Derivatives resveratrol

In a recent study, Howitz et al. [2003] showed red-wine-derived resveratrol could increase the SIRT1 activity 13-fold by inhibiting apoptotic cell death through the deacetylation of p53. In the same study they also showed that resveratrol extended the life span by 70% by mimicking calorie restriction by stimulating SIR2 in the yeast cells and, thus, increased DNA stability. In another very recent study on calorie restriction experiments on monkey and other mammalian species, the concept of wine as fountain of youth was reconfirmed [Kujoth et al., 2005],... 

Stojanovic S, Brede O. (2002) Elementary reactions of the antioxidant action of trans-stilbene derivatives Resveratrol, pinosylvin and 4-hydroxystilbene. Phys Chem Chem Phys A 757-764. 

It is interesting to note that in vitro incubations of 1 with horseradish peroxidase [108] as well as with growing B. cinerea cultures [106] and B. cinerea culture medium filtrates [107] have yielded a unique resveratrol oligomer known as the resveratrol trans-dehydrodimer (42). This dimer shares a similar structural design with the more common plant-derived resveratrol dimer, f-viniferin (11). It has been proposed that the B. cinerea mediated transformation of 1 to 42 may be facilitated by other stilbene oxidizing enzymes such as copper-containing laccases [106,107]. 

Addition. Resveratrol. The biosynthetic pathway to resveratrol diverges from the flavonoid pathway after the third malonyl-CoA condensation. Cyclization of the common polyketide intermediate catalyzed by resveratrol synthase yields the stilbene derivative resveratrol, whereas the same intermediate catalyzed by chal-cone synthase yields the common flavonoid precursor chalcone (Fig. 6.8). Resveratrol, well known as a functional food ingredient (e.g., grape skin, red wine) with strong antioxidant properties (cardiovascular protection), and its 3-glucopyranoside piceid turned out to be also present in the skin of tomato fruits, S. lycopersicum (Ragab et al. 2006). 

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. 

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). 

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. 

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. 

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]. 

Members of the CHS/STS family of condensing enzymes are relatively modest-sized proteins of 40-47 kDa that function as homodimers. Each enzyme typically reacts with a cinnamoyl-CoA starter unit and catalyzes three successive chain extensions with reactive acetyl groups derived from enzyme catalyzed decarboxylation of malonyl-CoA.11 Release of the resultant tetraketide together with or prior to polyketide chain cyclization and/or decarboxylation yields chalcone or resveratrol (a stilbene). Notably, CHS and STS catalyze identical reactions up to the formation of the intermediate tetraketide. Divergence occurs during the termination step of the biosynthetic cascade as each tetraketide intermediate undergoes a distinct cyclization reaction (Fig. 12.2). 

Resveratrol is another type of polyphenol, a stilbene derivative, that has assumed greater relevance in recent years as a constituent of grapes and wine, as well as other food products, with antioxidant, anti-inflammatory, anti-platelet, and cancer preventative properties. Coupled with the cardiovascular benefits of moderate amounts of alcohol, and the beneficial antioxidant effects of flavonoids, red wine has now emerged as an unlikely but most acceptable medicinal agent. 

When the dehydration of 39 was carried out (H3PO4 or DMSO under reflux) instead of its dehydroxylation, a different class of stilbene derivatives, such as pinosilvine 44, resveratrol 45 or piceatannol 46, were easily obtained . From these compounds, resver-atrol has shown very potent anticancer properties in vivo, this activity being proven in rats . 

Set detector at 280 nm for catechins (flavan-3-ols), naringin, and benzoic acid derivatives 320 nm for chlorogenic acid, resveratrol, and hydroxycinnamic acids 370 nm for flavones and flavonols and 520 nm for anthocyanins and anthocyanidins (see Table 11.3.1). 

For the red wines (82-84), which were injected directly into the HPLC without sample preparation, a ternary-gradient system using aqueous acetic acid (1% and 5% or 6%), and acidified acetonitrile (acetonitrile-acetic acid-water, 30 5 6) was used for cinnamic acid derivatives, catechins, flavonols, flavonol glycosides, and proanthocyanidins. Due to the large number of peaks, the gradient was extended to 150 min for the resolution of many peaks of important phenolics. This direct injection method was able to separate phenolic acids and esters, catechins, proanthocyanidins, flavonols, flavonol glycosides, and other compounds (such as tyrosol, and rrans-resveratrol) in wine in a single analysis. However, use of acetic acid did not permit the detector (PDA) to be used to record the UV spectra of phenolics below 240 nm (84). 

G., Moon, R. C., and Pezzuto, J. M., 1997, Cancer chemopreventive activity of resveratrol, a natural product derived lfom grapes, Science 275 218-220. 

The evaluation of pharmacokinetic analysis of resveratrol was carried out in different animal models such as rats, mice, and rabbits [Asensi et al., 2002 Chen et al., 2007 Juan et al., 2002 Marier et al., 2002 Sale et al., 2004] furthermore, pharmacokinetic analysis was also evaluated with other resveratrol derivatives such as piceid [Lv et al., 2006 Zhou et al., 2007], a Smilax china root extract [Huang et al., 2008], 3,4,5,4 -tetramethoxystilbene [Sale et al., 2004], piceatan-nol, pinosylvin, and rhapontigenin [Roupe et al., 2006] (Table 13.4). 

Resveratrol plays critical roles in signaling mechanisms of different tumors. Currently, it is well documented that many factors play a role in the patho-mechanisms of cancers. However, the exact mechanisms are not precisely known. If resveratrol could provoke an influence in only one pathological factor, then the effects of anticancer drugs (i.e., in combination therapy) might beneficially modulate the signal transduction pathways. This is the basic reason to investigate the precise mechanisms and effects of resveratrol and its derivatives on various cancers. 

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