flavonoids

CHEMISTRY OF NATURAL PRODUCTS

Introduction of Flavonoids

The flavonoids are polyphenolic compounds possessing 15 carbon atoms; two benzene rings joined by a linear three carbon chain.

The skeleton above, can be represented as the

C₆ - C₃ - C₆ system.

Flavonoids constitute one of the most characteristic classes of compounds in higher plants. Many flavonoids are easily recognised as flower pigments in most angiosperm families (flowering plants). However, their occurence is not restricted to flowers but include all parts of the plant.

The chemical structure of flavonoids are based on a C₁₅ skeleton with a CHROMANE ring bearing a second aromatic ring B in position 2, 3 or 4.

In a few cases, the six-membered heterocyclic ring C occurs in an isomeric open form or is replaced by a five - membered ring.

AURONES (2-benzyl-coumarone)

The oxygen bridge involving the central carbon atom (C₂) of the 3C - chain occurs in a rather limited number of cases, where the resulting heterocyclic is of the FURAN type.

Various subgroups of flavonoids are classified according to the substitution patterns of ring C. Both the oxidation state of the heterocyclic ring and the position of ring B are important in the classification.

Examples of the 6 major subgroups are:

1. Chalcones

2. Flavone (generally in herbaceous families, e.g. Labiatae, Umbelliferae, Compositae).
Apigenin (Apium graveolens, Petroselinum crispum).
Luteolin (Equisetum arvense)

3. Flavonol (generally in woody angiosperms)
Quercitol (Ruta graveolens, Fagopyrum esculentum, Sambucus nigra)
Kaempferol (Sambucus nigra, Cassia senna, Equisetum arvense, Lamium album, Polygonum bistorta).
Myricetin ().

4. Flavanone

5. Anthocyanins

6. Isoflavonoids

Most of these (flavanones, flavones, flavonols, and anthocyanins) bear ring B in position 2 of the heterocyclic ring. In isoflavonoids, ring B occupies position 3.

A group of chromane derivatives with ring B in position 4 (4-phenyl-coumarins = NEOFLAVONOIDS) is shown below.

The Isoflavonoids and the Neoflavonoids can be regarded as ABNORMAL FLAVONOIDS.

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CHALCONE

Chalcone is derived from three acetates and cinnamic acid as shown below.

ANTHOCYANIDIN

Anthocyanidin is an extended conjugation made up of the aglycone of the glycoside anthocyanins. Next to chlorophyll, anthocyanins are the most important group of plant pigments visible to the human eye.

The anthocyanodins constitute a large family of differently coloured compounds and occur in countless mixtures in practically all parts of most higher plants. They are of great economic importance as fruit pigments and thus are used to colour fruit juices, wine and some beverages.

The anthocyanidins in Hydrangea, colours it RED in acid soil and BLUE in alkali soil.

They will chelate with metal ions like Ca²⁺ and Mg²⁺ under alkali conditions.

This extends the conjugation as shown below.

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ISOFLAVONOIDS

In contrast to most other flavonoids, isoflavonoids have a rather limited taxonomic distribution, mainly within the Leguminosae. Most of our knowledge about the biosynthesis of isoflavonoids originates from studies with radioactive isotopes, by feeding labelled ¹⁴C cinnamates.

The isoflavonoids are all colourless. It has been established that acetate gives rise to ring A and that phenylalamine, cinnamate and cinnamate derivatives are incorporated into ring B and C-2, -3, and -4 of the heterocyclic ring.

Since chalcones and flavanones are efficient precursors of isoflavonoids, the required aryl migration of ring B from the former 2 or beta position to the 3 or alpha position of the phenylpropanoid precursor must take place after formation of the basic C₁₅ skeleton.

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Example of a BIOLOGICALLY ACTIVE ISOFLAVONOID

Rotenone comes from Derris root and Lonchocarpus species leaf (Family: Leguminosae)
It is an insecticide and also used as a fish poison.

* (blue): carbons derived from methionine.
(red): carbons derived from PRENYL (isoprenoid).

Biochemical pathway to the formation of rotenone.

Six rotenoid esters occur naturally and are isolated from the plant Derris eliptica found in Southeast Asia or from the plant Lonchocarpus utilis or L. urucu native to South America.

Rotenone is the most potent. It is unstable in light and heat and almost all toxicity can be lost after two to three days during the summer. It is very toxic to fish, one of its main uses by native people over the centuries being to paralyze fish for capture and consumption. Crystalline rotenone has an acute oral LD50 of 60, 132 and 3000mg/kg for guinea pigs, rats, and rabbits (Matsumura, 1985). Because the toxicity of derris powders exceeds that of the equivalent content of rotenone, it is obvious that the other esters in crude preparations have significant biologic activity.

Acute poisoning in animals is characterized by an initial respiratory stimulation followed by respiratory depression, ataxia, convulsions, and death by respiratory arrest (Shimkin and Anderson, 1936). The anesthetic-like action on nerves appears to be related to the ability of rotenone to block electron transport in mitochondria by inhibiting oxidation linked to NADH₂, this resulting in nerve conduction blockade (O'Brien, 1967; Corbett, 1974). The estimated fatal oral dose for a 70kg man is of the order of 10 to 100g.

Rotenone has been used topically for treatment of head lice, sacbies, and other ectoparasites, but the dust is highly irritating to the eyes (conjunctivitis), the skin (dermatitis), and to the upper respiratory tract (rhinitis) and throat (pharyngitis).