Methoxsalen

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Methoxsalen
Methoxsalen.svg
Systematic (IUPAC) name
9-methoxy-7H-furo[3,2-g]chromen-7-one
Clinical data
AHFS/Drugs.com Consumer Drug Information
Legal status
?
Pharmacokinetic data
Half-life ~2 hours
Identifiers
CAS number 298-81-7 YesY
ATC code D05AD02 D05BA02
PubChem CID 4114
DrugBank DB00553
ChemSpider 3971 YesY
UNII U4VJ29L7BQ YesY
KEGG D00139 YesY
ChEBI CHEBI:18358 YesY
ChEMBL CHEMBL416 YesY
NIAID ChemDB 001590
Chemical data
Formula C12H8O4 
Mol. mass 216.19 g/mol
 YesY (what is this?)  (verify)

Methoxsalen — also called xanthotoxin, marketed under the trade names Oxsoralen, Deltasoralen, Meladinine — is a drug used to treat psoriasis, eczema, vitiligo, and some cutaneous lymphomas in conjunction with exposing the skin to UVA light from lamps or sunlight. Methoxsalen modifies the way skin cells receive the UVA radiation, allegedly clearing up the disease. The dosage comes in 10 mg tablets, which are taken in the amount of 30 mg 75 minutes before a PUVA (psoralen + UVA) light treatment. Chemically, methoxsalen belongs to a class of organic natural molecules known as furanocoumarins. They consist of coumarin annulated with furan.

Natural occurrences[edit]

Methoxsalen is extracted from Ammi majus, a plant of the family Apiaceae. The substance is also present in other Apiaceae as well as Rutaceae, for example bergamot oil which is used in many perfumes and aromatherapy oils.

Biosynthesis[edit]

The biosynthetic pathway is a combination of the shikimate pathway, which produces umbelliferone, and the mevalonate pathway.

Synthesis of umbelliferone[edit]

Umbelliferone is a phenylpropanoid and as such is synthesized from L-phenylalanine, which in turn is produced via the shikimate pathway. Phenylalanine is lysated into cinnamic acid, followed by hydroxylation by cinnamate 4-hydroxylase to yield 4-coumaric acid. The 4-coumaric acid is again hydroxylated by cinnamate/coumarate 2-hydroxylase to yield 2,4-dihydroxy-cinnamic acid (umbellic acid) followed by a bond rotation of the unsaturated bond adjacent to the carboxylic acid group. Finally an intramolecular attack from the hydroxyl group of C2' to the carboxylic acid group closes the ring and forms the lactone umbelliferone.

Synthesis of methoxsalen[edit]

The biosynthetic route then continues with the activation of dimethylallyl pyrophosphate (DMAPP), produced via the mevalonate pathway, to form a carbo-cation via the cleavage of the diphosphates. Once activated, the enzyme umbelliferone 6-prenyltransferase catalyzes a C-alkylation between DMAPP and umbelliferone at the activated position ortho to the phenol, yielding demethylsuberosin. This is then followed by a hydroxylation catalyzed by the enzyme marmesin synthase to yield marmesin. Another hydroxylation is catalyzed by psoralen synthase to yield psoralen. A third hydroxylation by the enzyme psoralen 8-monooxygenase yields xanthotoxol which is followed by a methylation via the enzyme xanthotoxol O-methyltransferase and S-adenosyl methionine to yield methoxsalen.[1]

Risks and side effects[edit]

Patients with high blood pressure or a history of liver problems are at risk for inflammation and irreparable damage to both liver and skin. The eyes must be protected from UVA radiation. Side effects include nausea, headaches, dizziness, and in rare cases insomnia. Methoxsalen has also been classified as an IARC Group 1 carcinogen (known to cause cancer) but is only cancerous when combined with UVA radiation.

Cultural aspects[edit]

Author John Howard Griffin (1920–1980) used the chemical to darken his skin in order to investigate racial segregation in the American South. He wrote the book Black Like Me (1961) about his experiences.[2]

Some cologne/perfume contains bergamot oil as one of the ingredients (for the scent). People wearing the concoction on places where the skin receives UV radiation was radiated by the sun noticed that their skin turned brownish at those spots (due to the phototoxic effects of methoxsalen present in the bergamot oil[3]). Most modern formulations of perfumes containing bergamot have the Methoxalen removed.

Chemical synthesis[edit]

Methoxsalen synthesis:[4]

References[edit]

  1. ^ Dewick, P. M. (2009). Medicinal Natural Products: A Biosynthetic Approach (3rd ed.). John Wiley & Sons. pp. 161, 164–165. 
  2. ^ Dead Like Me on snopes.com
  3. ^ "Bergamot". oilsandplants.com. Retrieved 2010-12-29. 
  4. ^ Lagercrantz, C.; Hanshoff, G.; Ulfvarson, U.; Stenhagen, E.; Thorell, B. (1956). "Dihydrofurocoumarins. Synthesis of some Long Chain 4-n-Alkyl Substituted Dihydroxanthotoxins, 4-Phenyl-dihydroxanthotoxin, and Methyl 8-(4-Dihydroxanthotoxin)-n-octanoate". Acta Chemica Scandinavica 10: 647. doi:10.3891/acta.chem.scand.10-0647.  edit