to their possible prooxidant activity (see above) polyphenols and flavonoids may influence cancer cells via their antioxidant properties. Recently, Jang et al. [219] studied cancer chemopreventive activity of resveratrol, a natural polyphenolic compound derived from grapes (Chapter 29). These authors showed that resveratrol inhibited the development of preneoplastic lesions in carcinogen-treated mouse mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer model. Flavonoids silymarin and silibinin also exhibited antitumor-promoting effects at the stage I tumor promotion in mouse skin [220] and manifested antiproliferative effects in rat prostate cancer cells [221]. 

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