Isoflavonoids

The isoflavonoids form a quite distinct subclass of flavonoid compound, being structural variants in which the shikimate-derived aromatic ring has migrated to the adjacent carbon of the heterocycle. This rearrangement process is brought about by a cytochrome P-450-dependent enzyme requiring NADPH and O2 cofactors, which transforms the flavanones liquiritigenin or naringenin into the isoflavones daidzein or genistein respectively via intermediate hydrox-yisoflavanones (Figure 4.47). A radical mechanism has been proposed. This rearrangement is quite rare in nature, and isoflavonoids are almost entirely restricted to the plant family the Legu-minosae/Fabaceae. Nevertheless, many hundreds of different isoflavonoids have been identified, and structural complexity is brought about by hydroxylation and alkylation reactions, varying the oxidation level of the heterocyclic ring, or forming additional heterocyclic rings. Some of the many variants are shown in Figure 4.48. Pterocarpans, e.g. medicarpin from lucerne (Medicago sativa), and pisatin from pea (Pisum sativum), have anti-fungal activity and form part of these plants' natural defence mechanism against fungal attack. Simple isoflavones such as daidzein and coumes-tans such as coumestrol from lucerne and clovers (Trifolium species), have sufficient oestrogenic activity to seriously affect the reproduction of grazing animals, and are termed phyto-oestrogens*. These planar molecules undoubtedly mimic the shape and polarity of the steroid hormone estradiol

R = H, liquiritigenin R = OH, naringenin (flavonoid)

R = H, daidzein R = OH, genistein (isoflavonoid)

R = H, daidzein R = OH, genistein (isoflavonoid)

Figure 4.47

daidzein (an isoflavone)

daidzein (an isoflavone)

coumestrol (a coumestan)

coumestrol (a coumestan)

Figure 4.47

formononetin (an isoflavone)

OMe formononetin (an isoflavone)

Formononetin Rotenone

OMe rotenone OMe (a rotenoid)

Figure 4.48

OMe rotenone OMe (a rotenoid)

medicarpin (a pterocarpan)

medicarpin (a pterocarpan)

pisatin (a pterocarpan)

OMe pisatin (a pterocarpan)

Figure 4.48

(see page 276). The consumption of legume fodder crops by animals must therefore be restricted, or low isoflavonoid producing strains have to be selected. Isoflavonoids in the human diet, e.g. from soya (Glycine max) products, are believed to give some protection against oestrogen-dependent cancers such as breast cancer, by restricting the availability of the natural hormone. In addition, they can feature as dietary oestrogen supplements in the reduction of menopausal symptoms, in a similar way to hormone replacement therapy

(see page 279). The rotenoids take their name from the first known example rotenone, and are formed by ring cyclization of a methoxyisoflavone (Figure 4.49). Rotenone itself contains a C5 iso-prene unit (as do virtually all the natural rotenoids) introduced via dimethylallylation of demethyl-munduserone. The isopropenylfurano system of rotenone, and the dimethylpyrano of deguelin, are formed via rotenonic acid (Figure 4.49) without any detectable epoxide or hydroxy intermediates (compare furocoumarins, page 145). Rotenone

OMe oxidation of OMe group (hydroxylation and loss of hydroxide, compare Figure 2.21) HO

rotenone OMe

O cyclization to 5-membered ring

OMe deguelin OMe

C-alkylation at activated position ortho to phenol

rotenone OMe

cyclization to

6-membered ring OMe rotenonic acid

C-alkylation at activated position ortho to phenol

DMAPP HO

DMAPP HO

OMe addition of hydride

(reduction)

OMe addition of hydride

(reduction)

OMe demethylmunduserone

OMe demethylmunduserone

OMe deguelin OMe

Figure 4.49

and other rotenoids are powerful insecticidal and piscicidal (fish poison) agents, interfering with oxidative phosphorylation. They are relatively harmless to mammals unless they enter the blood stream, being metabolized rapidly upon ingestion.

Rotenone thus provides an excellent biodegradable insecticide, and is used as such either in pure or powdered plant form. Roots of Derris elliptica* or Lonchocarpus* species are rich sources of rotenone.

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