Griseofulvin

Griseofulvin
Systematic (IUPAC) name
(2S,6'R)- 7-chloro- 2',4,6-trimethoxy- 6'-methyl- 3H,4'H-spiro [1-benzofuran- 2,1'-cyclohex[2]ene]- 3,4'-dione
Clinical data
Trade names Gris-peg
AHFS/Drugs.com monograph
MedlinePlus a682295
  • B3 (Australia), C (United States)
  • POM (UK), ℞-only (U.S.)
Oral
Pharmacokinetic data
Bioavailability Highly variable (25 to 70%)
Metabolism Hepatic demethylation and glucuronidation
Half-life 9-21 hours
Identifiers
126-07-8 Yes
D01AA08 D01BA01
PubChem CID 441140
DrugBank DB00400 Yes
ChemSpider 389934 Yes
UNII 32HRV3E3D5 Yes
KEGG D00209 Yes
ChEBI CHEBI:27779 Yes
ChEMBL CHEMBL562 Yes
Chemical data
Formula C17H17ClO6
352.766 g/mol
 Yes (what is this?)  (verify)

Griseofulvin (marketed under the proprietary name Grifulvin V by Orthoneutrogena Labs, according to FDA orange book) is an orally administered antifungal drug. It is used both in animals and humans, to treat fungal infections of the skin (commonly known as ringworm) and nails. It is produced by culture of some strains of the mold Penicillium griseofulvum, from which it was isolated in 1939.[1][2]

It is an antibiotic produced by the mycelial fungus Penicillium patulum.[3][4][5][6][7][8][9][10]

It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[11]

Biosynthetic pathway of griseofulvin

Biosynthetic process

The first step in the biosynthesis of griseofulvin by P. griseofulvin is the synthesis of the 14-carbon poly-β -keto chain by a type I iterative polyketide synthase (PKS) via iterative addition of 6 malonyl-CoA to an acyl-CoA starter unit. The 14-carbon poly-β -keto chain undergoes cyclization/aromatization, using cyclase/aromatase, respectively, through a Claisen and aldol condensation to form the benzophenone intermediate. The benzophenone intermediate is then methylated via S-adenosylmethionine twice to yield griseophenone C. The griseophenone C is then halogenated at the activated site ortho to the phenol group on the left aromatic ring to form griseophenone B. The halogenated species then undergoes a single phenolic oxidation in both rings forming the two oxygen diradical species. The right oxygen radical shifts alpha to the carbonyl via resonance allowing for a stereospecific radical coupling by the oxygen radical on the left ring forming a tetrahydrofuranone species . [12] The newly formed grisan skeleton with a spiro center is then O-methylated by SAM to generate dehydrogriseofulvin. Ultimately, a stereoselective reduction of the olefin on dehydrogriseofulvin by NADPH affords griseofulvin. [13][14]

Medical uses

Griseofulvin is used orally only for dermatophytosis. It is ineffective topically. It is reserved for cases with nail, hair, or large body surface involvement.[15]

Side effects

Known side effects of griseofulvin include:

  • Can reduce the effectiveness of oral contraceptives as it is a cytochrome p450 enzyme inducer
  • Confusion
  • Considered unsafe for those with porphyria
  • Diarrhea
  • Dizziness
  • Fatigue
  • Headache
  • Urticaria
  • Impairment of performance of routine activities
  • Impairment of liver enzymatic activity
  • Inability to fall or stay asleep
  • Itching
  • Loss of taste sensation
  • Nausea
  • Oral thrush (yeast infection of the mouth)
  • Possibly a teratogen inducing mutations
  • Sensitivity to alcohol, with a disulfiram- (Antabuse)-like reaction
  • Sensitivity to prolonged sun exposure
  • Skin rashes (including Steven-Johnson syndrome)
  • Swelling
  • Tingling in the hands or feet
  • Upper abdominal pain

Common brand names

Mechanism

The drug binds to tubulin, interfering with microtubule function, thus inhibiting mitosis. It binds to keratin in keratin precursor cells and makes them resistant to fungal infections. The drug reaches its site of action only when hair or skin is replaced by the keratin-griseofulvin complex. Griseofulvin then enters the dermatophyte through energy-dependent transport processes and bind to fungal microtubules. This alters the processing for mitosis and also underlying information for deposition of fungal cell walls.

References

  1. ↑ Michael Ash; Irene Ash (2004). Handbook of Preservatives. Synapse Info Resources. p. 406. ISBN 978-1-890595-66-1.
  2. ↑ Goldman, Leon (6 February 1960). "Current status of Griseofulvin". Journal of the American Medical Association 172 (6): 532. doi:10.1001/jama.1960.03020060022006.
  3. ↑ GB 784618
  4. ↑ U.S. Patent 2,900,304
  5. ↑ U.S. Patent 3,038,839
  6. ↑ U.S. Patent 3,069,328
  7. ↑ U.S. Patent 3,069,329
  8. ↑ http://www.biochemj.org/bj/033/bj0330240.htm
  9. ↑ J.F. Grove, D. Ismay, J. Macmillan, T.P.C. Mulholland, M.A.T. Rogers, Chem. Ind. (London), 219 (1951).
  10. ↑ Grove, J. F.; MacMillan, J.; Mulholland, T. P. C.; Rogers, M. A. T. (1952). "762. Griseofulvin. Part IV. Structure". Journal of the Chemical Society (Resumed): 3977. doi:10.1039/JR9520003977.
  11. ↑ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  12. ↑ Birch, Arthur (1953). "Studies in relation to biosynthesis I. Some possible routes to derivatives of orcinol and phloroglucinol". Australian Journal of Chemistry 6 (4): 360. doi:10.1071/ch9530360.
  13. ↑ Dewick, Paul M. (2009). Medicinal Natural Products: A Biosynthetic Approach (3rd ed.). UK: John Wiley & Sons Ltd. ISBN 0-471-97478-1.
  14. ↑ Harris, Constance (1976). "Biosynthesis of Griseofulvin". Journal of the American Chemical Society 98 (17): 5380–5386. doi:10.1021/ja00433a053.
  15. ↑ Tripathi. Textbook of Pharmacology. Jaypee Brothers. pp. 761–762. ISBN 81-8448-085-7.

External links