Drug Containing Glycosides PDF

Drug containing Glycosides By Abyot E. (B.Pharm, MSc.)  Learning objectives After completing this unit you will be able to : – Define and classify glycosides – List general properties of glycosides – State crude drug containing glycosides along with their biological source...

Drug containing Glycosides By Abyot E. (B.Pharm, MSc.)  Learning objectives After completing this unit you will be able to : – Define and classify glycosides – List general properties of glycosides – State crude drug containing glycosides along with their biological source, main chemical constituent and Use.  Drug containing glycosides GIYCOSIDES – Compounds that yield one or more sugars upon hydrolysis – Have two moieties: – sugar portion (glycone) – non-sugar portion (aglycone or genin). Drug containing glycosides  Drug containing glycosides Glycosides of many different aglycones are extensively found in the plant kingdom – Many of these glycosides are formed from phenols, polyphenols, steroidal and terpenoidal alcohols through glycosidic attachment to sugars  Drug containing glycosides Among the sugars found in natural glycosides, D-glucose is the most prevalent o – Othrs L-rhamnose, D- and L-fructose and L- arabinose also occur quite frequently – Of the pentoses, L-arabinose is more common than D-xylose – sugars often occur as oligosaccharides.  Drug containing glycosides The sugar moiety of a glycoside can be joined to the aglycone in various ways – the most common being via an oxygen atom (O- glycoside) – The bridging atom can also be a carbon (C- glycoside), a nitrogen (N-glycoside) or a sulphur atom (S-glycoside)  Drug containing glycosides – By virtue of the aglycone and/or sugar, glycosides are extremely important pharmaceutically and medicinally Physical Characters – Solids either amorphous or crystalline – Non volatile – Usually bitter in taste – Soluble in water and polar organic solvents – Reduce Fehling’s solutions only after hydrolysis  Extraction and Isolation Destruction of hydrolyzing enzymes De-fating or purification of the plant material (in case of seeds). Extraction of the glycosidal Concentrate the alcoholic extract Purify aqueous extract Isolation  Drug containing glycosides Classification – Based on sugar component Glycosides that contain glucose are called glucoside Similarly, when the sugars are fructose or galactose, the glycosides are called fructoside or galactoside, respectively Drug containing glycosides  Drug containing glycosides  Based on aglycone Glycosides can be classified on the basis of the structural types of aglycone present in the glycoside Anthraquinone Flavonoid Flavonoid Iridoid  lignan steroid glycosides  Drug containing glycosides Based on properties or functions – Glycosides that have ‘soap like’ properties are called saponins – Similarly, glycosides that liberate hydrocyanic acid (HCN) on hydrolysis are known as cyanogenic glycosides – glycosides that have an effect on heart muscle are called cardiac glycosides  Drug containing glycosides  Chemical test for glycosides Keller-Kiliani test  Keller-Kiliani test Dissolve the solution to acetic acid containing a trace of ferric chloride transferred to the surface of concentrated sulphuric acid At the junction of the liquids a reddish brown colour is produced which gradually becomes blue Used for identification of deoxy-sugars in cardiac glycosides  Drug containing glycosides Borntrager’s Test – The drug is boiled with dilute sulphuric acid, filtered and to the filtrate benzene, or ether or chloroform is added and shaken well – The organic layer is separated to which ammonia is added slowly – The ammoniacal layer shows pink to red color due to presences of anthraquinone glycosides  Drug containing glycosides Test for hydrocyanic acid (HCN) – The liberation of hydrocyanic acid due to complete hydrolysis of cyanogenic glycosides can be determined by a simple colour test using sodium picrate paper (yellow), which turns red (sodium isopurpurate) in contact with HCN  Drug containing glycosides Liebermann’s test: Used for identification of Steroidal or cardiac glycosides Flavonoidal glycosides and/or aglycones give characteristic color with, NH4OH, AlCl3, FeCl3 Sulphur containing glycosides give black precipitate of silver sulphate upon treatment with AgNO3 solution  Medicinal importance of glycosides Cardiac drugs: cardiotonic glycosides e.g., digitalis glycosides, strophanthus, squill Laxatives e.g., anthraquinone glycosides of senna, aloes, rhubarb, cascara, frangula. Counter irritants e.g., thioglycosides Analgesics e.g., methylsalicylate  Anti rheumatic e.g., salicin. Some glycosides are claimed to reduce the capillary fragility e.g., flavonoidal glycosides, rutin, hisperidin Anti-inflamatory: e.g., the glycoside glycyrrhizin has a demulcent, expectorant and antispasmodic action Anticancer agent e.g., amygdalin known  Anthracene/anthraquinone glycosides Learning objectives – distinguish the basic skeletal of anthraquinone glycosides – Discus some crude drugs containing anthraquinone glycosides  Anthracene/anthraquinone glycosides… belong to structural category of anthracene derivatives Most of them possess an anthraquinone skeleton Glucose and rhamnose are the most common Increases peristaltic action of large intestine – Used in laxative preparations – The use of anthraquinone drugs be restricted to short term treatment of constipation only, as frequent or long term use may cause intestinal tumours  structural variations within anthraquinone aglycones Anthraquinone Anthrone Anthranol O O OH 8 1 8 1 7 9 2 4H 7 9 2 6 10 3 6 10 3 5 4 5 H H 4 O H O 2H 8 1 7 9 2 6 10 3 5 H OH 4 Oxanthrone Dimeric anthraquinone and their derivatives Some Drugs containing Anthracene derivatives Senna – Senna leaf and fruit are obtained from Cassia angustifolia (Leguminosae/Fabaceae), known as Tinnevelly senna, or less commonly from Cassia senna (syn Cassia acutifolia) – The plants are low, branching shrubs, Cassia angustifolia being cultivated in India and Pakistan, and Cassia senna being produced in the Sudan, much of it from wild plants. Some Drugs containing Anthracene derivatives…  Some Drugs containing Anthracene derivatives… The active constituents in both senna leaf and fruit are dianthrone glycosides, principally sennosides A and B  Some Drugs containing Anthracene derivatives… Senna is a stimulant laxative and acts on the wall of the large intestine to increase peristaltic movement – After oral administration, the sennosides are transformed by intestinal flora into rhein anthrone, which appears to be the ultimate purgative principle  Some Drugs containing Anthracene derivatives… The glycoside residues in the active constituents are necessary for water solubility and subsequent transportation to the site of action  Some Drugs containing Anthracene derivatives… Cascara bark – From the dried bark of Rhamnus purshiana (Rhamnaceae) – The collection must be made at least one year before the bark is used (fresh bark contains an emetic principle Some Drugs containing Anthracene derivatives… OH O OH O OH Gl O CH2 OH CH2 OH H Gl H Gl Barbaloin Cascaroside A& B O OH Gl O O OH OH CH3 CH3 H Gl H Gl Chrysaloin Cascaroside C & D  Some Drugs containing Anthracene derivatives… Cascara is a purgative, mainly in the form of liquid extract, elixir or as tablets prepared from a dry extract – The laxative action of the crude drugs is always higher than from their content of anthracene derivative – Thus, the naturally occurring anthracene glycosides were found superior to the synthesis of numerous hydroxyl anthracene derivative  Some Drugs containing Anthracene derivatives… Aloes – the solid residue obtained by evaporating the liquid which drains from the transversely cut leaves of various species of Aloe (Liliaceae)  Some Drugs containing Anthracene derivatives… The major glycoside in Aloes is the C-glycoside Barbaloin – The C-linked glucose at C-10 protect anthrones from oxidation.  Some Drugs containing Anthracene derivatives… Aloe is employed as purgative It is seldom prescribed alone and Its activity is increased when it is administered with small quantities of soap or alkaline salt  Some Drugs containing Anthracene derivatives… Hypericum/St John’s Wort – The dried flowering tops of Hypericum perforatum (Hypericaceae)  Some Drugs containing Anthracene derivatives… The dried herb contains OH O OH significant amounts of phenolic derivatives – Aromatic polycyclic dianthrones-hypericin HO Me HO Me Hypericin is Tranquilizer, antidepressant and antiviral (anti-HIV) OH O OH  Cardiac Glycosides After completing this session you will be able to: – Distinguish the basic skeletal of cardiac glycosides – List sub-class of cardiac glycosides – Discuss crude drug containing cardiac glycosides  Cardiac Glycosides… The genins of all cardiac glycosides are steroidal in nature, that act as cardiotonic agents They are characterized by their highly specific action on cardiac muscle – increasing tone, excitability and contractility Allowing the weakened heart to function more efficiently  Lactone ring 12 CH3 17 11 13 1 16 R 9 14 2 15 10 8 OH 3 5 7 Sugar O 6 4  Characterized by the following structural features: – The presence of β-OH at position C-3 which is always involved in aglycosidic linkage to a mono, di, tri, or tetra saccharide. – The presence of another β-OH group at C-14 – The presence of unsaturated 5 or 6- membered lactone ring at position C-17 – The A/B ring junction is usually (cis), while the B/C ring junction is always (trans) and the C/D ring junction is in all cases (cis). – Additional OH groups may be present at C-5, C-11 and C- 16  Cardiac glycosides Cardenolides Cardiac glycosides that α-β unsaturated 5-membered O O lactose rings in position C-17 represented by the digitalis OH 12 CH3 and straphanthus group 17 11 13 1 R 16 9 14 2 15 10 8 OH 3 5 7 Sugar O 6 4  Cardiac glycosides … Bufadienolides O – Cardiac agents that have doubly unsaturated 6- O membered lactone ring in position C-17 OH12 – Found in squill and frogs 17 11 13 1 16 9 14 2 15 10 8 R1 3 R2 7 Sugar O 5 4 6  Cardiac glycosides … Give +Ve with Liebermann’s and Salkoviski’s test Keller Kiliani’s test  Cardiac glycosides … Digitalis leaf – the dried leaf of Digitalis purpurea and D. lanata (Scrophulariaceae) – is a biennial herb, common in Europe and North America  Cardiac glycosides … The principal glycosides in the fresh leaves are purpurea glycoside A and purpurea glycoside B The glycosides comprise two series of compounds – those with a tetrasaccharide : glucose–(digitoxose)3– unit – those with a trisaccharide (digitoxose)3– unit. Cardiac glycosides … Cardiac glycosides …  Cardiac glycosides … Digoxin has a rapid action and is more quickly eliminated from the body than digitoxin; therefore, it is the most widely used of the cardioactive glycosides  Cardiac glycosides … Strophanthus The dried ripe seeds of Strophanthus kombe or S. gratus (Apocynaceae) – little drug use today, though was formerly used medicinally as a cardiac stimulant.  Cardiac glycosides … The main glycoside (about 80%) of S. kombe is K-strophanthoside O O whereas S. gratus contains 4–8% of ouabain OH OH 17 12 OH 11 13 Ouabain: It has been used for CH2 9 14 16 1 15 emergency treatment in cases of 2 3 10 8 OH acute heart failure Rhamnose O 4 5 6 7 OH  Cardiac glycosides … Squill – Squill (white squill) consists of the dried sliced bulbs of the white variety of Urginea maritima (Liliaceae/Hyacinthaceae) which grows on seashores around the Mediterranean. – The plant contains bufadienolides (up to 4%), principally scillaren A and proscillaridin A.  Squill is not usually used for its cardiac properties, as the glycosides have a short duration of action. – Instead, squill is employed for its expectorant action in preparations such as Gee’s linctus – Large doses cause vomiting and a digitalis-like action on the heart  O O OH Glucose-Glucose-Rhamnose O Scillaridin A Proscillaridin A Scillarin A Glucoscillarin A  SAPONIN GLYCOSIDES Saponins are a group of amorphous colloidal glycodides which is widely distributed in the higher plants. Have ability to form lasting foam when shaking in aqueous solution. – They are excellent emulsifying agents (modify surface tension). Formerly used as detergents to replace soap (e.g., quillaia).  SAPONIN GLYCOSIDES … colorless and optical active. They form colloidal solution with water and are soluble in alcohol and dilute alcohols. Have haemolytic properties, they precipitate the cholesterol and lethisins that exist in the memberanes of the red blood cells and thus haemoglobin is liberated. – So, extremely toxic when injected into the blood stream. – However, they are not harmful when taken orally and some of our valuable food materials, e.g. beans, lentils, soybeans, spinach, and oats, contain significant amounts. SAPONIN GLYCOSIDES …  Classification: According to the nature of the aglycone saponins are classified into Steroidal and Triterpenoidal saponins. Sug-O Sug-O Steroidal Saponins Triterpenoidal Saponins  Medicinal importance of saponins They are a suitable precursors in the partial synthesis of sex hormones, e.g., Diosgenin (sapogenins) isolated from the rhizome of Dioscoria species. Saponins increase the rate of absorption of many pharmacological active substances Many saponin-containing drugs are used as expectorants (e.g., Ipeca, Senaga and liquorice) as their contents of saponins stimulate bronchial secretion and also activate the ciliary epithelium of the bronchi SOME DRUGS CONTAINING SAPONIN GLYCOSIDES Liquorice – Liquorice (licorice; glycyrrhiza) is the dried unpeeled rhizome and root of the perennial herb Glycyrrhiza glabra (Leguminosae/Fabaceae)  2- Liquorice Source: Glycyrrhiza glabra. Constituents: Sweet triterpenoidal saponins “Glycyrrhizin”.  - COO O Glc Glc O Glycyrrhetic acid Glycyrrhizinic acid Glycyrrhizin Uses: – Flavoring agent in Pharmaceutical preparation. – Demulcent and expectorant. – Treatment of peptic ulcer. – Treatment of Rheumatoid arthritis and Inflammatory conditions as it has cortisone like action. – 50–150 times as sweet as sucrose (Sweetener) – Treatment of liver diseases and liver protection  Quillaia – Quillaia bark or soap bark is derived from the tree Quillaja saponaria (Rosaceae) and other Quillaja species found in Chile, Peru, and Bolivia. – The bark contains up to 10% saponins, a mixture known as ‘commercial saponin’ which is used as a foaming agent in beverages and emulsifier in foods  Saponins from quillaia are also showing great promise as immuno adjuvants, substances added to vaccines and other immunotherapies designed to enhance the body’s immune response to the antigen.  Ginseng – The roots of the herbaceous plants Panax ginseng (Araliaceae) from China, Korea and Russia, and related Panax species, – widely used in China and Russia for the treatment of a number of diseases, including anaemia, diabetes, gastritis, insomnia, sexual impotence, and as a general restorative, promoting health and longevity.  Ginseng Saponins (Ginsenosides) Source: Roots of Panax ginseng  Nature: They are C-30 compounds but they have typical Steroidal skeleton. Classification: a- Protopanaxdiols b- Protopanaxtriols Protopanaxdiols Protopanaxatrion OH OH Sug-O Sug-O Sug-O Sug-O O-Sug  Uses: – It has an adaptogenic (antistress, anti-fatigue) effect. – It improves both physical and mental performance including learning, memory and physical capabilities. – It improves the immune function and metabolism. – Improve liver functions. – Stabilize blood glucose and blood pressure  It is an ‘adaptogen’, an agent that helps the body to adapt to stress, improving stamina and concentration, and providing a normalizing and restorative effect. Long-term use of ginseng can lead to symptoms similar to those of corticosteroid poisoning, including hypertension, nervousness, and sleeplessness in some subjects  Flavonol and isoflavonol Glycosides They are derivatives of 1,3-diphenylpropane, are a large group of natural products, which are widespread in higher plants but also found in some lower plants, including algae Most flavonoids are yellow compounds, and contribute to the yellow colour of the flowers and fruits, where they are usually present as glycosides  All derived from the same parent nucleus, 2- phenyl-benzopyran (flavan), thus they have a basic C-15 skeleton.  1 2' 3' 8 9 O 1' O 7 2 4' 6 4 3 10 6' 5' 5 Flavan O Flavone O O OH O O Flavonol Isoflavone O H H O Flavanone  Most flavonoids are potent antioxidant compounds – Several flavonoids possess anti-inflammatory, antihepatotoxic, antitumour, antimicrobial and antiviral properties – Many traditional medicines and medicinal plants contain flavonoids as the bioactive compounds  Rutin, a flavonoid glycoside found in many plants is the most studied of all flavonoids, and is included in various multivitamin preparations Hesperidin from Citrus peels, is also included in a number of dietary supplements, and claimed to have a beneficial effect for the treatment of capillary bleeding  Exmples of Isoflavones – The main food source of isoflavonoids is the soya bean (Glycine max; HO O Leguminosae/Fabaceae), which contains significant levels of the isoflavones daidzein and genistein. – Genistein show significant OH O oestrogenic and anticancer activity OH  Rotenone and other rotenoids are powerful insecticidal and piscicidal (fish poison) agents, interfering with oxidative phosphorylation. – relatively harmless to mammals unless they enter the bloodstream, – provides an excellent biodegradable insecticide and is used as such either in pure or powdered plant form. – Roots of Derris elliptica (ብርብራ) species are rich sources of rotenone. O O O O  Flavono-lignans – Coupling of a flavonoid moiety with hemi-lignan molecule by oxidative coupling result in the formation of flavono-lignans The leaves and fruits of Silybum marianum (Asteraceae) contain silymarin (silybin)  Silymarin is a very effective lipotropic and hepato protective therapy. It is a free radical scavenger. OH O A B O – Supportive treatment of acute OH and chronic alcoholic poisoning OH O and toxin induce hepatitis. OH O OCH3 It is used for treatment of Silybin OH liver cirrhosis caused by plant toxins It is available in the market in the form of tablets, effervescent granules.  Simple Alcoholic and phenolic glycosides Phenols probably constitute the largest group of plant secondary. – They range from simple structure with one aromatic ring to highly complex polymeric substances. – Phenols are important constituents of some medicinal plants and in the food industry are utilized as colouring agent, flavourings, aromatizers and antioxidants  The salicyl alcohol derivative salicin, found in many species of willow (Salix species; Salicaceae), is typical example of phenolic glycoside – Salicin is responsible for the analgesic and antipyretic effects of willow barks, widely used for centuries. – It provided the template for synthesis of acetylsalicylic acid (aspirin) amore effective and widely used pain-killer.  Salicin is used for many years as a remedy in the treatment of fever and rheumatism.  Arbutin: is a phenolic glycoside that occurs in bearberry leaves Arectostaphyllos uva ursi (Ericaceae). It is used as diuretic and also has bactericidal action. This activity is due to the hydroquinone given by hydrolysis.  It is used as diuretic and also has OH OCH3 bactericidal action. Uva ursi leaf contains also methyl arbutin (the methyl ether of arbutin), that also contributes to the diuretic and urinary antiseptic O-Gl O-Gl action of the leave Arbutin Methylarbutin  Coumarin Glycosides The coumarins are shikimate-derived metabolites – The majority of the coumarins are oxygenated at position C7 – Coumarins have a limited distribution in the plant kingdom and have been used to classify plants according to their presence (chemotaxonomy)  It has long been known that animals fed sweet clover (Melilotus officinalis, Fabaceae) die from haemorrhaging. – The poisonous compound responsible for this adverse effect was identified as dicoumarol.  Coumarins are commonly found in the plant families Apiaceae, Rutaceae, Asteraceae and Fabaceae  A number of compounds have been synthesized based on the dicoumarol structure, e.g. warfarin, which is widely used as anticoagulant  Cyanogenic glycosides Cyanogenesis is the ability of certain living organisms, plants in particular, to produce hydrocyanic acid (HCN, prussic acid). – Cyanogenesis in plants is a chemical defense mechanism against organism damaging or feeding on plant tissues and lead to release of HCN gas, which is toxic They are distributed in over 2000 plant species belonging to 110 families.  Cyanogenic glycosides… Most cyanogenetic glycosides are biosynthetically derived from the amino acids: valine, leucine, isoleucine, tyrosine or phenylalanine – are easy to detect with a strip of filter paper impregnated with reagents able to give a color reaction with the hydrocyanic acid released upon crushing the plant material (e.g., picric acid/sodium carbonate or benzidine/cupric  Cyanogenic glycosides… Although hydrocyanic acid is a violent poison, it is important to remember that oral intake of cyanogenetic drugs does not necessarily cause severe intoxication – the range of dangerous concentrations (0.5-3.5 mg/kg) can only be achieved by rapid and massive ingestion of plant parts rich in cyanogenetic glycosides  Linamarin in linseed (Linumu sitatissimum). It is biosynthetically derived from valine. H3C O glc C H3C CN  almond Amygdalin in bitter almonds (Prunus amygdalus). It is biosynthetically derived from phenylalanine.  Thioglycoside Glucosinolates- Sulphur Glycosides They are S-glycosides widely distributed in family Cruciferae. Sinigrin: In seeds of Brassica nigra (black mustard). Sinalbin: In Seeds of Brassica alba (white mustard). S-Glc H C H2C C C H2 N-O-SO3K Sinigrin Uses: Rubefacients, Counter irritants and condiment.  Activity Categorize the following glyglycosides – Silymarin – Warfarin – Amygdalin – Rehin – Arbutin – Ouabain – Hypericin – Barbaloin – Quilic acid – Sinigrin – Digoxin – Rotenone – scillaren A 1. Borntrager’stest: a. Steroidal b. Anthraqinone c. Cardiac 2. antraquinone containing drug a. Senna b. Digitalis c. Qualia bark 3. resistant to acid hydrolysis a. S-Glycoside b. C-Glycoside C. N-Glycoside 4. C-Glycoside a. Rhein b. Senosoid C. Aloin 5. S-glycoside a. Amygdalin b. Sinigirin C. Arbutin Thank you for attention !