Griseofulvin

Griseofulvin is an antifungal agent produced by cultures of Penicillium griseofulvum and a number of other Penicillium species, including P. janczewski, P. nigrum, and P. patulum. Griseofulvin is the drug of choice for widespread or intractable dermatophyte infections, but is ineffective when applied topically. However, it is well absorbed from the gut and selectively concentrated into keratin, so may be used orally to control dermatophytes such as Epidermophyton, Microsporium, and Trichophyton. Treatment for some conditions, e.g. infections in fingernails, may have to be continued for several months, but the drug is generally free of side-effects. The antifungal action appears to be through disruption of the mitotic spindle, thus inhibiting fungal mitosis.

Initial inspection of the structure of griseofulvin shows the alternate oxygenation pattern, and also a methyl group which identifies the start of the polyketide chain. Cyclization of the C14 poly-|3-keto chain folded as shown allows both

Claisen (left-hand ring) and aldol (right-hand ring) reactions to occur giving a benzophenone intermediate. Two selective methylations lead to griseophenone C, which is the substrate for chlorination to griseophenone B; both these

SEnz ft ft

Claisen aldol

OH O OMe

OH O OH

OH O OMe

OH O OH

2 x SAM

benzophenone intermediate

2 x SAM

benzophenone intermediate

OH MeO

OH O OMe

OH MeO

(+) griseophenone C

OH O OMe

MeO' "f O Cl stereospecific radical coupling resonance forms

Cl halogenation at activated site ortho to phenol group phenolic oxidation in

(+) griseophenone C

Cl halogenation at activated site ortho to phenol group phenolic oxidation in

rings

OH

O

OMe

O

-«— 1

( J

1 1

MeO

OH '

Cl

stereospecific reduction of double bond OMe o OMe

°Me O OMe griseophenone B

stereospecific reduction of double bond OMe o OMe

Figure 3.42

MeO' ^f O Cl dehydrogriseofulvin

Figure 3.42

griseofulvin

Cl griseofulvin compounds appear as minor metabolites in P. griseofulvin cultures. One-electron oxidations on a phenolic group in each ring give a diradical and its mesomer, the latter allowing radical coupling to the basic grisan skeleton. Griseofulvin is then the result of methylation of the remaining phenol group and stereospecific reduction of the double bond in dehydrogriseofulvin.

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