Phenols

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Chapter 21 Phenols

Chapter contents

Shikimic acid 150

Abridged phenylpropanoids 150

Simple phenols 151

Quinones 152

Xanthones 155

Coumarins 156

Flavonoids 157

Tannins 161

Lignin 165

Phenols constitute probably the largest group of plant secondary metabolites, varying in size from a simple structure with an aromatic ring to complex ones such as lignins. Although many of the essential oils are terpenes, some are phenolic compounds, for example thymol from Thymus spp. (thyme) (Figure 21.1). Many simple phenols are responsible for taste, for example eugenol in cloves. They are called the phenylpropanoids because they originate from phenylalanine (see Figure 11.1, p. 82) and they have a six-carbon (C6) and three-carbon (C3) structure (Figure 21.2). They comprise several groups:

• coumarins, including furanocoumarins and chromones

• flavonoids

• tannins

• lignin and lignans.

Figure 21.1 The structure of simple phenols.

Figure 21.2 Showing the development of simple phenylpropenes from shikimic acid and demonstrating the C3 and C6 units.

Many of these are attached to sugars that have to be cut or cleaved before activity (see Chapter 24 ‘Glycosides’, p. 181).

Shikimic Acid

The starting point for the production of phenylpropanoids is shikimic acid (Figure 21.2). Shikimic acid (or shikimate) is the precursor for:

• Amino acids: e.g. phenylalanine, tryptophan and tyrosine (see Figure 11.1, p. 82).

• Aromatic aldehydes: e.g. vanillin.

• Simple aromatic acids: e.g. gallic acid.

The shikimic acid pathway is absent in mammals.

Abridged Phenylpropanoids

These possess no side chain or a side chain with one carbon atom (Figure 21.3).

Figure 21.3 Abridged phenylpropanoids.

Simple Phenols

These are based around:

• Benzoic acid derivatives: e.g. salicylic acid, hydroquinone, catechol, vanillin.

• Cinnamic acid derivatives: e.g. rosmarinic acid found in Rosmarinus spp. (rosemary) and Melissa officinalis (lemon balm).

• Benzoic, cinnamic, salicylic and rosmarinic acids (Figure 21.4) are carboxylic acid derivatives (see Figure 5.1, p. 30).

Figure 21.4 Demonstrating derivations of phenolic acids from benzoic and cinnamic acid.

Phenols are are found in:

• Ericaceae: Arctostaphylos uva-ursi (bearberry, uva-ursi).

• Rosaceae: Filipendula ulmaria (meadowsweet, Queen of the meadow), Agrimonia spp. (agrimony, Xian He Cao), Crataegus spp. (hawthorn, Shan Zha).

• Vitaceae: Vitis spp. (grape).

• Asteraceae: Cichorium intybus (chicory).

• Labiatae (Laminaceae): Mentha spp. (mint, Bo He).

• Boraginaceae: Pulmonaria officinalis (lungwort), Lithospermum erythrorhizon (Zi Cao).

Action of Phenols

Phenols have a benzene ring with at least one hydroxyl group attached to it. Other compounds attached to the benzene ring change its function.

Stilbenes

These are found in the heartwood of plants. They are thought to be responsible for ‘French paradox’ whereby deaths from heart disease in France are lower than in other countries. Resveratrol (Figure 21.6), a component of red wine, acts not only as an antioxidant and an anti-inflammatory but also as an antitumour agent. It is found in blueberries, bilberries, cranberries, and in the skins and seeds of grapes.

Figure 21.6 Chemical structure of resveratrol.

Quinones

Derived from the oxidation of phenols, quinones are closely involved in photosynthesis because they have the ability to gain and lose electrons, which enables the conversion of light energy in a form of energy a plant can use (see Chapter 2 ‘Atoms’, p. 10). They are able to carry electrons between the components that are involved in light reactions (Figure 21.7). Quinones are very lipid soluble.

Figure 21.7 Comparison of quinones and naphthoquinones.

Anthraquinones

• Yellow–brown or orangey red in colour.

• Can be found free and as glycosides (see Chapter 24 ‘Glycosides’, p. 181). Most commonly occur as O- or C-glycosides.

• The basic aglycone (see Chapter 24 ‘Glycosides’, p. 182) has a central quinone with a phenol group either side (Figure 21.8).

• There are variants of anthraquinones such as anthranols (alcohols) and anthrones (ketones).

Figure 21.8 Diagram showing the relationship between anthraquinones, anthrones, dianthols and dianthrones.

• Relationship Between Anthraquinone Derivatives

Anthrones tend to be unstable. The dianthols exist only as glycosides. Anthrones can exist as dianthrones, which creates a stable compound. This occurs when a herb containing an anthrone compound is dried. There are two types of dianthrone:

• Homodiathrones (Figures 21.8 and 21.9): the two dianthrones are the same.

• Heterodianthrones where the two dianthrones are different.

Figure 21.9 Two of the same anthrones forming a dianthrone (homoanthrones).

These compounds were originally thought to exert their laxative effect by irritating the gut wall. However, this is now thought to be incorrect and the effect is more likely to be due to stimulation of the peristaltic action and inhibition of water and electrolyte reabsorption by the gut.

Hypericin is two of the same anthrone joined together to form a homoanthrone.

• Pharmacokinetics of Anthraquinone Action

The glycosides of anthraquinones and dianthrones are polar (see Chapter 3 ‘Bonds’, p. 15) and therefore not easily absorbed across the phospholipid membranes of the cells of the gut wall. Once the bacteria have cleaved the sugar off, the compound becomes non-polar and is absorbed across the non-polar cell membrane of the gut wall cells.

Excessive consumption of anthraquinones can cause severe disruption of the colon with resultant pain and diarrhoea. The length of use of herbs containing anthraquinones should therefore be limited.

The action of an anthrone (Figures 21.8 and 21.9) is excessively vigorous, which is why certain herbs, such as Frangula (buckthorn bark), have to be stored before use. The storage time allows the anthrones to become oxidized so that they form the less reactive anthraquinone glycosides.

Coumarins

• Are lactones: compare with sesquiterpene lactones such as artemisinin (see Figure 22.5, p. 171).

• Coumarin variants (Figure 21.11) are common in plants both as aglycones and glycosides.

• 1000 natural coumarins have been isolated. Coumarin itself is found in about 150 species belonging to over 30 different families.

• The coumarin is probably present as a trans-O-glycoside (see Chapter 24 ‘Glycosides’, p. 181).

Figure 21.11 Structures of various coumarins.

Coumarins are commonly found in:

• Compositae (Asteraceae): Artemisia spp.

• Fabaceae: Trifolium spp.

• Rutaceae: Ruta graveolens (rue) as furanocoumarins.

• Umbelliferae (Apiaceae): Apium graveolens (celery), Ledebouriella spp. (Fang Feng) as pyranocoumarins.

• Leguminosae: sweet clover, melitot, woodruff.

Anticoagulant Actions

Coumarin itself is not an anticoagulant. However, it can be converted into the dicoumarol (usually when the plant is damaged), which is an anticoagulant (Figure 21.12). Dicoumarol interferes with the activation by vitamin K of clotting, as it is similar in structure to vitamin K, and competes with the enzyme involved in vitamin K production (see Figure 28.1, p. 212). Dicoumarol is similar in structure to vitamin K, so is able to inhibit vitamin K production.

Figure 21.12 Comparison of chemical structures of coumarin, dicoumarol, coumadin (warfarin) and vitamin K.

Psoralens (Furanocoumarins)

Psoralens are coumarins that possess a furan ring (see Figure 21.11, and compare with the structure of furanose sugar in Figure 9.4, p. 65), which is why they are also called furanocoumarins. This extra ring on the coumarin structure means that they absorb light readily, so consideration of the exposure a patient who is given herbs containing furanocoumarins will be getting to sunlight is important.

Ingestion of Psoralea corylifoliae (Bu Gu Zhi) has been documented as having an association with skin reaction to sunlight because it contains the furanocoumarin psoralen. However, skin reactions are rare. This effect has been utilized in the treatment of psoriasis. Psoralens are ingested by the patient, who is then exposed to UVA in PUVA treatments.

Psoralens are commonly found in:

• Rutaceae: Ruta graveolens (rue).

• Umbelliferae: Apium graveolens (celery fruits contain rutaretin and apiumentin), Angelica archangelic (angelica), Petroselenium crispum (parsley).

Chromones

• Structural isomers coumarins. compare their structures in Figure 21.11; the oxygen in the chromone is in a different position to that in the coumarin.

• Display antibacterial activity.

Flavonoids

• Polyphenols: slightly larger than the quinones and are found in all vascular plants. They can be found in foods such as fruits, vegetables, teas and wines.

• Phenylpropene (six- and three-carbon units; source shikimic acid) + six-carbon unit. Three molecules of malonyl-coA = triketide unit (see Figure 21.3). Their basic structure is based on a skeleton of 15 carbon atoms (C15).

• All flavonoids have the same biosynthetic origin.

• Carotenoids are often confused with flavonoids because they both end with –oid. Comparison of structures will clearly show the difference between the two (see Figure 9.1, p. 64 and Chapter 22 ‘Terpenes’, p. 174).

• Antioxidants: the ability of flavonoids to act as antioxidants depends on their molecular structure. The arrangement of the hydroxyl groups and other groups is important for the antioxidant activities. Catechin-based quercitin is very good at free radical scavenging for this reason (see Figure 7.6, p. 47).

• Water soluble.

• Are very often attached to sugars.

• Are not present in algae.

• Anti-inflammatories: flavonoids influence arachidonic acid metabolism and hence have an anti-inflammatory effect (see Figure 30.5, p. 229).

• Flavonoids are resistant to boiling and fermentation (Kim et al 1998).

Formation of Flavonoids

The formation of flavonoids is illustrated in Figure 21.13. The structures of different flavonoids are shown in Figure 21.14.

Figure 21.13 The synthesis of flavonoids from shikimic acid.

Figure 21.14 Comparison of various flavonoid structures. Boxes highlight differences between the groups.

Colours Associated with Flavonoids

Colour is dependent on the placement of the hydroxyl groups around the basic skeleton:

• Chalcones: yellow or colourless.

• Flavanones: colourless.

• Flavones: pure flavones are colourless but the more hydroxyl groups that are present, the more intense the yellow colour. Flavones are co-pigments that protect anthrocyanins.

• Flavonols: colourless co-pigments that protect anthrocyanins.

• Anthocyanidins: red, blue, purple, violet.

• Isoflavones: colourless.

• Catechins: colourless.

Tannins

• Polyphenols (made up of more than one unit of phenol).

• They bind and precipitate proteins, but they are not the only plant chemicals to do this. They can bind with proteins, starch, cellulose and minerals.

• Many tannins are glycosides.

• There are two main groups: hydrolysable and condensed (proanthocyanidin).

• They are soluble in water, with the exception of some high-molecular-weight structures.

• Tannins are produced in two ways: (1) from phenols synthesized via the shikimic acid pathway (hydrolysable tannins); or (2) polymerization (condensation reactions; see Figure 4.7, p. 26) of flavonoids.

Tannins are found in He Ye and Jin Yin Hua. They are present in plant parts: bark, wood, fruit, fruit pods, leaves, and roots.

Proanthrocyanidins (Condensed Tannins)

• Do not have glycosides (no sugar attached) (Figure 21.17).

• Catechins (found in green tea) are intermediates in their synthesis.

• Are more common than hydrolysable tannins.

• Oligomers or polymers of flavonoid units linked by carbon–carbon bonds not susceptible to cleavage by hydrolysis.

• Are called ‘condensed tannins’ because of their condensed chemical structure.

• Proanthocyanidins come from the acid catalysed oxidation reaction that produces red anthocyanidins when the proanthocyanidins are heated in acidic alcohol solutions.

• The polymers of proanthocyanidins are variable because the flavonoid units can differ.

• Are responsible for the astringent taste of wine.

• Belong to the flavonoid family and can be indicated by the initials OPC (oligomeric procyanidins) or PCO (procyanidolic oligomers).

Figure 21.17 Chemical structures of proanthocyanidin monomers (above) and the condensation reaction to form a proanthocyanidin (condensed tannin) (below).

The Importance of Tannin Interactions

Tannins provide astringent and haemostatic properties to a compound. They interact with:

• carbohydrates

• proteins and therefore enzymes

• polysaccharides

• bacterial cell membranes.

• Reaction with Carbohydrates

• Starch can create cavities in which tannins and other hydrophobic complexes, such as lipid, are embedded.

• Tannins interact directly with cellulose: the tannins seem to react with plant cell walls like lignin. However, this is not clear, as there is a difference in location of tannins and cell wall carbohydrates in living plants, and after digestion by animals.

• The higher the molecular weight of the carbohydrate, the more it interacts with tannins. These carbohydrates are usually not very soluble and mobile in their structure.

• Reaction with Proteins

This is a well-recognized interaction; an example is leather tanning. For bonding to take place, the following characteristics have to be present in both the tannins and the proteins. Proteins need:

• large molecular size

• open and flexible structures

• to be rich in proline.

Tannins need:

• high molecular weight

• mobile structures.

How Binding Takes Place: Hydrophobic and Hydrogen Bonding

Hydrolysable tannins and proanthocyanins form tannin–protein complexes in similar ways. These complexes are very stable structures and are very difficult for the gut to break down.

It is possible for proteins to interact with tannins when the amount of protein is in excess of that of the tannin. When this occurs, there is no precipitation and it is difficult to see whether the reaction has taken place.

Insoluble complexes will only form when the amount of tannins exceeds that of protein and a hydrophobic outer layer is formed.

Precipitation is very important and care should be taken when mixing herbs containing tannins; a highly tanninized herb might bind useful constituents. Herbalists can usually see this straight away when they mix tinctures, as they become cloudy. One of the reason that strong black tea is supposed to be good for diarrhoea is that it binds with the proteins in the gut wall and acts as a barrier to prevent water loss.

Pseudotannins

Derived from cinnamic acid, pseudotannins (Figure 21.18) are so named because they have some, but not all, the astringent properties of true tannins. For example, they do not react to Goldbeater’s skin test (see Chapter 41 ‘Scientific tests’, p. 338).