Imperatorin (Synonyms Ammidin; Pentosalen; Marmelosin)

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

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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Bergapten (Synonyms Bergapten; Heraclin; Majudin; Psoraderm; 5-Methoxypsoralen; 5-MO)

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

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.

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Methoxsalen (Synonyms Xanthotoxin; Meloxine; Ammoidin; Meladinine; 8-Methoxypsoralen; 8-MOP; 8-MP; Oxsoralen)

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

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.

---------------------------------------

* 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.

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Psoralen-Synonyms Ficusin; 6-Hydroxy-5-Benzofuranacrylic acid d-lactone; Furo (3, 2-d)-coumarin

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

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.***

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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

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

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.

---------------------------------------

* 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 Angelicaarchangelica 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

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

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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Fraxetin (Synonyms 7, 8-Dihydroxy-6-methoxycoumarin)

2.3.2.5 Fraxetin

Synonyms 7, 8-Dihydroxy-6-methoxycoumarin.

Biological Source It is the aglucon of fraxin. Fraxin is present in the seeds of Acsculus hippocastanum L. (Hippocastanaceae)-Horse Chestnut.

Preparation Fraxetin is obtained by heating fraxin with dilute sulphuric acid to affect the hydrolysis of glucoside and get the desired aglucon residue as shown here under:

Characteristic Features Fraxetin is obtained as plates from ethanol having mp 228°C. It has been observed that it turns first yellow at 150°C and subsequently brown at mp. It is soluble in 10 L of cold water, but in 300 ml of boiling water. It is somewhat more soluble in alcohol and practically insoluble in ether.

Identification Tests It forms the corresponding dimethyl ether termed as 6,7,8-trimethoxycoumarin (C₁₂H₁₂O₅) which has a mp 104°C and bp_0.2 90-100°C.

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Daphentin (Synonyms 7, 8-Dihydroxycoumarin)

2.3.2.4 Daphentin

Synonyms 7, 8-Dihydroxycoumarin;

Biological Sources It is the aglucon of daphnin. It is obtained from the seeds and fruits of Daphne mezereum L. (Thymelaeaceae)-Mezereon; and the seeds of Euphorbia lathyris L. (Euphorbiaceae)-Mole Plant, Petroleum Plant, Caper Spurge.

Preparation Daphentin is prepared conveniently from its glucoside known as daphnin i.e., 7, 8-dihydroxycoumarin 7-β-D-glucoside by treating the latter in three different ways, namely: (i) By boiling with dilute mineral acids; (ii) By enzymatic hydrolysis; and (iii) By sublimation as given below:

Characteristic Features The crystals obtained from dilute ethanol has a mp 256°C (decomposes). It undergoes sublimation on heating. It is soluble in boiling water, hot dilute alcohol and hot glacial acetic acid. It is found to be sparingly soluble in ether, CS2, chloroform, and benzene.

Identification Tests

1. An aqueous solution of daphentin gives a green colouration with FeCl3 solution, which turns red on the addition of sodium carbonate.

2. An alkaline solution of daphentin in alkali carbonate or alkali gives a yellow colour.

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Scopoletin (Synonyms Chrysatropic acid; Gelseminic acid; 6-Methoxyumbelliferone; β-Methylesculetin; 7-Hydroxy 6-methoxycoumarin)

2.3.2.3 Scopoletin

Synonyms Chrysatropic acid; Gelseminic acid; 6-Methoxyumbelliferone; β-Methylesculetin; 7-Hydroxy 6-methoxycoumarin.

Biological Sources It is the aglucone of scopolin. Scopoletin occurs in the roots of Arnica montana L. (Asteraceae)-Mountain Tobacco, Leopard’s-bane; leaves of Artemesia abrotanum L. (Asteraceae)-Southernwood, Old Man; roots and leaves of Atropa belladona L. (Solanaceae)-Belladonna, Deadly Nightshade; barks of Brunfelsia uniflorus (Phol.) D. Don. (Solanaceae)-Manaca, Manacan; fruits of Capsicum annuum L. (Solanaceae)-Chili, Sweet Peppers, Paprika; oil of the plant Chamaemelum nobile (L.) All. (Asteraceae)-Roman Comomile; English Camomile, Comomile; and roots of Withania somniferum (L.) Dunal (Solanaceae)-Ashwagandha.

Preparation It is obtained by the hydrolysis of the glucoside scopolin i.e., 7-(β-D glucopyranosyloxy)-6-methoxy-2H-1-benzopyran-2-one as follows:

Characteristic Features Scopoletin occurs as prisms or needles from either acetic acid or chloroform. It melts at 204°C and has a uvmax: 230, 254, 260, 298, 346 nm (log ε 4.11, 3.68, 3.63, 3.68, 4.07). It is slightly soluble in water or cold ethanol and quite soluble in hot ethanol and hot glacial acetic acid. It is moderately soluble in chloroform, but practically insoluble in the non-polar solvent benzene.

Identification Tests

1. Dissolve 0.1 g in ethanol and warm it in an electric water-bath to affect dissolution. The resulting solution gives a blue fluorescence.

2. A solution of 0.1 g in 3 ml of hot ethanol reduces the Fehling’s solution thereby leaving behind a brick-red precipitate of cupric oxide (CuO).

It is pertinent to mention here that there exists some rarer species of hydroxycoumarins, such as: daphentin and fraxetin, which shall now be discussed in the sections that follows:

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Esculetin (Synonyms Aesculetin; Chicorigenin; 6, 7-Dihydroxy-coumarin)

2.3.2.2 Esculetin

Synonyms Aesculetin; Chicorigenin; 6, 7-Dihydroxy-coumarin.

Biological Source It is the aglucon of esculin and cichorlin: Esculin is derived from two different plant sources, namely: (a) the barks of Crataegus oxycantha L. (Rosaceae)-Hawthorn; and (b) the flowers of Centarea cyanus Linn., (Compositae). It is a glucoside which upon hydrolysis gives the aglucon esculetin.

Esculetin is also obtained from cichorlin, which is a glucoside and found to be isomeric with esculin. Cichorlin is present in the flowers of the chicory plant (Chichorium intybus L., family: Compositae).

Preparation It is obtained by the hydrolysis of the following two glucosides, namely:

(a) From Esculin:

(b) From Cichorlin:

Characteristic Features It is obtained as prisms from glacial acetic acid and as leaflets by vacuum sublimation. Its mp is 268-270°C. It is soluble in dilute alkalies (2M solution) with the emission of blue fluorescence. It is almost insoluble in ether and in boiling water, but moderately soluble in hot ethanol and in glacial acetic acid.

Uses It is mostly in filters for absorption of uv-light

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Umbelliferone (Synonyms Hydrangin; Skimmetin)

2.3.2.1 Umbelliferone

Synonyms Hydrangin; Skimmetin.

Biological Sources Umbelliferone is present in a variety of medicinal plants, for instance: Apium graveolens L. (Apiaceae) Celery; Artemisia abrotanum L. (Asteraceae)-Southernwood, Old Man; Daphne mezereum L. (Thymelaeaceae)-Mezereon; Dipteryx odorata (Aubl.) Willd. (Fabaceae)-Tonka Bean, Tonga, Cumaru; Ferula sumbul Hook. (Apiaceae)-Sumbul, Mask Root; Hydrangea paniculata Seib. (Saxifragaceae)-Peegee; Lavandule angustifolia Mill. (Lamiaceae)-Lavender; Matricaria chamomilla L. (Asteraceae)-Hungarian Camomile, German Camomile, Manzanilla; and Pimpinella anisum L. (Apiaceae)-Anise.

Preparation Asafoetida contains resin (40-65%) which consits of chiefly a resin-alcohol asaresinotannol both in the free or combined form with ferulic acid, and of course, free umbelliferone is totally absent in the drug. Thus, umbelliferone is prepared by treating ferulic acid with HCl which gets converted to umbellic acid and the latter loses a molecule of water to give rise to umbelliferone as given below:

Umbelliferone may also be obtained by distillation of resin from Umbelliferae.*

Characteristic Features It is obtained as needles from water. It develops the characteristic odour of coumarin on heating. Its mp is 225-228°C. It usually sublimes. Its solubility in water is very poor i.e., it dissolves 1 g in nearly 100 ml of boiling water. It is freely soluble in ethanol, chloroform, acetic acid and dilute alkaline solution. It is sparingly soluble in ether and the solutions exhibit a distinct blue fluorescence.

Identification Test When 0.5 g of umbelliferone is triturated with pure sand (SiO₂) and 5 ml of HCl, added 5 ml of water, filtered and to the filtrate added an equal volume of ammonia solution, it gives a beautiful blue fluorescence.

Uses

1. It is an important ingredient in most sunscreen lotions and creams.

2. It is most importantly used as an intracellular and pH sensitive fluorescent indicator and bloodbrain-barrier (BBB) probe.

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* Z wenger, Ann., 115, 1, 15 (1860).

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Hydroxycoumarins (Umbelliferone, Esculetin, Scopoletin, Daphentin, Fraxetin

2.3.2 Hydroxycoumarins

Hydroxycoumarins are invariably found in a large number of plant families. However, the relatively more common ones are based upon the following substances, such as: umbelliferone (7-hydroxy coumarin), aesculetin (6, 7-dihydroxy-coumarin) and scopoletin (6-methoxy-7-hydroxy coumarin) as given below.

Interestingly, some rarer hydroxycoumarins are, namely, dephentin (7, 8-dihydroxy coumarin) and fraxetin (6-methoxy, 7-8-dihydroxy coumarin) are both obtained from plant sources.

A few typical examples of hydroxycoumarins shall be described in the sections that follow, e.g., Umbelliferone, Esculetin, and Scopoletin.

2.3.2.1 Umbelliferone

Synonyms Hydrangin; Skimmetin.

Biological Sources Umbelliferone is present in a variety of medicinal plants, for instance: Apium graveolens L. (Apiaceae) Celery; Artemisia abrotanum L. (Asteraceae)-Southernwood, Old Man; Daphne mezereum L. (Thymelaeaceae)-Mezereon; Dipteryx odorata (Aubl.) Willd. (Fabaceae)-Tonka Bean, Tonga, Cumaru; Ferula sumbul Hook. (Apiaceae)-Sumbul, Mask Root; Hydrangea paniculata Seib. (Saxifragaceae)-Peegee; Lavandule angustifolia Mill. (Lamiaceae)-Lavender; Matricaria chamomilla L. (Asteraceae)-Hungarian Camomile, German Camomile, Manzanilla; and Pimpinella anisum L. (Apiaceae)-Anise.

Preparation Asafoetida contains resin (40-65%) which consits of chiefly a resin-alcohol asaresinotannol both in the free or combined form with ferulic acid, and of course, free umbelliferoneis totally absent in the drug. Thus, umbelliferone is prepared by treating ferulic acid with HCl which gets converted to umbellic acid and the latter loses a molecule of water to give rise to umbelliferone as given below:

Umbelliferone may also be obtained by distillation of resin from Umbelliferae.*

Characteristic Features It is obtained as needles from water. It develops the characteristic odour of coumarin on heating. Its mp is 225-228°C. It usually sublimes. Its solubility in water is very poor i.e., it dissolves 1 g in nearly 100 ml of boiling water. It is freely soluble in ethanol, chloroform, acetic acid and dilute alkaline solution. It is sparingly soluble in ether and the solutions exhibit a distinct blue fluorescence.

Identification Test When 0.5 g of umbelliferone is triturated with pure sand (SiO₂) and 5 ml of HCl, added 5 ml of water, filtered and to the filtrate added an equal volume of ammonia solution, it gives a beautiful blue fluorescence.

Uses

1. It is an important ingredient in most sunscreen lotions and creams.

2. It is most importantly used as an intracellular and pH sensitive fluorescent indicator and bloodbrain-barrier (BBB) probe.

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* Z wenger, Ann., 115, 1, 15 (1860).

2.3.2.2 Esculetin

Synonyms Aesculetin; Chicorigenin; 6, 7-Dihydroxy-coumarin.

Biological Source It is the aglucon of esculin and cichorlin: Esculin is derived from two different plant sources, namely: (a) the barks of Crataegus oxycantha L. (Rosaceae)-Hawthorn; and (b) the flowers of Centarea cyanus Linn., (Compositae). It is a glucoside which upon hydrolysis gives the aglucon esculetin.

Esculetin is also obtained from cichorlin, which is a glucoside and found to be isomeric with esculin. Cichorlin is present in the flowers of the chicory plant (Chichorium intybus L., family: Compositae).

Preparation It is obtained by the hydrolysis of the following two glucosides, namely:

(a) From Esculin:

(b) From Cichorlin:

Characteristic Features It is obtained as prisms from glacial acetic acid and as leaflets by vacuum sublimation. Its mp is 268-270°C. It is soluble in dilute alkalies (2M solution) with the emission of blue fluorescence. It is almost insoluble in ether and in boiling water, but moderately soluble in hot ethanol and in glacial acetic acid.

Uses It is mostly in filters for absorption of uv-light

2.3.2.3 Scopoletin

Synonyms Chrysatropic acid; Gelseminic acid; 6-Methoxyumbelliferone; β-Methylesculetin; 7-Hydroxy 6-methoxycoumarin.

Biological Sources It is the aglucone of scopolin. Scopoletin occurs in the roots of Arnica montana L. (Asteraceae)-Mountain Tobacco, Leopard’s-bane; leaves of Artemesia abrotanum L. (Asteraceae)-Southernwood, Old Man; roots and leaves of Atropa belladona L. (Solanaceae)-Belladonna, Deadly Nightshade; barks of Brunfelsia uniflorus (Phol.) D. Don. (Solanaceae)-Manaca, Manacan; fruits of Capsicum annuum L. (Solanaceae)-Chili, Sweet Peppers, Paprika; oil of the plant Chamaemelum nobile (L.) All. (Asteraceae)-Roman Comomile; English Camomile, Comomile; and roots of Withania somniferum (L.) Dunal (Solanaceae)-Ashwagandha.

Preparation It is obtained by the hydrolysis of the glucoside scopolin i.e., 7-(β-D glucopyranosyloxy)-6-methoxy-2H-1-benzopyran-2-one as follows:

Characteristic Features Scopoletin occurs as prisms or needles from either acetic acid or chloroform. It melts at 204°C and has a uvmax: 230, 254, 260, 298, 346 nm (log ε 4.11, 3.68, 3.63, 3.68, 4.07). It is slightly soluble in water or cold ethanol and quite soluble in hot ethanol and hot glacial acetic acid. It is moderately soluble in chloroform, but practically insoluble in the non-polar solvent benzene.

Identification Tests

1. Dissolve 0.1 g in ethanol and warm it in an electric water-bath to affect dissolution. The resulting solution gives a blue fluorescence.

2. A solution of 0.1 g in 3 ml of hot ethanol reduces the Fehling’s solution thereby leaving behind a brick-red precipitate of cupric oxide (CuO).

It is pertinent to mention here that there exists some rarer species of hydroxycoumarins, such as: daphentin and fraxetin, which shall now be discussed in the sections that follows:

2.3.2.4 Daphentin

Synonyms 7, 8-Dihydroxycoumarin;

Biological Sources It is the aglucon of daphnin. It is obtained from the seeds and fruits of Daphne mezereum L. (Thymelaeaceae)-Mezereon; and the seeds of Euphorbia lathyris L. (Euphorbiaceae)-Mole Plant, Petroleum Plant, Caper Spurge.

Preparation Daphentin is prepared conveniently from its glucoside known as daphnin i.e., 7, 8-dihydroxycoumarin 7-β-D-glucoside by treating the latter in three different ways, namely: (i) By boiling with dilute mineral acids; (ii) By enzymatic hydrolysis; and (iii) By sublimation as given below:

Characteristic Features The crystals obtained from dilute ethanol has a mp 256°C (decomposes). It undergoes sublimation on heating. It is soluble in boiling water, hot dilute alcohol and hot glacial acetic acid. It is found to be sparingly soluble in ether, CS2, chloroform, and benzene.

Identification Tests

1. An aqueous solution of daphentin gives a green colouration with FeCl3 solution, which turns red on the addition of sodium carbonate.

2. An alkaline solution of daphentin in alkali carbonate or alkali gives a yellow colour.

2.3.2.5 Fraxetin

Synonyms 7, 8-Dihydroxy-6-methoxycoumarin.

Biological Source It is the aglucon of fraxin. Fraxin is present in the seeds of Acsculus hippocastanum L. (Hippocastanaceae)-Horse Chestnut.

Preparation Fraxetin is obtained by heating fraxin with dilute sulphuric acid to affect the hydrolysis of glucoside and get the desired aglucon residue as shown here under:

Characteristic Features Fraxetin is obtained as plates from ethanol having mp 228°C. It has been observed that it turns first yellow at 150°C and subsequently brown at mp. It is soluble in 10 L of cold water, but in 300 ml of boiling water. It is somewhat more soluble in alcohol and practically insoluble in ether.

Identification Tests It forms the corresponding dimethyl ether termed as 6,7,8-trimethoxycoumarin (C₁₂H₁₂O₅) which has a mp 104°C and bp_0.2 90-100°C.

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Coumarins-Synonyms cis-o-Coumarinic acid lactone; Cumarin; Coumarinic anhydride; Tonka bean comphor

2.3.1 Coumarins

The chemistry of coumarin may be understood more vividly with the help of geometrical isomers of o-hydroxycinnamic acids, one of which instantly yields the lactone coumarin (or benzopyran), whereas the other fails to do so. Therefore, the former is the cis-isomer called coumarinic acid, and the latter the trans-isomer known as the coumaric acid as given below:

Coumarin

Synonyms cis-o-Coumarinic acid lactone; Cumarin; Coumarinic anhydride; Tonka bean comphor.

Biological Sources Coumarin is present in a large number of medicinal herbs, such as:

Acacia farnesiana (L.) Willd (Fabaceae)-Cassie, Huisache; Apium graveolens L. (Apiceae)-Celery; Artemisia dracunculus L. (Asteraceae)-Tarragon; Chamaemelum nobile (L.) All. (Asteraceae)-Roman Camomile, English Camomile, Camomile; Cinnamomum verum J.S. Presler (Lauraceae)-Ceylon Cinnamon; Dipteryx odorata (Aubl.) Willd (Fabaceae)-Tonka Bean, Tonga, Cumaru; Hyoseyamus niger L. (Solanaceae)-Henbane, Henblain, Jusquaime; Myroxylon balsamum var. Pereirae (Royle) Harms. (Fabaceae)-Balsam of Peru; Peumus boldus Molina (Monimiaceae)-Boldo; Pimpinella anisum L. (Apiaceae)-Anise; and Trilisa odoratissima (J.F.Gemel.) Cass (Asteraceae)-Deertongue, Deer's Tongue.

Characteristic Features Coumarin crystals have an orthorhombic and rectangular plates. They have a pleasant, fragrant odour resembling to that of the vanilla beans and a burning taste. The physical characteristics are, namely: mp 68-70°C and bp 297-299°C. Its solubility in water is very poor, viz., 1g dissolves in m 400 ml of cold and 50 ml of boiling water. However, it is freely soluble in ethanol, chloroform, ether, oils and also in alkaline solutions of NaOH or KOH.

Uses It is used extensively as a flavouring agent in pharmaceutical formulations.

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Coumarins (hydroxy-coumarins and furanocoumarins)

2.3 Coumarins

Coumarin and its derivatives, such as: hydroxy-coumarins and furanocoumarins are present in a plethora of medicinal plants. However, the most common and the most widespread plant coumarin is the parent compound i.e., coumarin itself, which is reported to occur in more than twenty-seven plant families viz., Caprifoliaceae, Leguminosae, Oleaceae, Rubiaceae, Solanaceae, Umbelliferae to name a few such families.

In a broader sense, the coumarins may be classified into three major categories, namely:

(a)Coumarins,

(b)Hydroxycoumarins, and

(c)Furanocoumarins.

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