Furanocoumarins (Psoralen, Methoxsalen, Bergapten, Imperatorin)

2.3.3 Furanocoumarins

Furanocoumarins, represent a class of relatively more complex coumarins that occur in various natural plant products. A few important members of this particular class are, namely: Psoralen;
Methoxsalen; Bergapten; and Imperatorin, which shall be discussed below in an elaborated manner.

2.3.3.1 Psoralen

Synonyms Ficusin; 6-Hydroxy-5-Benzofuranacrylic acid d-lactone; Furo (3, 2-d)-coumarin.
Biological Source Psoralen belongs to one of a group of furanocoumarins occurring naturally in more than two dozen different plant sources, for instance: Rutaceae (e.g., Bergamot, Limes, Cloves); Umbelliferae (Celery; Parsnips); Leguminosae (e.g., Psoralen coryfolia); and Moraceae (e.g., Figs). It is also found in the Rue Oil obtained from Ruta graveolens L. (Rutaceae)-known as Rue, Garden Rue or German Rue. It is obtained from the leaves of Ficus carica Linn. (Moraceae)-Figs, Anjir.
Chemical Structure

Psoralen
Characteristic Features Psoralen crystals from ether have two sets of melting points e.g., 163-164°C and 169-179°C (Spath). It is very soluble in chloroform, less soluble in alcohol, sparingly soluble in ether and practically insoluble in petroleum ether (60-80°C).
Identification Tests
1. Dissolve 1 mg of psoralen is 5 ml of ethanol and add to it 15 ml of a mixture made up of 3 parts of propylene glycol, 5 parts of acetic acid and 43 parts of water. The resulting mixture on being exposed to the uv-light in a uv-chamber, gives a distinct blue-fluorescence.
2. When 1 mg is dissolved in 2 ml ethanol, mixed with two drops of NaOH solution (0.1 M) and the resulting solution is subjected to uv-light, it emits a yellow fluorescence.
Uses
1. It is used in the treatment of leucoderma patches.
2. Psoralens have also exhibited photosensitizing and phototoxic effects in animals and human beings and, hence have been employed extensively in photochemotherapy for the treatment and management of vitiligo*, psoriasis** and mycosis fungoides.***

2.3.3.2 Methoxsalen

Synonyms Xanthotoxin; Meloxine; Ammoidin; Meladinine; 8-Methoxypsoralen; 8-MOP; 8-MP; Oxsoralen.
Biological Source Methoxsalen is a naturally occurring analogue of psoralen, found in various species of Rutaceae, Leguminosae, and Umbelliferae. It is obtained from the fruits of Fragara xanthoxyloides and the fruits of Ammi majus belonging to the natural order Umbelliferae. It is also found in the herb Ruta graveolens (Rutaceae).
Chemical Structure

 Methoxsalen
9-Methoxy-7H-furol [3,2-g][1] benzopyran-7-one; (C12H8O4).
Isolation The various steps involved are as under:
1. The A. majus fruits are dried, powdered, sieved and extracted with petroleum ether to complete exhaustion.
2. The petroleum ether extract is filtered and concentrated to obtain a dark green semi-crystalline solid mass (crude methoxalen) crystallizes out.
Note: The petroleum ether layer is carefully deeanted off while hot and reserved separately for the isolation of imperatorin.
3. The residual dark-green solid mass is dissolved in minimum quantity of ethanol and boiled over an electric water-bath for 45-60 minutes. The contents are filtered immediately and the filtrate is concentrated under vacuo. It is cooled in a refrigerator overnight when pale-green crystals separate out. The crystals of methoxsalen thus obtained are purified first by washing with boiling water and finally recrystallizing from ethyl acetate.
Characteristic Features
1. It is obtained in two forms: first—as silky needles either from hot water or benzene + petroleum ether; secondly—as long rhombic prisms from ethanol + ether, having mp 148°C.
2. It is odourless but has a distinct bitter taste followed by tingling sensation.
3. It has uvmax: 219, 249, 300 nm (log ε 4.32, 4.35, 4.06).
4. It has a pH 5.5.
5. Solubility Profile: It is practically insoluble in cold water; sparingly soluble in boiling water,
liquid petroleum, ether; soluble in boiling ethanol, acetone, acetic acid, vegetable fixed oils, propylene glycol, benzene; freely soluble in chloroform; and soluble in aqueous alkalies with ring cleavage, but is reconstituted upon neutralization.
Identification Tests These are as follows:
1. A few crystals of methoxsalen on being triturated with little sulphuric acid in a porcelain dish produces an orange-yellow colour that gets changed to light green finally.
2. Wagner’s Reagent Test: Xanthotoxin gives an instant precipitate with Wagner’s Reagent (I2 + KI).
3. HNO3 Test: It gives a distinct yellow colouration with dilute HNO3, which on rendering to alkaline with KOH or NaOH, changes to crimson colour.
Uses
1. It is used extensively in the treatment of leukoderma.
2. It is employed as a pigmentation agent.
3. It is also used in the treatment of psoriasis and mycosis fungoides.
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* T.F. Anderson, J.J. Voorhees, Ann. Rev. Pharmacol. Toxicol., 20, 235 (1980); Vitiligo: An acquired cutaneous disorder characterised by white patches, surrounded by areas of normal pigmentation.
** A. Kornhauser et al., Science, 217, 733 (1982); Psoriasis: A common chronic disease of the skin consisting of erythematous papules that coalesce to form plaques with distinct borders.
*** B.J. Parsons, Photochem. Photobiol., 32, 813-821 (1980); Mycosis Fungoides: A non-Hodgkin's form of cutaneous
T-cell lymphoma of unknown etiology caused by a fungus.

2.3.3.3 Bergapten (e)

Synonyms Bergapten; Heraclin; Majudin; Psoraderm; 5-Methoxypsoralen; 5-MOP.
Biological Source Bergapten is the naturally occurring analogue of psoralen and an isomer of methoxsalen, mostly found in a wide variety of plants, such as: roots and fruits of Angelica archangelica L. (Apiaceae)-Angelica, Garden Angelica, European Angelica; seeds of Apium graveolens L. (Apiaceae)-Celery; leaves, stems and fruits of Petroselinum crispum (Mill.) Nym. (Apiaceae)-Parsley; Rue Oil of Ruta graveolens L. (Rutaceae)-Rue, Garden Rue, German Rue.
Preparation Bergapten was first isolated from the oil of bergamot from Citrus bergamia Risso., belonging to the natural order Aurantiodiae*. It was also isolated from Fagara xanthoxyloides Lam., belonging to family Rutaceae.**
Chemical Structure

Bergapten (e)
Characteristic Features The crystals obtained from ethanol are needle-shaped having mp 188°C. It sublimes on heating. It is practically insoluble in boiling water, slightly soluble in glacial acetic acid, chloroform, benzene, and warm phenol. It is soluble in absolute ethanol (1 part in 60).
Identification Test It gives a distinct yellow-gold colouration when its solution is treated with a few drops of concentrate H2SO4.
Uses
1. It is used in photochemotherapy of psoriasis.
2. It has been used to promote tanning in suntan preparations e.g., creams and lotions.

2.3.3.4 Imperatorin

Synonyms Ammidin; Pentosalen; Marmelosin;
Biological Sources It is obtained from the roots and fruits of Angelica archangelica L. (Apiaceae)
(Angelica, Garden Angelica, European Angelica); from the roots of Imperatoria osthruthium L. (Umbelliferae); from fruit of Pastinaea sativa L. (Umbelliferae); and also in the fruits of Ammimajus (Umbelliferae). However, the seed oil of A. archangelica is said to contain upto 0.5% imperatorin.
Chemical Structure

Imperatorin
9-[(3-Methyl-2-butenyl)oxy]-7H-furo [3, 2-g] [1] benzopyran-7-one; (C16H14O4).
Isolation The various steps involved are as follows:
1. The petroleum ether mother liquor left after the separation of methoxsalen (Xanthotoxin), is concentrated under vacuo and allowed to cool in a refrigerator overnight when the crude imperatorin separates out.
2. The crude product is collected, dissolved in ether, filtered and concentrated under reduced pressure. It is kept in a refrigerator, and the crystals separating out are purified subsequently by recrystallization from ethanol.
Characteristic Features These are as given below:
1. It is obtained in two forms: First—as prisms from ether, and secondly—as long fine needles from hot water, having mp 102°C.
2. It has uvmax: 302, 265, 250 nm (log ε 3.95, 4.00, 4.24).
3. Solubility Profile: It is practically insoluble in cold water; very sparingly soluble in boiling water; freely soluble in chloroform; and soluble in benzene, ethanol, ether, petroleum, ether alkali hydroxides.
Identification Tests These are as stated below:
1. Sulphuric Acid Test: Imperatorin gives an intense deep orange colouration with a few drops of sulphuric acid which ultimately changes to brown colour.
2. Marqui’s Reagent: It gives an orange colouration with Marqui’s Reagent that rapidly changes to brown.
3. Tollen’s Reagent (Ammoniacal AgNO3): It reduces Tollen’s Reagent to produce a silver mirror.
4. Fehlings Test: It reduces Fehling’s solution to give a brick-red precipitate of cupric oxide.
5. Nitric Acid Test: It gives a distinct yellow colour on boiling with dilute HNO3, and this colour changes to purple on being treated with strong alkali e.g. NaOH or KOH.
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* Pomeranz, Monatsh, 12, 379 (1891), 14, 28 (1893).
** H. Thoms., E. Baeteke, Ber., 44, 3326 (1911).

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