Anthraquinones and its glycosides Pharmacognosy I Mosul University/ College of Pharmacy L.A. Dilbreen Barzanji

Anthraquinones and its glycosides Substances of the anthraquinone type were recognized both in the free state and as glycosides. Natural products also contained reduced derivatives of the anthraquinones (oxanthrones, anthranols and anthrones) and compounds formed by the union of two anthrones molecules (i.e dianthrones). Because glycosides are often easily hydrolysed, the earlier workers tended to isolate products of hydrolysis rather than the primary glycosides.

The following aglycones have long been established: Crysophanol or crysophanic acid from rhubarb and cascara. Aloe-emodin from rhubarb and senna. Rhein from rhubarb and senna. Emodin or frangula-emodin from rhubarb and cascara. Improved extraction methods, developed by Stoll and his colleagues, led to the isolation of main senna glycosides, sinnosides A and B, in 1941. Since this date many new glycosides including C-glycosides and various stereoisomers have been isolated and their structures determined.

Anthraquinones The derivatives of anthraquinone present in purgative drugs may be dihydroxy phenols such as crysophanol, trihydroxy phenols such as emodin or tetrahydroxy phenols such as carminic acid. Other groups are often present, for example, methyl in crysophanol, hydroxyl-methyl in aloe-emodin or carboxyl in rhein and carminic acid. Anthraquinones containing a free carboxylic acid group (e.g. rhein) can be separated from other anthraquinones by extraction from an organic solution with sodium bicarbonate solution. When such substances occur as glycosides, the sugar may be attached to various positions. Anthraquinones derivatives are often orange-red compounds, which may sometimes be observed in situ (e.g. in the medullary rays of rhubarb and cascara).

Anthranols and anthrones These reduced anthraquinones derivative occur either free or combined as glycosides. They are isomeric and may be partially converted to the other in solution. The parent substance, anthrone is a pale yellow, non-flourescent substance which is insoluble in alkali; its isomer anthanol, is brownish-yellow and forms a strongly fluorescent solution in alkali.

Oxanthrones These are intermediate products between anthraquinones and anthranols.

Dianthrones These are compounds derived from two anthrone molecules, which may be identical or different; they are readily formed as a result of mild oxidation of the anthrone or mixed anthrones (e.g. a solution in acetone and presence of atmosprheric oxygen). Reidin A,B and C which occur in senna and rhubarb are heterodianthrones, i.e. composed of unlike anthrones.

Aloin-type or C-glycosides The aloin obtained from species of Aloe, although one of the first glycoseides to be isolated, was a problem for investigators for a long of time. It is strongly resistant to normal acid hydrolysis but may be oxidized with ferric chloride. A study of its degradation products indicated a sugar-like chain and the structure shown, in which the sugar is joined to the aglycone with a direct C-C linkage (a C-glycoside). two aloins are known (A and B).

Senna leaf Senna (Sennae Folium) consist of the dried leaflets of Cassia senna which are known in commerce as Alexandrian or Khartoum senna. The senna plant is a small shrubs of the family leguminosae, about 1 m high, with paripinnate compound leaves. It may be grown either in dry lands or wetter conditions. Alexandrian senna is collected mainly in September, from both wild and cultivated plants. The branches bearing leaves and pods are dried in the sun and then conveyed to place where pods and large stalks are separated by sieves, the leaves are then graded. Owing to the carefully way in which the drug is collected and compressed into bales, few leaflets are usually broken.

Constituents: aloe-emodin and rhein were first isolated in 1913 Constituents: aloe-emodin and rhein were first isolated in 1913. Many compounds based on these two have been obtained. Two active crystalline glycosides, sennoside A and sennoside B. they both hydrolysed to give two molecules of glucose and the aglycones sennidin A and B. Sennidin A is dextrorotary and B is its mesoform. Sennosides C and D, which are the glycosides of heterodianthrones involving rhein and aloe-emodin. It also contains other anthraquinone glycosides such as palmidin A, etc.

Evaluation: it is difficult to remove all fragments of rachis, petiole and stalk from the drug, but the amount of these structures is limited by BP to 3%. The BP/EP determines the total senna leaf glycosides in terms of sennoside B (not less than 2.5%).

Senna fruit Senna pods (Sennae Fructus) are the dried ripe fruits of C. senna . The pods are collected with the leaves and dried as described above. After separation from the leaves they are hand-picked into various qualities. The active constituents are located in the pericarp; they are similar to those of the leaves, together with sennoside A, which constitutes about 15% of sennoside mixture. Uses: the use of laxative is increasing and senna constitutes a useful purgative for either habitual constipation or occasional use. They lack astringent after-effect of rhubarb. Despite the availability of a number of synthetics, sennoside preparations remain among the most important pharmaceutical laxatives.

Cascara bark Cascara sagrada is the dried bark of Rhamnus purshianus. The bark is collected from wild trees which are 6-18 high, growing in the pacific coast of North America. The bark is collected from mid-April to the end of August, when it separate readily from the wood. Longitudinal incisions about 5-10 cm apart are first made in the trunk and the bark removed. The pieces are dried in the shade with the cork uppermost. During preparation and storage the bark must be protected from the rain and damp, or partial extraction of the constituents may occur or the bark may be mouldy.

That the bark must be kept for at least 1 year before use is no longer a BP requirement but the bark appears to increase in medicinal value and price until it is about 4 years old. Many companies prefer to use bark which has been stored for considerably more than 1 year which are better tolerated but as effective as those prepared from more recently collected bark, this is presumably due to hydrolysis or other changes during storage.

Cascara contains about 6-9% anthracene derivatives which are present both as O- and C-glycosidic linkages. The following groups are now manifest: Four primary glycosides or cascarosides A,B,C and D, they contain both O- and C-glycosidic linkages. Two aloins, barbaloin derived from the aloe-emodin anthrones and chrysaloin derived from crysophanol anthrone. These C-glycosides are probably breakdown products from (1). A number of O-glycosides derived from emodin oxanthrone, aloe-emodin and crysophanol. Various dianthrones, including those of emodin, aloe-emodin and crysaphanol and heterodianthrones palmidin A, B and C. Aloe-emodin, crysophanol and emodin in the free state.

Uses: cascara is a purgative resembling senna in its action Uses: cascara is a purgative resembling senna in its action. It is mainly used in the form of liquid extract or elixir or as tablets prepared from a dry extract. It is also used in veterinary work.

Frangula bark Frangula bark, alder buckthorn, is obtained from Rhamnus frangula (f. Rhamnaceae), a shrub 3-5 m high and found in Britain and Europe. The bark included in the BP/EP is required to contain not less than 7.0% glucofrangulins calculated as glucofrangulin A. Frangula contains anthraquinone derivatives present mainly in the form of glycosides. The rhamnoside franguloside, or frangulin, consist of two isomers, frangulosides A and B, formed by partical hydrolysis of the corresponding rhamnoglycosides, glucofrangulins A and B.

Rhubarb Rhubarb consists of the dried underground parts of Rheum palmatum. The drug appears to obtained from both wild and cultivated plants grown on the high plateau of Asia and Tibet to south-east China. Chinese rhubarb has a long history. It is mentioned in herbal of about 2700 BC. The BP/EP drug is required to contain not less than 2.2% of hydroxyanthraquinone derivatives calculated as rhein. Collection and preparation: the rhizomes are grown at a high altitude dug up in autumn or spring when about 6-10 years old, decorticated and dried.

Constituents: Following type of anthraquinones in rhubarb: anthraquinones without a carboxyl group (e.g. crysophanol, aloe-emodin, emodin and physcion) also their glycosides (crysophanein and glucoaloe-emodin). Anthraquinones with a carboxyl group (e.g. rhein and its glycoside, glucorhein). Anthrones or dianthrones of crysophanol, or emodin or aloe-emodin or physcion. Heterodianthrones derived from two different anthrone molecules. For example, palmidin A from aloe-emodin anthrone and emodin anthrone. Uses: rhubarb is used as a bitter stomachic and in the treatment of diarrhea, purgation being followed by an astringent effect. The drug is suitable as an occasional aperients but not for the treatment of chronic constipation.

Aloes Aloe is the solid residue obtained by evaporating the liquid which drains from the transversely cut leaves of various species of Aloe (Liliaceae). The juice is usually concentrated by boiling and solidifies on cooling. 180 known species of Aloe, the drug mainly obtained from: A. ferox and A. Barbadensis. the genus Aloe includes herbs, shrubs and trees, bearing spikes of white, yellow or red flower. Aloe leaves are fleshy, are strongly cuticularized and usually prickly at the margins.

Constituents: Aloe contain C-glycosides and resins Constituents: Aloe contain C-glycosides and resins. The crystallines glycosides known as ‘aloin’. Aloin BP contain not less than 70% anhydrous barbaloin. The main crystalline glycoside, barbaloin, is found in all the commercial varieties. Barbaloin is a C-glycoside ; a 10-gluco-pyranosyl derivative of aloe-emodin anthrone. Unlike O-glycosides, it is not hydrolysed by heating with dilute acids or alkalis. However It can be decomposed oxidative hydrolysis, with reagents such as ferric chloride, when it yields glucose, aloe-emodin anthrone and little aloe-emodin. Small quantities of aloe-emodin are sometimes present in aloes, Cape aloe (A. Ferox) also contains aloinosides A and B, which are O-glycosides of barbaloin.

As with other anthraquinone producing plants, in Aloe species the content of anthraquinones is subject to seasonal variation. Anthraquinone derivatives are confined to the leaf juices and that aloin reaches a maximum concentration in the dried leaf juices in the summer and lowest in the winter. Uses: aloes is employed as purgative.

‘Aloe vera’ products Aloe vera products are derived from the mucilage located in parenchymatous cells of aloe vera leaf and should not be confused with aloes (which originate from the aloetic juice of the pericyclic region). The mucilaginous gel has been used from early times for the treatment of numerous conditions but in recent years its use in herbal and cosmetic industries has become very big business in the USA, Europe and elsewhere. There are doubts about the true usefulness of the products which feature as suntan lotions, tonics and food additives.

Research over the last ten years has , however, largely upheld a number of the therapeutic properties ascribed to the gel. These include the anti-inflammatory properties (wound healing, burn healing, frost bite), gastrointestinal activity (peptic ulcer), antidiabetic activity, antifungal activity, antibacterial activity and radiobiological protection. Not all these properties have been unequivocally accepted. The complex chemistry of the gel makes the attribution of the various activities to specific compounds difficult. Indeed beneficial clinical results for a particular condition may arise from more than one component. Thus wound-healing benefits may derive from the anti-inflammatory, fibroblast-stimulating, antibacterial and hydrophilic properties of the gel.

Hypericum- St. John’s wort Hypericum consists of the dried aerial parts of Hypericum perforatum, gathered usually at the time of flowering or shortly before. Commercial extracts are standardized on their naphthodianthrone content, expressed as hypericin. Care should be taken during collecting as contact photosensitivity has been reported. Drying at 700 for 10 hours is recommended.

Hypericum contains a variety of constituents with biological activity: Anthraquinones: principally hypericin and pseudohypericin, also isohypericin and emodin-anthrone. The BP/EP requires not less than 0.08% of total hypericin. Prenylated phloroglucinol derivatives: hyperforin (2.0-4.5%), adhyperforin and furohyperforin. These phloroglucinols constitute the principal components of the lipophilic extract of the plant and considered to be the most important active constituents regarding antibiotic and antidepressant properties. Unfortunately they are very prone to oxidative transformations and a number of such degradation products have been identified. Flavonoids Volatile oils Other constituents

Action and uses: An explosion in the popularity of St. John’s wort related to its unregulated availability for the treatment of mild to moderate depression. In the USA,for the first eight months of 1999, it ranked second to ginkgo as the best-selling product of herbal mainstream market with retail sales valued at over 78 million dollars. In Germany, it represented 25% of all antidepressant presicriptions. It was described as ‘nature’s Prozac’, without the disadvantegeuos side-effects of the latter. However, a cautionary warning was struck. St John’s wort will adversely affect the performance of a number of a common drugs by causing their rapid elimination from the body, either by enhanced metabolism or as a result of increased action of the drug transporter P-glycoprotien. Among common drugs so affected are anticoagulants sucha s warfarin, digoxin, tricyclic antidepressant agents, simvastatin and others.

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