Flavonoids And Stilbenes

The Red Wine Diet

The Red Wine Diet

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Flavonoids and stilbenes are products from a cinnamoyl-CoA starter unit, with chain extension using three molecules of malonyl-CoA. This initially gives a polyketide (Figure 4.39), which, according to the nature of the enzyme responsible, can be folded in two different ways. These allow aldol or Claisen-like reactions to occur, generating aromatic rings as already seen in Chapter 3 (see page 80). Enzymes stilbene synthase and chalcone synthase couple a cinnamoyl-CoA unit with three malonyl-CoA units giving stilbenes, e.g. resveratrol or chalcones, e.g. naringenin-chalcone respectively.

Both structures nicely illustrate the different characteristic oxygenation patterns in aromatic rings derived from the acetate or shikimate pathways. With the stilbenes, it is noted that the terminal ester function is no longer present, and therefore hydrolysis and decarboxylation have also taken place during this transformation. No intermediates, e.g. carboxylated stilbenes, have been detected, and the transformation from cinnamoyl-CoA/malonyl-CoA to stilbene is catalysed by the single enzyme. Resveratrol 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

CoAS

CoAS

4-hydroxycinnamoyl-CoA

3 x malonyl-CoA

chain extension; acetate pathway with a cinnamoyl-CoA starter group

4-hydroxycinnamoyl-CoA

chain extension; acetate pathway with a cinnamoyl-CoA starter group

OH

resveratrol (a stilbene)

resveratrol (a stilbene)

NADPH

(reductase)

NADPH

(reductase)

OH O

OH O

aldol (stilbene synthase)

Claisen (chalcone synthase)

Claisen (chalcone synthase)

OH O

naringenin-chalcone

Claisen

OH O

naringenin-chalcone

isoliquiritigenin

(a chalcone) Michael-type nucleophilic (a chalcone) attack of OH on to a,ß-unsaturated ketone

OH O

naringenin (a flavanone)

OH O

naringenin (a flavanone)

liquiritigenin (a flavanone)

liquiritigenin (a flavanone)

Claisen

isoliquiritigenin

the cardiovascular benefits of moderate amounts of alcohol, and the beneficial antioxidant effects of flavonoids (see page 151), red wine has now emerged as an unlikely but most acceptable medicinal agent.

Chalcones act as precursors for a vast range of flavonoid derivatives found throughout the plant kingdom. Most contain a six-membered heterocyclic ring, formed by Michael-type nucle-ophilic attack of a phenol group on to the unsatu-rated ketone giving a flavanone, e.g. naringenin (Figure 4.39). This isomerization can occur chemically, acid conditions favouring the flavanone and basic conditions the chalcone, but in nature the reaction is enzyme catalysed and stereospe-cific, resulting in formation of a single fla-vanone enantiomer. Many flavonoid structures, e.g. liquiritigenin, have lost one of the hydroxyl groups, so that the acetate-derived aromatic ring has a resorcinol oxygenation pattern rather than the phloroglucinol system. This modification has been tracked down to the action of a reductase enzyme concomitant with the chalcone synthase, and thus isoliquiritigenin is produced rather than naringenin-chalcone. Flavanones can then give rise to many variants on this basic skeleton, e.g. flavones, flavonols, anthocyanidins, and cate-chins (Figure 4.40). Modifications to the hydroxy-lation patterns in the two aromatic rings may occur, generally at the flavanone or dihydroflavonol stage, and methylation, glycosylation, and dimethylal-lylation are also possible, increasing the range of compounds enormously. A high proportion of flavonoids occur naturally as water-soluble gly-cosides. Considerable quantities of flavonoids are consumed daily in our vegetable diet, so adverse biological effects on man are not particularly intense. Indeed, there is growing belief that some

OH O R = H, naringenin R = OH, eriodictyol (flavanones)

R O2

2-oxoglutarate

OH O R = H, naringenin R = OH, eriodictyol (flavanones)

2-oxoglutarate

2-oxoglutarate

R O2

2-oxoglutarate

OH OH O R = H, dihydrokaempferol R = OH, dihydroquercetin (dihydroflavonols)

NADPH

R O2

2-oxoglutarate

OH OH OH R = H, leucopelargonidin R = OH, leucocyanidin (flavandiols; leucoanthocyanidins)

OH OH OH R = H, leucopelargonidin R = OH, leucocyanidin (flavandiols; leucoanthocyanidins)

OH OH O

R = H, kaempferol

R = OH, quercetin

(flavonols)

OH OH

OH OH

R = H, pelargonidin R = OH, cyanidin (anthocyanidins)

epicatechin trimer

epicatechin trimer

Figure flavonoids are particularly beneficial, acting as antioxidants and giving protection against cardiovascular disease, certain forms of cancer, and, it is claimed, age-related degeneration of cell components. Their polyphenolic nature enables them to scavenge injurious free radicals such as superoxide and hydroxyl radicals. Quercetin in particular is almost always present in substantial amounts in plant tissues, and is a powerful antioxidant, chelating metals, scavenging free radicals, and preventing oxidation of low density lipoprotein. Flavonoids in red wine (quercetin, kaempferol, and anthocyanidins) and in tea (cate-chins and catechin gallate esters) are also demonstrated to be effective antioxidants. Flavonoids contribute to plant colours, yellows from chal-cones and flavonols, and reds, blues, and violets from anthocyanidins. Even the colourless materials, e.g. flavones, absorb strongly in the UV and are detectable by insects, probably aiding flower pollination. Catechins form small polymers (oligomers), the condensed tannins, e.g. the epicatechin trimer (Figure 4.41) which contribute astringency to our foods and drinks, as do the simpler gallotannins (see page 122), and are commercially important for tanning leather. Theaflavins, antioxidants found in fermented tea (see page 395), are dimeric catechin structures in which oxida-tive processes have led to formation of a seven-membered tropolone ring.

The flavonol glycoside rutin (Figure 4.42) from buckwheat (Fagopyrum esculentum; Polygo-naceae) and rue (Ruta graveolens; Rutaceae), and the flavanone glycoside hesperidin from Citrus

theaflavin

4.41

peels have been included in dietary supplements as vitamin P, and claimed to be of benefit in treating conditions characterized by capillary bleeding, but their therapeutic efficacy is far from conclusive. Neohesperidin (Figure 4.42) from bitter orange (Citrus aurantium; Rutaceae) and naringin from grapefruit peel (Citrus paradisi) are intensely bitter flavanone glycosides. It has been found that conversion of these compounds into dihy-drochalcones by hydrogenation in alkaline solution (Figure 4.43) produces a remarkable change to their taste, and the products are now intensely sweet, being some 300-1000 times as sweet as sucrose. These and other dihydrochalcones have been investigated as non-sugar sweetening agents.

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