8-Methoxypsoralen

Description

8-Methoxypsoralen (8-MOP) and other psoralens are naturally found in plants, including common fruit and vegetable crops.

Chemical properties

White to cream-colored, crystalline solid; odorless. Slightly soluble in alcohol; practically insoluble in water. Combustible.

Originator

Oxsoracen,Eider,US,1955

The Uses of 8-Methoxypsoralen

8-Methoxypsoralen, is used in Photochemotherapy (methoxsalen with long wave ultraviolet radiation) is indicated for the repigmentation of idiopathic vitiligo. It is also used in Photopheresis (methoxsalen with long wave ultraviolet radiation of white blood cells) is indicated for use with the UVAR* System in the palliative treatment of the skin manifestations of cutaneous T-cell lymphoma.

The Uses of 8-Methoxypsoralen

Naturally occurring analog of psoralen. Use in treatment of psoriasis and mycosis fungoides

The Uses of 8-Methoxypsoralen

antipsoriatic, pigmentation agent

The Uses of 8-Methoxypsoralen

Naturally occurring analog of Psoralen (P839800). Use in treatment of psoriasis and mycosis fungoides.

The Uses of 8-Methoxypsoralen

For the treatment of psoriasis and vitiligo

The Uses of 8-Methoxypsoralen

A potent suicide inhibitor of cytochrome P-450.

Indications

For the treatment of psoriasis and vitiligo

Background

A naturally occurring furocoumarin compound found in several species of plants, including Psoralea corylifolia. It is a photoactive substance that forms DNA adducts in the presence of ultraviolet A irradiation.

What are the applications of Application

Methoxsalen (8-Methoxypsoralen) is a potent suicide inhibitor of cytochrome P-450

Definition

ChEBI: A member of the class of psoralens that is 7H-furo[3,2-g]chromen-7-one in which the 9 position is substituted by a methoxy group. It is a constituent of the fruits of Ammi majus. Like other psoralens, trioxsalen causes photosensitization of the skin. It is administered topically or orally in conjunction with UV-A for phototherapy treatment of vitiligo and severe psoriasis.

Indications

Methoxsalen has effects similar to those of trioxsalen. Methoxsalen is superior to trioxsalen in producing erythema and tanning and is the drug used in PUVA therapy. Methoxsalen is also available as a 1% lotion.

Manufacturing Process

It has been found that the compound 8-geranoxy psoralen is present in citrus oils, particularly lemon and lime oils. This compound can be isolated from the oil by a process which involves primarily absorption on an adsorbent material followed by elution with a suitable solvent.
(A) Cleavage of 8-Geranoxypsoralen: 275 mg of 8-geranoxypsoralen was dissolved with mechanical stirring in 4 ml glacial acetic acid. After 10 minutes,one drop of concentrated sulfuric acid was added to the solution. In 4 minutes thereafter a light tan precipitate began to form. Stirring was continued for 35 minutes and the reaction mixture was refrigerated for one hour and 20 minutes. The precipitate was then removed by suction filtration and washed on the filter with glacial acetic acid followed by ice-cold ethyl ether. The product, 8-hydroxypsoralen, weighed 115 mg, that is, 74% of theory.
(B) Methylation of 8-Hydroxypsoralen: 115 mg of 8-hydroxypsoralen was dissolved in 10 ml absolute methanol, an excess of diazomethane dissolved in ether was added and the mixture allowed to stand at room temperature with occasional stirring for 3 hours. The next day the reaction mixture was reduced in volume to 3 ml by evaporation on the steam bath and the concentrate was held in a refrigerator overnight. The next day, fine needles (80 mg) of 8- methoxypsoralen were filtered from the solution. The compound had a MP of 145 to 146°C and was obtained in a yield of 65% of theory.
There is also a wholly synthetic route to Methoxsalen as outlined by Kleeman and Engel.

brand name

8-Mop (Valeant); Oxsoralen (Valeant); Uvadex (Therakos).

Therapeutic Function

Dermal pigmentation enhancer

General Description

Odorless white to cream-colored crystalline solid. Bitter taste followed by tingling sensation.

Air & Water Reactions

Sensitive to light and air. Insoluble in water.

Reactivity Profile

8-Methoxypsoralen is incompatible with strong oxidizing agents.

Fire Hazard

Flash point data for 8-Methoxypsoralen are not available; however, 8-Methoxypsoralen is probably combustible.

Contact allergens

This fur(an)ocoumarin is an phototoxic compound that causes phototoxic dermatitis. Many plants of the Apiaceae–Umbelliferae and most of the Rutaceae family contain 5-methoxypsoralen and 8-methoxypsoralen. Their spectra is in the UVA range (300–360 nm). It is used in combination with UVA to treat various skin disorders such as psoriasis.

Pharmacokinetics

Methoxsalen selectively inhibits the synthesis of deoxyribonucleic acid (DNA). The guanine and cytosine content correlates with the degree of Methoxsalen-induced cross-linking. At high concentrations of the drug, cellular RNA and protein synthesis are also suppressed.

Safety Profile

Confirmed carcinogen. Poison by intraperitoneal route. Moderately toxic by ingestion and subcutaneous routes. Human mutation data reported. When heated to decomposition it emits acrid smoke and irritating fumes. A drug used to treat slun diseases.

Environmental Fate

The industrial use of 8-MOP results in its release into the environment through multiple pathways, and its existence as a natural substance in plants further expands exposure to the environment. Airborne 8-MOP will exist in the vapor and particulate phases, and will be degraded in air by reaction with photochemically produced hydroxyl radicals, with an estimated half-life of approximately 1.2 h, it may also be subject to direct photolysis by sunlight. Particulate 8-MOP will be removed from the atmosphere by wet or dry deposition. If released into the soil, it is expected to have high mobility and is not expected to volatilize. 8-MOP does not biodegrade. In aqueous environments, 8-MOP is not expected to hydrolyze, it will, however, adsorb to suspended solids and sediment. Due to 8-MOP’Ks resistance to degradation by many routes, it is expected to remain in the environment for a prolonged period, and as such will also be subject to long-range transport. 8-MOP has an estimated bioconcentration factor (BCF) of 9, meaning that bioconcentration and bioaccumulation are low in aquatic organisms.

Metabolism

Not Available

Purification Methods

Purify xanthotoxin by recrystallisation from *C6H6/pet ether (b 60-80o) to give silky needles, or from EtOH/Et2O to give rhombic prisms or from hot H2O to give needles. It is soluble in aqueous alkali due to ring opening of the cyclic lactone but recyclises upon acidification. It has UV max in EtOH at 219, 249 and 300nm (log  4.32, 4.35 and 4.06) and 1H NMR in CDCl3 with  at 7.76 (d, 1H, J 10 Hz), 7.71 (d, 1H, J 2.5 Hz), 7.38 (s, 1H), 6.84 (d, 1H, J 2.5 Hz), 6.39 (d, 1H, J 10 Hz) and 4.28 (s, 3H)ppm. [Nore & Honkanen J Heterocycl Chem 17 985 1980.] It is a DNA intercalator, is used in the treatment of dermal diseases, and is a human carcinogen [Tessman et al. Biochemistry 24 1669 1985.] [Beilstein 19 I 711, 19/6 V 15.]

Toxicity evaluation

The toxic effects of psoralens almost never occur without exposure to UV light. These are photosensitizing materials that exert their primary effect on the skin. 8-MOP, when activated by long-wavelength UV light in the range of 320–400 nm, is strongly erythemogenic, melanogenic, and cytotoxic in the epidermis. The mechanisms of action of 8-MOP in inducing repigmentation of vitiliginous skin have not been established. Repigmentation depends on the presence of functioning melanocytes and UV light. 8-MOP may activate the functional and dihydroxyphenylalanine-positive melanocytes present in vitiliginous skin. An increase in the activity of tyrosinase, the enzyme that catalyzes the conversion of tyrosine to dihydroxyphenylalanine (a precursor of melanin), has been shown in melanin-producing cells exposed in vitro to trioxsalen and UVA light. In addition, binding of photoactivated psoralens (in triplet states) to pyrimidine bases of nucleic acids, with subsequent inhibitions of DNA synthesis, cell division, and epidermal turnover, has been demonstrated. Following photoactivation, 8-MOP forms covalent bonds with DNA to produce monofunctional (addition to a single strand of DNA) and bifunctional adducts (cross-linking to both strands of DNA). Reactions with other proteins also occur. Psoralens may also increase melanin formation by producing an inflammatory reaction in the skin. Other mechanisms of increased pigmentation may include an increase in the number of functional melanocytes (and possibly activation of dormant melanocytes); enhancement of melanin granule synthesis; stimulation of the movement of melanocytes up hair follicles resulting in melanocytic repopulation of the epidermis; and/or hypertrophy of melanocytes and increased arborization of their dendrites. Since psoriasis is a hyperproliferative disorder and other agents effective in the treatment of psoriasis are known to inhibit DNA synthesis, the therapeutic effect of 8-MOP in the treatment of psoriasis probably involves binding to DNA and inhibition of DNA synthesis resulting in decreased cell proliferation; other vascular, leukocyte, or cell regulatory mechanisms may be involved. It has been suggested that at low drug load, 8-MOP binds to DNA as an intercalator, whereas at higher ratios of 8-MOP to DNA, it binds to the outside of DNA, probably in the minor groove and causes some compaction in DNA. Protective eyewear is used to prevent irreversible binding of 8-MOP to proteins and DNA components of the lens. The central hypothesis for the reproductive toxicity of 8-MOP is that it produces reproductive effects by disrupting the hypothalamus– pituitary axis, and the alternative hypothesis is that this compound targets gonadal function, resulting in alteration of pregnancy outcome.