Psoralen
Encyclopedia
Psoralen is the parent compound in a family of natural products known as furocoumarins. It is structurally related to coumarin
by the addition of a fused furan
ring, and may be considered as a derivative of umbelliferone
. Psoralen occurs naturally in the seeds of Psoralea corylifolia
, as well as in the common Fig
, celery
, parsley
and West Indian satinwood
. It is widely used in PUVA
(=Psoralen +UVA) treatment for psoriasis
, eczema
, vitiligo
, and cutaneous T-cell lymphoma. Many furocoumarins are extremely toxic to fish, and some are indeed used in streams in Indonesia to catch fish.
treatment for skin problems such as psoriasis
and (to a lesser extent) eczema and vitiligo
. This takes advantage of the high UV
absorbance of psoralen. The psoralen is applied first to sensitise the skin, then UVA light is applied to clean up the skin problem. Psoralen has also been recommended for treating alopecia
. Psoralens are also used in photopheresis where they are mixed with the extracted leukocytes before UV radiation is applied.
Psoralen is a mutagen
and is used for this purpose in molecular biology research. Psoralen intercalates into the DNA and, on exposure to ultraviolet (UVA) radiation, can form covalent interstrand cross-links
(ICL) with thymines preferentially at 5'-TpA sites in the genome, inducing apoptosis
. Psoralen plus UVA (PUVA) therapy has shown considerable clinical efficacy. Unfortunately, a side effect of PUVA treatment is a higher risk of skin cancer.
Despite the photocarcinogen
ic properties of psoralen, It had been used as a tanning activator
in sunscreens until 1996.
Psoralens are used in tanning accelerators, but users should keep in mind that psoralen increases your skin’s sensitivity to light.
Some patients have even had severe skin loss after sunbathing with psoralen-containing tanning activators.
Patients with lighter skin colour suffer four times as much from the melanoma-generating properties of psoralens than those with darker skin
The synthetic amino-psoralen, amotosalen HCl, has been developed for the inactivation of infectious pathogens (bacteria, viruses, protozoa)in platelet and plasma blood components prepared for transfusion support of patients. The technology is currently in routine use in European blood centers.
One isomer
of psoralen is angelicin
, and most furocoumarins can be regarded as derivatives of psoralen or angelicin. Some important psoralen derivatives are Imperatorin
, xanthotoxin, bergapten
and nodekenetin.
Another important feature of this class of compounds is its ability in generating singlet oxygen.
of coumarin, such as ring opening by alkali
to give a coumarinic acid or coumaric acid
derivative. Potassium permanganate
causes oxidation of the furan ring, while other methods of oxidation produce furan-2,3-carboxylic acid.
undergoes substitution
at the 8-position rather than at the desired 6 position. Benzofuran
reacts preferentially in the furan
ring rather than in the benzene
ring. However the 7-hydroxy derivative of 2,3-dihydrobenzofuran (also called coumaran) does undergo substitution at the desired 6-position allowing the following synthesis of the coumarin system via a Gattermann-Koch reaction
followed by a Perkin condensation using acetic anhydride
. The synthesis is then completed by dehydrogenation
of the five-membered ring to produce the furan ring.
Psoralen originates from coumarins of the shikimate pathway; its biosynthesis is shown in the figure below. The aromatic ring in 6 is activated at positions ortho to the hydroxyl group, and is alkylated by 5, an alkylating agent. The dimethylallyl group in 7 then undergoes cyclization with the phenol group to give 8. This transformation is catalysed by a cytochome P-450-dependent monooxygenase17 (psoralen 5-monooxygenase), and cofactors (NADPH) and molecular oxygen.
Another biosynthesis pathway of psoralen is shown below in the figure. A second P-450-dependent monooxygenase enzyme (psoralen synthase
) then cleaves off 10 (in the form of 11) from 8 to give 1. This pathway does not involve any hydroxylated intermediate, and cleavage is postulated to be initiated by a radical reaction.
, Pastinaca sativa, Petroselinum crispum, Levisticum officinale, Foeniculum vulgare (Fruit), Daucus carota, Apium graveolens.
Coumarin
Coumarin is a fragrant chemical compound in the benzopyrone chemical class, found in many plants, notably in high concentration in the tonka bean , vanilla grass , sweet woodruff , mullein , sweet grass , cassia cinnamon and sweet clover...
by the addition of a fused furan
Furan
Furan is a heterocyclic organic compound, consisting of a five-membered aromatic ring with four carbon atoms and one oxygen. The class of compounds containing such rings are also referred to as furans....
ring, and may be considered as a derivative of umbelliferone
Umbelliferone
Umbelliferone, also known as 7-hydroxycoumarin, hydrangine, skimmetine, and beta-umbelliferone, is a widespread natural product of the coumarin family. It occurs in many familiar plants from the Apiaceae family such as carrot, coriander and garden angelica, as well plants from other families such...
. Psoralen occurs naturally in the seeds of Psoralea corylifolia
Psoralea corylifolia
Psoralea corylifolia is an important plant in the Indian Ayurveda and Tamil Siddha systems of medicine, and also Chinese medicine. The seeds of this plant contain a variety of coumarins including psoralen. The seeds have a variety of medicinal uses, but the specific role of psoralen in these uses...
, as well as in the common Fig
Common fig
The Common fig is a deciduous tree growing to heights of up to 6 m in the genus Ficus from the family Moraceae known as Common fig tree. It is a temperate species native to the Middle East.-Description:...
, celery
Celery
Apium graveolens is a plant species in the family Apiaceae commonly known as celery or celeriac , depending on whether the petioles or roots are eaten: celery refers to the former and celeriac to the latter. Apium graveolens grows to 1 m tall...
, parsley
Parsley
Parsley is a species of Petroselinum in the family Apiaceae, native to the central Mediterranean region , naturalized elsewhere in Europe, and widely cultivated as an herb, a spice and a vegetable.- Description :Garden parsley is a bright green hairless biennial herbaceous plant in temperate...
and West Indian satinwood
Zanthoxylum
Zanthoxylum is a genus of about 250 species of deciduous and evergreen trees and shrubs in the citrus or rue family, Rutaceae, native to warm temperate and subtropical areas worldwide. Common names include Prickly-ash and Hercules' Club.The fruit of several species are used to make the spice...
. It is widely used in PUVA
PUVA
PUVA is a psoralen + UVA treatment for eczema, psoriasis, graft-versus-host disease and vitiligo, and mycosis fungoides. The psoralen is applied or taken orally to sensitize the skin, then the skin is exposed to UVA. Long term use has been associated with higher rates of skin cancer.Psoralens are...
(=Psoralen +UVA) treatment for psoriasis
Psoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
, eczema
Eczema
Eczema is a form of dermatitis, or inflammation of the epidermis . In England, an estimated 5.7 million or about one in every nine people have been diagnosed with the disease by a clinician at some point in their lives.The term eczema is broadly applied to a range of persistent skin conditions...
, vitiligo
Vitiligo
Vitiligo is a condition that causes depigmentation of sections of skin. It occurs when melanocytes, the cells responsible for skin pigmentation, die or are unable to function. The cause of vitiligo is unknown, but research suggests that it may arise from autoimmune, genetic, oxidative stress,...
, and cutaneous T-cell lymphoma. Many furocoumarins are extremely toxic to fish, and some are indeed used in streams in Indonesia to catch fish.
Uses
An important use of psoralen is in PUVAPUVA
PUVA is a psoralen + UVA treatment for eczema, psoriasis, graft-versus-host disease and vitiligo, and mycosis fungoides. The psoralen is applied or taken orally to sensitize the skin, then the skin is exposed to UVA. Long term use has been associated with higher rates of skin cancer.Psoralens are...
treatment for skin problems such as psoriasis
Psoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
and (to a lesser extent) eczema and vitiligo
Vitiligo
Vitiligo is a condition that causes depigmentation of sections of skin. It occurs when melanocytes, the cells responsible for skin pigmentation, die or are unable to function. The cause of vitiligo is unknown, but research suggests that it may arise from autoimmune, genetic, oxidative stress,...
. This takes advantage of the high UV
Ultraviolet
Ultraviolet light is electromagnetic radiation with a wavelength shorter than that of visible light, but longer than X-rays, in the range 10 nm to 400 nm, and energies from 3 eV to 124 eV...
absorbance of psoralen. The psoralen is applied first to sensitise the skin, then UVA light is applied to clean up the skin problem. Psoralen has also been recommended for treating alopecia
Alopecia
Alopecia means loss of hair from the head or body. Alopecia can mean baldness, a term generally reserved for pattern alopecia or androgenic alopecia. Compulsive pulling of hair can also produce hair loss. Hairstyling routines such as tight ponytails or braids may induce Traction alopecia. Both...
. Psoralens are also used in photopheresis where they are mixed with the extracted leukocytes before UV radiation is applied.
Psoralen is a mutagen
Mutagen
In genetics, a mutagen is a physical or chemical agent that changes the genetic material, usually DNA, of an organism and thus increases the frequency of mutations above the natural background level. As many mutations cause cancer, mutagens are therefore also likely to be carcinogens...
and is used for this purpose in molecular biology research. Psoralen intercalates into the DNA and, on exposure to ultraviolet (UVA) radiation, can form covalent interstrand cross-links
Crosslinking of DNA
Crosslinks in DNA occur when various exogenous or endogenous agents react with two different positions in the DNA. This can either occur in the same strand or in the opposite strands of the DNA . Crosslinks also occur between DNA and protein...
(ICL) with thymines preferentially at 5'-TpA sites in the genome, inducing apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. Psoralen plus UVA (PUVA) therapy has shown considerable clinical efficacy. Unfortunately, a side effect of PUVA treatment is a higher risk of skin cancer.
Despite the photocarcinogen
Photocarcinogen
A photocarcinogen is a substance which causes cancer following illumination. This destructive effect often results from free radicals generated by the photocarcinogen. Many chemicals that are not carcinogenic can be photocarcinogenic...
ic properties of psoralen, It had been used as a tanning activator
Tanning activator
Tanning activators are chemicals that increase the effect of UV-radiation on the human skin.-Overview:Since sunburn and suntan are induced by the same mechanism , these substances increase the likelihood for sunburn as well. The best known tanning activator is psoralen which is an ingredient of...
in sunscreens until 1996.
Psoralens are used in tanning accelerators, but users should keep in mind that psoralen increases your skin’s sensitivity to light.
Some patients have even had severe skin loss after sunbathing with psoralen-containing tanning activators.
Patients with lighter skin colour suffer four times as much from the melanoma-generating properties of psoralens than those with darker skin
The synthetic amino-psoralen, amotosalen HCl, has been developed for the inactivation of infectious pathogens (bacteria, viruses, protozoa)in platelet and plasma blood components prepared for transfusion support of patients. The technology is currently in routine use in European blood centers.
Chemistry
Isomer
In chemistry, isomers are compounds with the same molecular formula but different structural formulas. Isomers do not necessarily share similar properties, unless they also have the same functional groups. There are many different classes of isomers, like stereoisomers, enantiomers, geometrical...
of psoralen is angelicin
Angelicin
Angelicin is a furanocoumarin. It can be found in Bituminaria bituminosa. It is present in the list of IARC Group 3 carcinogens ....
, and most furocoumarins can be regarded as derivatives of psoralen or angelicin. Some important psoralen derivatives are Imperatorin
Imperatorin
Imperatorin is a furocoumarin and a phytochemical that has been isolated from Urena lobata L. , Angelica archangelica, Angelica dahurica, Glehnia littoralis, Saposhnikovia divaricata, Cnidium monnieri, Incarvillea younghusbandii, and Zanthoxylum americanum mill...
, xanthotoxin, bergapten
Bergapten
Bergapten is a psoralen found in bergamot essential oil, in other citrus essential oils, and in grapefruit juice. It is the chemical in bergamot oil that causes phototoxicity. Bergapten-free bergamot essential oil or synthetics are now used in perfumery....
and nodekenetin.
Another important feature of this class of compounds is its ability in generating singlet oxygen.
Structure
The structure of psoralen was originally deduced using its degradation reactions. It exhibits the normal reactions of the lactoneLactone
In chemistry, a lactone is a cyclic ester which can be seen as the condensation product of an alcohol group -OH and a carboxylic acid group -COOH in the same molecule...
of coumarin, such as ring opening by alkali
Alkali
In chemistry, an alkali is a basic, ionic salt of an alkali metal or alkaline earth metal element. Some authors also define an alkali as a base that dissolves in water. A solution of a soluble base has a pH greater than 7. The adjective alkaline is commonly used in English as a synonym for base,...
to give a coumarinic acid or coumaric acid
Coumaric acid
Coumaric acid is a hydroxycinnamic acid, an organic compound that is a hydroxy derivative of cinnamic acid. There are three isomers, o-coumaric acid, m-coumaric acid, and p-coumaric acid, that differ by the position of the hydroxy substitution of the phenyl group...
derivative. Potassium permanganate
Potassium permanganate
Potassium permanganate is an inorganic chemical compound with the formula KMnO4. It is a salt consisting of K+ and MnO4− ions. Formerly known as permanganate of potash or Condy's crystals, it is a strong oxidizing agent. It dissolves in water to give intensely purple solutions, the...
causes oxidation of the furan ring, while other methods of oxidation produce furan-2,3-carboxylic acid.
Synthesis
Psoralen synthesis is challenging, due the fact that umbelliferoneUmbelliferone
Umbelliferone, also known as 7-hydroxycoumarin, hydrangine, skimmetine, and beta-umbelliferone, is a widespread natural product of the coumarin family. It occurs in many familiar plants from the Apiaceae family such as carrot, coriander and garden angelica, as well plants from other families such...
undergoes substitution
Electrophilic aromatic substitution
Electrophilic aromatic substitution EAS is an organic reaction in which an atom, usually hydrogen, appended to an aromatic system is replaced by an electrophile...
at the 8-position rather than at the desired 6 position. Benzofuran
Benzofuran
Benzofuran is the heterocyclic compound consisting of fused benzene and furan rings. This colourless liquid is a component of coal tar. Benzofuran is the "parent" of many related compounds with more complex structures. For example, psoralen is a benzofuran derivative that occurs in several...
reacts preferentially in the furan
Furan
Furan is a heterocyclic organic compound, consisting of a five-membered aromatic ring with four carbon atoms and one oxygen. The class of compounds containing such rings are also referred to as furans....
ring rather than in the benzene
Benzene
Benzene is an organic chemical compound. It is composed of 6 carbon atoms in a ring, with 1 hydrogen atom attached to each carbon atom, with the molecular formula C6H6....
ring. However the 7-hydroxy derivative of 2,3-dihydrobenzofuran (also called coumaran) does undergo substitution at the desired 6-position allowing the following synthesis of the coumarin system via a Gattermann-Koch reaction
Gattermann-Koch reaction
The Gattermann–Koch reaction, named after the German chemists Ludwig Gattermann and Julius Arnold Koch, in organic chemistry refers to a Friedel–Crafts acylation reaction in which carbon monoxide and hydrochloric acid are used in situ with Friedel–Crafts catalyst, namely AlCl3 to produce a...
followed by a Perkin condensation using acetic anhydride
Acetic anhydride
Acetic anhydride, or ethanoic anhydride, is the chemical compound with the formula 2O. Commonly abbreviated Ac2O, it is the simplest isolatable acid anhydride and is a widely used reagent in organic synthesis...
. The synthesis is then completed by dehydrogenation
Dehydrogenation
Dehydrogenation is a chemical reaction that involves the elimination of hydrogen . It is the reverse process of hydrogenation. Dehydrogenation reactions may be either large scale industrial processes or smaller scale laboratory procedures....
of the five-membered ring to produce the furan ring.
Biosynthesis
Psoralen originates from coumarins of the shikimate pathway; its biosynthesis is shown in the figure below. The aromatic ring in 6 is activated at positions ortho to the hydroxyl group, and is alkylated by 5, an alkylating agent. The dimethylallyl group in 7 then undergoes cyclization with the phenol group to give 8. This transformation is catalysed by a cytochome P-450-dependent monooxygenase17 (psoralen 5-monooxygenase), and cofactors (NADPH) and molecular oxygen.
Another biosynthesis pathway of psoralen is shown below in the figure. A second P-450-dependent monooxygenase enzyme (psoralen synthase
Psoralen synthase
In enzymology, a psoralen synthase is an enzyme that catalyzes the chemical reaction-marmesin + NADPH + H+ + O2 \rightleftharpoons psoralen + NADP+ + acetone + 2 H2O...
) then cleaves off 10 (in the form of 11) from 8 to give 1. This pathway does not involve any hydroxylated intermediate, and cleavage is postulated to be initiated by a radical reaction.
Plants containing Psoralen
Ficus carica is probably the largest source But it is also found in small quantities in Ammi visnagaAmmi visnaga
Ammi visnaga is a species of flowering plant in the carrot family known by many common names, including bisnaga, toothpickweed, and khella. It is native to Europe, Asia, and North Africa, but it can be found throughout the world as an introduced species. This is an annual or biennial herb growing...
, Pastinaca sativa, Petroselinum crispum, Levisticum officinale, Foeniculum vulgare (Fruit), Daucus carota, Apium graveolens.