Glycosides .pdf

Glycosides Glycosides non-reducing substances , on hydrolysis by acids or enzymes yield:...

Glycosides Glycosides non-reducing substances , on hydrolysis by acids or enzymes yield: hydrolysis‫ لفهلنج اال بعد الـ‬reduction ‫مبتعملش‬ non-sugar part or parts hydrolysis One or more reducing sugar in medicine as medicinal agents ‫عوامل طبية‬ have possible use as potential source of new drugs.‫مصدر لألدوية الجديدة‬. have important role in the life of the plants themselves; e.g., as regulatory agent, as protective agent... etc.‫ كعامل حماية‬، ‫تنظيم‬ ‫ي‬ ‫ عامل‬... Uses Digitoxin: Cardiac stimulant ‫طبيع‬ ‫ي‬ Sinigrin: local irritant Examples Sennoside: laxative Salicin: analgesic ‫من الصفصاف‬ Classification: According to: O- S- N- C- The usual and the common linked to the thiol linked to linked to the aglycone linked between the sugar and the (sulfhydryl) group of the the amino- by a carbon- carbon aglycone is an oxygen linkage, aglycone group of bond Chemical connecting the reducing group of the require an oxidizing group of sugar and the alcoholic or aglycone agent for hydrolysis, the phenolic hydroxyl-group of the e.g. Ferric chloride aglycone aglycone (FeCl3), hydrogen (type of peroxide (H2O2)... etc. glycosidic Salicin sinigrin Adenosine Barbaloin linkage) Sugar-C-N-R β-glycosides α —glycosides configuration The majority only few especially the rhamnosides. of the glycosidic The sugar involved has the β the sugar involved has the α configuration at the hemiacetal linkage configuration at the hemiacetal carbon. carbon; the sugar is usually of the L-series e.g. L-rhamnose. Same → Cis opposite → trans Nature of Holosides Heterosides aglycon The aglycone is also a sugar The aglycone is a non-sugar e.g., maltose, lactose and all oligo- and polysaccharides. e.g., rutin, digitoxin, sinigrin, barbaloin... etc. 1  Glycosides Cyanogenetic Specific Cyano-group (CN) glycosides(Amygdalin) group in the molecule Sulphur (S) Thioglycoside (Sinigrin) Phenol Arbutin Alcohol Salicin Lactone Daphnin Flavone Rutin Chemical Anthraquinone Gluco-aloe-emodin nature of the aglycone Aldehyde Gluco-vanillin Heterosides Cyanophore Amygdalin Thiocyanate Sinigrin Steroid Digitoxin Saponin Diosgenin unchanged from which Primary occur naturally in the Purpurea glycoside A (Mother glcoside) fresh plant & not The product of hydrolysis nature of ‫عشان كده بجمع النبات‬ glycoside result from the Afternoon hydrolysis of other ‫ألن بالليل بيتحول‬ Secondary glycoside by enzymatic Digitoxin secondary‫ الـ‬form‫للـ‬ activity with splitting of one or more sugar unit Physiological cardiac glycoside... etc activity 2  Glycosides Hydrolysis ‫مهمة‬ by Acid by alkali by Enzymes glycosides are undergo hydrolysis in Don’t affect the According to the configuration at C-1 of the sugar, acid medium but relatively stable in glycosidic linkage glycosides are divided into two main groups, each alkaline medium. Cause breakage either of which is affected with the corresponding enzyme-group: in the aglycone or in Stability towards hydrolysis with acid ‫ بيكرسها خاص بيها‬enzyme ‫ ليها‬configuration ‫كل‬ is related to the nature of the sugar: the sugar portion. ‫ بيأثر‬Sugar‫نوع الـ‬ normal‫ يتكرس أرسع وأسهل من الـ‬Deoxysuger‫الـ‬ Lactone Acetyl group α- Glycosidase β- Glycosidase ring of the attached Glycosides Glycosides affects the α- affects the β - glycosidic cardiac by ester containing 2— containing normal glycosidic linkage, linkage, glycosides linkage deoxy sugar sugar e.g., Rhamnase e.g. Amygdalase Easily hydrolyzed Quite resistant to opened by removed for α-rhamnoside. for amygdalin. hydrolysis strong under by weak acids need strong acids alkali. controlled at room temp. with heating. conditions of Myrosin hydrolyses all sulfur containing glycosides. (e.g. cardiac mild alkaline glycosides) hydrolysis. (Deacetylation Sugars present in glycosides : may be ---- 9 ‫ و ممكن توصل ل‬1 ‫من‬ One molecule of a Two or more molecules of In a chain as a disaccharide, The different sugars are linked at two or monosaccharide monosaccharide which may trisaccharide or polysaccharide three different positions at the aglycone e.g. Glucose in salicin. be similar or different. which is linked to the aglycone e.g. Sennoside. at one position. ‫الغالبية‬ ‫ن‬ Glycosides‫مكاني عىل الـ‬ ‫ متصل ن يف‬Sugar‫الـ‬ Due to the aglycone: Stabilization. Function of Solubilization: Glycosides are more water soluble than the respective aglycons. the sugar By attaching sugar moiety to the molecule the hydrophilicity is increased. group Modify ‫ بيحسن‬the pharmacodynamic properties of the aglycone. e.g. circulation, ‫مهمة‬ elimination and the concentrations in the body fluids, thus modifies the intensity and duration of the glycoside effect. Carry the aglycone ‫ بيشيله‬to the site of its action. Higher numbers of sugar units → the glycoside more soluble in polar solvents (water, alcohols) Physical less soluble in non-polar organic solvents. Properties polar solvent‫ بعملها بـ‬glycosides‫ للـ‬extraction ‫ فلما أعمل‬more polar ‫ يكون‬glycoside‫بيخىل الـ‬ ‫ي‬ Sugar‫الـ‬ 3  Glycosides » The reactions due to aglycone: The characteristic chemical tests for glycosides are due to the aglycone moieties. Chemical The only special test for sugar is Keller-kiliani test properties » The reactions due to sugar part: The potential of the glycosides to reduce Fehling's solution after hydrolysis is due to the release of the sugar part. non-sugar part of the glycosides, represented by a wide variety of organic compounds containing Aglycones free hydroxyl-group. By glycoside formation, i.e., glycosidation; the aldehyde group of glycone is blocked. 1. Trivial name (Common name): ending with in due to the botanical origin (the source). Example: digitoxin from Digitalis salicin from Salix 2. Chemical name (Systemic name): chemical name + (α- or β-) (D or L) (sugar) oside. Nomenclature 3- O-glycosides may be named according to the simple sugar produced on hydrolysis ending with (oside), generally glycoside. Produced sugar Name Glucose Glucoside Rhamnose Rhamnoside Glucose and Rhamnose Glucorhamnoside Rhamnose and Glucose Rhamnoglucoside Galactose Galactoside The most commonly used solvent for extraction : water & alcohol. (Polar solvent) no Chloroform or petroleum ether Precautions in extraction procedure: 1- Inactivation of enzymes: By one of the following methods: Boiling with alcohol or acetone. Drying at 100°C for 15 minutes then slow drying at low temperature. Extraction and Extraction at a very low temperature, e.g., by liquid CO2. isolation Freeze drying. (Lyophilization) 2- Insurance of neutral condition: Acidity is neutralized by addition of calcium carbonate in case of plant rich in acid. 3- Defatting: The lipids are removed by petroleum ether in case of plants rich in lipids. 4- Removal of other constituents: Such as tannin and resin...etc. ( to avoid interference ) They are removed by treating with lead acetate. It is not used in case of drugs containing flavonoids. 5- Extraction: Hydroalcohol solution is the best choice for extracting most glycosides. 6- Use of chromatography for isolation: e.g. Silica, cellulose, Peers etc. column chromatography. For Sugar: For aglycone: Qualitative tests Qualitative tests (fehling's test, Osazone test) (under each class of the glycosides; practical manual) Quantitative assays Quantitative assays Estimation (copper reduction, iodometry, (depending on the aglycone chemical nature) enzymatic) Bioassay by testing the biological action of the glycoside. Spectroscopic methods such as HPLC, GC-MS,..etc 4  Glycosides may be present in any organ of the plant in roots (loganin in gentian root), in leaves (sennoside in senna leaves), Occurrence in fruits (flavanones in Citrus species), in seeds (sinigrin in black mustard seeds), In flowers (anthocyanins). Reserved energy (sugar -content). Detoxifying role. Functions Regulatory role in plant physiology Defense role against micro-organisms and insects. ALCOHOL GLYCOSIDES Salicin Coniferin Structure contains free primary alcoholic group as well as a Alcoholic or a phenolic glycoside. Type phenolic glycoside as its aglycone is phenolic. from different species of Salix , principal family Coniferae (pine tree ‫)صنوبر‬ Source commercial source is Salix fragilis (White Willow) antirheumatic properties. Coniferin and coniferyl alcohol are considered among Its action closely resembles that of salicylic the commercial sources of vanillin. Uses acid, probably oxidized to salicylic acid in the human system. β glycosidase enzyme Hydrolysis Polymer of saligenin + Conc. H2SO4 → Bright red color ‫احفظ واحد بس‬ + conc. H2SO4 → red color. Identity + Freohde reagent → Violet color + phloroglucinol and conc. HCl → red color. test + Mandalin reagent → Purple color + Erdmann reagent → Red color Aldehyde Glycosides Vanillin (Glucovanillin) Naturally : Green vanilla pods, collected and carefully cured, slow drying, so as to permit enzymatic action on the glycoside (fermentation → hydrolysis ) with the liberation of vanillin (the aglycone). Source synthesis from: Coniferin, a glycoside present in pine trees. Eugenol, a phenol present in clove oil ‫زيت القرنفل‬ Lignin,(iso eugenol polymer) a by- product of the pulp (a by-product of timber) industry Uses flavoring agent in perfume and confectionary ‫الحلويات‬ 5  Glycosides Simple phenolic Glycosides carboxylic acid group as ester Arbutin ( Pure Simple phenolic Glycosides ) Gaultherin & monotropin bearberry (Uva ursi) leaves in leaves of Gaultheria and in bark of some Source species of Monotropa Monotropin: “Primary glycoside” Gaultherin: “secondary glycoside” Hydrolysis Chemically: it is methyl salicylate glucoxyloside By Acids or emulsin → hydroquinone + glucose Diuretic Renal antiseptic action due to the Uses hydroquinone given by hydrolysis. Hyperpigmentation disorders.→ Skin whitening Good inhibitor for melanin synthesis + ferric choride → blue color hydrolysis then Sublimation: needle Test crystals of hydroquinone. Winter green oil, Antiseptic, antirheumatic, counter irritant Coumarins Coumarin : Benzo α pyrone ring The aglycone is either coumarin or a coumarin derivative (Hydroxy and methoxy coumarins). All coumarins have fluorescence in UV 366 nm. Coumarins are lactones of ortho-hydroxy cis-cinnamic acid → Cyclization of cinnamic acid Dilute alkali opens the pyrone ring forming a salt of ortho-hydroxy-cis-cinnamic acid. natural fragrant substance has a sweet odor, and has been used in perfumes industry. precursor in the synthesis of a number of synthetic anticoagulant pharmaceuticals similar to Importance dicoumarol, e.g. warfarin, act in the liver by interfering with(inhibition) the action of vitamin K. Coumarins and other «n-benzopyrones, such as diosmin, are an edema modifier. Sunscreen agent : strong absorption of ultraviolet light at several wavelengths Umbelliferon Galbanum & Asafetide ( unorganized drug ) Source The aqueous solution of all coumarins and its derivatives have blue or violet fluorescence in UV 366 nm. Intensifies by aq ammonia solution. Use Antioxidant 6  Glycosides Anthracene Glycosides Have an important concept as the active constituents of the laxative vegetable drugs, where the principal structure present is 9, 10- anthraquinone. ‫ي‬ 1, 8-dihydroxyanthraquinone derivatives exert a more or less violent laxative or purgative activity. Anthraquinone glycosides may be considered prodrugs: the sugar moiety is Pharmacological essential for the pharmacological action, as it serves to transport the properties aglycone to the site of action in the large intestine..‫التأثث يف األمعاء الغليظة‬ ‫ر‬ ‫ إىل موقع‬aglycone ‫ ألنه يعمل عىل نقل‬، ‫الدوائ‬ ‫ي‬ ‫جزء السكر ضوري للعمل‬ Anti-inflammatory, antibacterial, antifungal, natural dyes. Prodrug biologically inactive compound which can be metabolized in the body to produce a drug. (A) ↑ peristaltic movement ‫الحركة الدودية‬of the large intestine → soft evacuation. Mechanism (B) Stimulate the secretion of water and electrolytes into the large intestine. ‫بطريقتي‬ ‫ر‬ peristaltic movement Waves of alternate circular contraction and relaxation Habit-forming, and long-term use may result in laxative dependence and loss of normal bowel Side effect function. ‫غثه‬ ‫فقدان وظيفة األمعاء الطبيعية ومقدرش أخش الحمام من ر‬ Fresh vegetable Dried drugs anthracene-type During Drying , 2 transformation process occur: compounds occur chiefly as glycosides Differences in of monomeric composition anthrones oxidation dimerization leads to anthraquinone Enzymatic reaction only observed if drying glycosides ‫عشان كده بخزن‬ is done at moderate temp. (40 °C). ‫سنتي قبل استخدامه‬ ‫ر‬ ‫النبات‬ which yields glycosides of dianthrone. Glycosides Aglycones Sugars present are glucose and Presence of hydroxyl group at C-1 and C-8 is essential for Forms rhamnose. The Glycosides are laxative action. ‫ هيدروكسيل‬8 ‫ و‬1 ‫الزم يكون فيه ف رقم‬ O-glycosides and C-glycosides. 1. Anthraquinones (oxidized form). ( laxative without gripping effect ) 2. Anthranols and Anthrones are tautomers (reduced form). Classification of Anthrone: C-10 is a methylene carbon which is easily oxidized Anthrone Diantharon anthracene These reduced forms exist only in the combined derivatives form as glycosides. Free ‫مش بتالقيه‬ according to 3. Dianthrones the oxidation The four mentioned subgroups may occur in the form of: level Aglycones. O-glycosides. Anthranol anthraquinone C- glycosides. 1  Glycosides Anthraquinones Tricycle skeleton and it is regarded as C6-C2-C6 compound. Can be reduced to anthrone with Zn dustand HCl. Solution of anthrone in alcohol contains an equilibrium mixture of anthrone + the tautomeric form anthranol. Anthraquinone derivatives are usually orange or red colored compounds. → Natural dyes soluble in hot water and in dilute alcohol. They occur in plants as free aglycones or in the form of glycosides. The glycosidation may be at various positions.( ‫) واحد أو أكث‬ Borntrager’s test Modified Borntrager’s test Micro-sublimation (Specific for free Anthraquinones) Boil + dil HCI → extract In case of anthrone or Powdered drug is heated on a slide a with ether → separate dianthrone glycosides , sublimate on the lower surface of the the ethereal layer. Add Borntrager’s test -ve upper slide is formed as needles or to the ether aq so we make modification droplets. Tests for ammonia (NH3) or Addition of mild identity NaOH. oxidizing agent [H2O2 or FeCl3] at the step of pink, red or violet color The sublimate assumes a red coloration hydrolysis with HCl, to is developed in the aq upon adding a drop of alkali. oxidize the produced layer. anthrone into anthaquinone Emodin ( Frangula-emodin) Aloe-emodin Rhein Occurs in both free and combined state (glycosides). It is the parent substance for Gives on hydrolysis frangula-emodin and rhamnose. ‫ مهمة‬In : sennoside A&B/C&D. Glucofrangulinn - glucose = Frangulin / - Rhamnose = Frangula emodin Cascara bark It can be separated from Senna leaves emodins by : Aloes. Extracting in sodium bicarbonate aq solution (due to the presence of a -COOH group). Anthranol and anthrone exist as Free & glycosides form The reduced form of anthraquinone. They are isomeric; the anthranol may be partially converted into Anthrone. Anthranols are converted to anthraquinones during storage of dried drugs by oxidation. Schontetens’ test (Borax test) Tests for identity Water extract of the drug shows a green fluorescence on adding borax (Sodium borate) the fluorescence is intensified by addition of water. Glycosidation 1. At Phenolic hydroxyl-group (O-glycosides). (oxidation) 2. At a carbon atom (C- glycosides) in C10 → methylene moiety, e.g.Aloin. 2  Glycosides Barbaloin Chrysarobin Aglycone : C-glycoside of aloe-emodin anthrone. Free anthranol obtained from different Aloe species. Benzene extraction of araroba (Goa powder), which is It contains anhydroglucose. a natural powder obtained from the trunk of the tree Optical isomers: barbaloin and isobarbaloin. known as Andra araroba Use: Keratolytic in cases of psoriasis and some other sorts of skin dermatitis. Dianthrone (Dimeric Anthracene derivatives) Homo-Dianthrones Hetero-Dianthrones Glu-O OH Glu-O Glu-O OH Glu-O O OH O OH O O COOH COOH CH2OH CH2OH H H H H H H H H HOOC HOOC HOOC HOOC O O O O-Glu O OH O-Glu OH O-Glu OH OH O-Glu Sennoside A Sennoside B Sennoside C Sennoside D The two anthrone moieties are similar. Dimers of two different anthrone moieties e.g. Sennidins A & B and their corresponding e.g. sennidin C and sennidin D and their corresponding glycosides Sennosides A&B. glycosides / sennoside C and sennoside D. Aglycone : 2 Rhein (anthrone not anthraquinone ) monomers. Aglycone : Aloe-emodin + Rhein The difference between A/B together and C/D together is the Configuration Sennidins A,B,C,D ‫هيدين‬ ‫ي‬ Sennosides A,B,C,D ‫ من الـ‬glucose‫ولو شلت الـ‬ Vegetable drugs containing laxative antnracene derivatives Aloe Rhubarb Contains the C-glycosides mainly barbaloin. Source: Rheum patmatumand R. officinak, Fam. Polygonaceae. C linked glucose at C-10 protect anthrones Adulteration: R. rhaponticum, it contains stilbene-derivatives. from oxidation. It contains : 𝟐 − Anthracene derivatives, of which 𝟑 are anthraquinone 𝟏 derivatives and 𝟑 are anthranol derivatives. − Tannins and flavonoids. − Sennoside E, F ( Oxalate ester of Sennoside A, B ) The presence of tannins in rhubarb makes the drug constipating, So, in small doses, rhubarb exerts no purgative action but acts only as intestinal astringent, but large doses cause purgation. 3  Glycosides Frangula bark Cascara bark Senna Leaves and fruits Glu-O OH Glu-O O OH O COOH COOH H H H H HOOC HOOC O O-Glu O OH OH O-Glu Sennoside A Sennoside B Glu-O OH Glu-O O OH O CH2OH CH2OH H H H H HOOC HOOC O O-Glu O OH OH O-Glu Sennoside C Sennoside D Source: Frangula alnus, Fam. » Source: The bark of Rhamnus The principal anthracene glycosides Rhamnaceae. Purstiana Fam. Rhamnceae. are the diathrone glycosides; namely: Stored at least 1 year before use? » It contains: Dimer : Sennidine A, B (Since fresh bark contains an 1. C- glycosides (C-10): mainly Monomer : Rhein irritant anthrones, mainly Gluco- barbaloin and chrysaloin frangulin anthrone. They cause 2. O- glycoside (C-8): mainly Dimer : Sennidine C, D strong gripping effect which glycosides of emodin, emodin- Monomer: Aloe-emodin + Rhein causes diarrhea, spasm and anthrone and iso-emodin. vomiting. Upon storage 3. Cascarosides: (A, B, C & D). anthrones are converted to their oxidized forms (the anthraquinones) dry Structure-Activity Relationship (SAR) Glycosylation is essential for activity. ( Glycosidic form > Free form ) Hydroxylation at C- 1 and C-8 is essential for activity. Oxidation level at C-9 and C-10 is important: ↑ oxidation - ↓ activity. – ↓ ‫مغص‬ ( anthraquinones < Anthrone < Anthranol ) Substitution at C-3 have great impact on activity: CH2OH > CH3 > COOH Aloe-emodin > Chrysophanol > Rhein 4  Glycosides Diacerein (diacetylrhein) Hypericin Semisynthetic derivative of rhein in which the two Sources: Dried flowering tops of Hypericum hydroxyl (Di acetyl derivatives of rhein) perforatum (St John's wort). Uses: treat joint diseases such as osteoarthritis (swelling Aglycone : Emodin Anthrone and pain in joints). Uses: It works by blocking the actions of interleukin-1 beta, a 1. Tranquilizer ‫مهدئ‬ protein involved in the inflammation and destruction of 2. antidepressant (MAO inhibitor) cartilage that play a role of development of symptoms 3. antiviral (anti-HIV). degenerative joint diseases such as osteoarthritis. Anthrone Anthranol Diantharon Anthraquinone CH3 Chrysophanol Barbaloin Chrysarobin Hypericin Diacerein (diacetylrhein) 5  Flavonoids Flavonoids and related flavonoid glycosides. C- 15 compounds. (C6 – C3 – C6 ) ((Remember: Anthraquinone C6 – C2 – C6 )) Flavonoids, constitute one of the most diverse and widespread group of naturally occurring phenols. The word flavone originates from the Latin word “Flavus”= “Yellow”. constitute the majority of the yellow-colored plant pigments (responsible for the colors of flowers and fruits) one of the most important constituents of the human diet. They are found in fruits, vegetables, nuts, seeds, stems, flowers and common drinks e.g. tea. bind to a range of cellular receptor sites and show a wide range of biological activities. They are benzo-γ-pyrone (chrmone) derivatives so not open by alkalis. occur both in the free state as aglycone or combined with different sugars as glycosides. The methylated, acylated, prenylated, or sulfated derivatives also occur. intensity of the yellow color is increased with the increased number of OH-groups and with increase of pH (Alkali). They are classified into many groups based on the oxidation level at ring C. Effect on capillaries: − Normalization of capillary permeability - ↓ capillary fragility ‫الشعيات الدموية‬‫ر‬ ‫هشاشة‬ − leading to reduction of capillary bleeding, e.g., rutin, hesperidin. → Daflon 500 Pharmacological effect Effect on heart and vessels: − heart tonics - ↓ blood pressure through the capillary dilatation. − Diuretic, e.g., Buchu. - Spasmolytic, choleretic and cholagogue. − Isoflavone derivatives have a distinct estrogenic effect. Bioflavonoids substances of flavonoid-type with biological action; they are mainly of 4-oxoflavans. Cholagoques Gastrointestinal agents that stimulate the flow of bile into the duodenum. Choleretic stimulate the production of bile by the liver. Estrogen female sex hormone. Aluminum chloride test Shinoda’s test Analcoholic solution of chalcones Yellow color fluoresnces under UV Alcoholic solution of gives with antimony pentachloride (SbCI5) Color test flavanone or flavonol in carbon tetrachloride (CCl4), a red or gives with Mg metal violet color or precipitate. and HCI, an orange, The test is negative with flavanone, red or violet color. flavone and flavonol. 1- Color in visible light. methods of 2- UV: all are visible in UV except flavane. detection 3- UV and fuming with ammonia. 4- AICl3-spary: It increases intensity of color and fluorescence in UV. 5- Gas chromatography (GC) after Silylation or Methylation. ‫تبق واضحة‬ ‫عشان ى‬ 1  Flavonoids flavone Flavonol Apiin Diosmin Rutin Quercitrin Aglycone : Apigenine Diosmatin Quercetin Sugar: Apiose, Glucose rhamnose + Glucose = Rutinose α-L-Rhamnose Source : leaves and Source: buchu leaves Source: leaves, stems, Source: wide seeds of parsley. hydrolysis → Rutinose and buds and seeds of distribution in Test: + FeCl3 → diosmatin. numerous plants. many plant reddish-brown Uses ttt disorders of BV: Tests: + FeCl3 → greenish- genera. color. − Decrease capillary fragility brown color hydrolysis → hydrolyzed with − Hemorrhoids hydrolysis acid→ rhamnose & emulsin or mineral − varicose veins ‫دوال‬ Rutinose and quercetin. quercetin. acids → apiose, − poor circulation in the legs Enzymatic → rhamnose, glucose and (venous stasis) quercetin 3-O glucoside apigenin. − bleeding (hemorrhags)in the eye or gums. Flavanone ( Flava ‫ – مفيش رابطة ثنائية‬none ‫ مفيهاش هيدروكسيل‬3 ‫) يعن‬ Hesperidin Source the rind of unripe, green Citrus fruits. by acid → rhamnose, glucose and hesperitin (aglycone) Alkali (NaOH) → opens the ring C of hesperidin → hesperidin chalcone which could be stabilized by methylation. Hydrolysis could be regenerated from hesperidin chalcone by action of acid. ‫ فقط‬Double bond‫ الـ‬Diosmin‫وبي الـ‬ ‫الفرق بينه ر‬ closely related to vitamin P. necessary for the absorption of vitamin C flavonoids (rutin, diosmin, quercitrin & hesperidin) are effective in combination with vitamin C to reduce capillary permeability and fragility blood coagulation thrombocytopenia thrombopenia.‫نقص الصفائح الدموية‬ Use hypertension habitual abortion ‫اإلجهاض المتكرر‬ hemorrhagic nephritis ‫التهاب الكلية اليف‬ Cerebro- and cardio-vascular diseases. ‫أمراض القلب واألوعية الدموية الدماغية‬. thrombopenia abnormally low levels of thrombocytoses, also known as platelets, in the blood. 2  Flavonoids Isoflavone Glycosides Chalcone & dihydrochalcone derived from 3—phyenylchroman. The conversion of chalcones to flavanones occurs readily in acid and the reverse in base. Genistin Rotenone Carthamin Sources : in a number of dietary The rotenoides are sources: Red pigment, of the flowers plants like soybean structurally related to of safflower hydrolyzed with HCl to produce isoflavones as they may both be regarded as Carthamin changes to carthamidin genistein (aglycon) and glucose. being derived from (5,7,8 OH) & isocarthamidin(5,6,7 OH) 3- phenylichroman. when treated with dilute HCI. Don’t has sugar Biological activity Uses − Estrogenic activity: Genistin, like broad-spectrum genistein, is a phytoestrogen, after insecticide, pesticide short term eating diet rich in and as a nonselective phytoestrogen the incidence of fish killer. breast cancer decreased.‫مكعبات يابان‬ used in powdered form − Antiviral activity: bioactive within to treat scabies ‫جرب‬and the neonatal intestine head lice ‫ قمل‬on may reduce the severity of rotavirus humans. infections. Anthocyanidins Flavonolignans related to the flavone. Source: The fruits of Silvybum marianum, Milk thistle, contain a Their glycosides : anthocyanins. mixture of flavonolignans (silymarin) consisting of silybin and They are sap pigments and the actual silychristin, and others. color of the plant organ. Phenolics consisting of C6-C3-C6-C3-C6: Flavolignans or Lignoflavons. change their color depending upon the it is a new group of natural substances. pH of their environment thus it may The molecule consists of a flavanonol and a lignan condensed serve Cyanin as pH indicator. together by oxidative combinations. indicator‫ فبستخدمه كـ‬pH‫بتغي الـ‬ ‫بيتغي ر‬ ‫ر‬ Uses: Very effective hepatoprotective and anti-hepatotoxic agent. lignan built up of C6 C3 3  Glycosides Glycosides of steroidal Origin - Cardio active Steroidal Glycosides – Cardiac glycosides Group of steroidal glycosides act as cardiotonic agent. They increase tone, excitability and contractility of cardiac muscle. Many have the same aglycone but different sugar residues. Some have identical sugar residues but with different aglycone (e.g., Digitoxin & Gitoxin). The aglycones are related chemically to sterols & bile acids. Glycosides of Triterpene Origin : classification » According to the type of lactone ring Cardinolides Bufadienolides ( Scilladienolides) C-23 C-24 5-membered unsaturated lactone ring 6-membered unsaturated lactone ring 4 carbon atoms & one oxygen atom 5 carbon atoms & one oxygen atom. One double bond Two double bonds One active (CH2) No (CH2) e.g. Digitalis & Strophanthus e.g. Squill Aglycone: » Steroidal, Tetracyclic skeleton. Differences in Aglycones: 1- Number and position of other OH- groups at C(12),(16). 2- Variations in oxidation extend of C(19). » Digitalis CH3 » Strophanthus -CH2OH or -CHO 3- Stereochemical differences. A double bond between C4=C5,Δ4 , Occure in Squill One, two, three or four monosaccharide units linked through OH-group at C (3). Sugar With the exception of glucose, all are of the desoxy-type. Components > 6-Deoxy-sugar → L-Rhamnose. > 2, 6-Deoxy-sugar → D-Digitoxose. > 3-O-Methyl-ether of 2, 6-deoxy-sugar→ D-Cymarose 1  Glycosides Liebermann’s test Keller-Kiliani’s Test Test for 5-membered lactone ring ( for steroids ) ( for Deoxysugars ) (specific for Cardenolidein) Glycoside in acetic Glycoside in acetic Reactions due to the (-CH2-) of the lactone ring anhydride + anhydride containing Legal’s test Kedde’s test Baljet test conc.H2SO4 → traces of FeCl3 + conc. Cardenolidein Cardenolide + cardiac gly. + Tests Reddish violet → H2SO4 on the wall of the pyridine + Na 3,5dinitrobenzoic Baljet Green tube → An intense blue nitroprusside acid (Kedde’s reagent color develops at the (picric acid + + NaOH → reagent A) + NaOH interface between two NaOH) → deep red color (Kedde’s reagent orange layers B) → violet color. yellow color Dil acids Enzymatic Elevated Alkali aglycones terminal Dehydration Mild (Na2CO3) Strong (NaOH) & the sugar sugar & by removal of removes the ester group opening of lactone ring units. secondary C-14 OH group (Deacetylation) attached to C(17). → glycoside. to give inactive Lanatoside A → Purpurea inactive form of anhydro form glycoside A glycosides because & double bond Lanatoside B → Purpurea lactone ring is essential Hydrolysis btw 14 - 15 glycoside B Sugar moiety Aglycone moiety 1- The sugar moieties have no cardiac activities, Essential : but when attached to the 3-OH group of the 1- Steroidal nucleus. Structure- steroid they influence the solubility, 2- lactone ring (opening by alkali → loss of Activity absorption and the pharmacokinetic, thus the the activity) Relationship potency of the cardiac glycosides. 3- Double bond at C20 and C22 of the (SAR) 2- Cardiac glycosides with 6-deoxy sugar are lactone ring. more potent than their 6-CH2OH analog 4- OH groub At positions 3 and 14. (normal suger) 5- Lactone ring linked at C17 β- Confeguration (α loss its activity) 1- Heart insufficiency: ttt Congestive heart failure. increase force of contraction of cardiac muscles without increase oxygen consumption‫استهالك‬. 2- Diuretic, due to increase amount of blood passing through the kidney. the most active in this respect is scillarin. Uses 3- The aglycones have the same pharmacological action as the glycosides do, but they are not medically used due to insolubilities. 4- Expectorant (white squill). 5- Rat poison (red squill). 2  Glycosides Bioassay Chemical methods Standardizati By determining the amount of Qualitative Quantitative on of drug necessary to stop the (1) Lactone ring: Baljet reaction Cardio- heart of a given animal under Legal’s , Kedde’s test “Colourimetry” active specified conditions. (2) Desoxy-Sugar: Glycosides Animals used are: Frog, Pigeon, Keller-Kiliani Cat, Guinea pigs. Digitalis leaves Strophanthus Seeds Squil bulb Crude Drugs Digitalis purpurea Digitalis Lanata Strophanthus White squil Red squil containing Purpurea glycoside A, B Lanatoside Kombe, S.Gratus Urginea Urginea Cardio- On hydrolysis with mineral A, B, C maritima maritima active acids, they give digitoxigenin (white (red Glycosides and gitoxigenin as aglycones. variety). variety). Glycosides derived from digitoxigenin Digitoxin 3 Digitoxose (Secondary) Gitoxin 3 Digitoxose (Secondary) Digoxin 3 Digitoxose (Secondary) Purpurea 3 Digitoxose + glucose Purpurea 3 Digitoxose + glucose glycoside A (Primary) glycoside B Lanatoside A 2 Digitoxose + glucose Lanatoside B 2 Digitoxose + glucose Lanatoside C 2 Digitoxose + Acetyldigitoxose (Primary) Acetyldigitoxose glucose Acetyldigitoxin 2 Digitoxose + Acetyldigitoxose Acetyldigitoxose (Primary) Acid Enzyme Strong Alkaline Mild Alkaline Hydrolysis remove: All suger Digitoxose + glucose terminal sugar glucose Opining lactone acetyl group remain: Aglycone digitoxigenin Digitoxin ring Purpurea glycoside A Lanatoside C < Digoxin > purpurea glycosides : absorbed from the GIT , Uses treatment of atrial fibrillation and congestive heart failure. Lanatoside C is less absorbed than digitoxin but it is less cumulative 3  Glycosides Stophanthus Kombe Glycosides Squill Glycosides 5 From Strophanthus kombe and S. gratus, From Urginea martitima Family Apocynaceae. Family Liliaceae. Cardinolides Cardio glycosides Aglycone : Scillaridin. (Without any glucose) Aglycone : K- Strophanthidine :‫ يف‬digitoxigenin‫يختلف عن الـ‬ :‫ يف‬digitoxigenin‫يختلف عن الـ‬ 5 ‫ و‬4 ‫ بي‬Double bond ‫ وجود‬-1 5 ‫ عند الذرة رقم‬OH -1 Six membered ‫ هنا‬Lactone ring‫ الـ‬-2 CHO‫ اتحولت لـ‬19 ‫ عند رقم‬CH3 -2 There are two varieties of squill: Principle glycosides: white variety red variety − K-strophanthoside (trioside) ‫سكر‬3‫يحتوي عىل‬ Glycoside : Scillarin A Glycoside Scilliroside, − K-strophanthin B (bioside) ‫سكر‬2 Two OH at C (3) , (14) Four OH-groups at − Cymarin (monoside).‫سكر واحد‬ 3 / 6 / 8 / 14. Chemical tests: (Two additional OH) Strophanthin + cold 80% sulfuric acid → emerald Have 3 Sugars Have one sugar green color Chemical test Uses Acid hydrolysis: K-Strophanthoside → + acetic anhydride + conc. Rat poison K-Strophanthidin + Trisaccharide. sulfuric acid →blood red color (D-Cymarose-O-β-D-Glucose-O-α-D-Glucose) → Blue → Bluish - green. K-Strophanthin B → K-Strophanthidin + D-Cymarose +O-β-D-Glucose K - Strophanthus gratus lactone ring at C (17) is six- membered, with two double ↓‫بيدين‬ ‫ي‬ bonds (α-pyrone). G-Strophanthoside (Ouabain) + 80% sulfuric acid → Red color double bond between C4=C5.. Δ4 Monoside: contain only rhamnose at C3 CHO at C19 OH at C5 , 12 , 11 → Most polar Stophanthus Saponin Glycosides Saponin : Glycosides characterized by : Producing froth ‫ رغوة‬in aqueous solution having hemolytic properties on R.B.Cs. (release heme) have bitter taste. hydrolysis: Aglycone(sapogenin) + Sugar Classification according to aglycone: 4  Steroidal Saponin Triterpenoid Saponin No. of C-atoms 27 30 No. of rings Tetracyclic penta or Tetracyclic Destribution less more Occurence many monocot-families ‫ذات فلقة واحدة‬ Dicot Acco.to type of the attached side chain Drugs containing triterpenoid acids Furostane type Liquorice ‫عرقسوس‬ Olibanum ‫لبان الدكر‬ Dried rhizomes and roots of Glycyrrhiza glabra, Occurence: Spirostane type Origin family (Leguminosae). A gum resin, obtained Active constituents glycyrrhizin (Ca2+ and K+ salts of glycyrrhizinic acid). from Boswellia serrate. Classification Active constituents: and Boswellic acid (Glycyrrhetinic acid) + 2 glucuronic acid examples hydrolysis with loss of the sweet taste. Uses − Expectorant & antitussive action. Antifungal − Flavoring agent,mask the taste of bitter drugs. Anti-bacterial − Obtained from Dioscoreatubers. analgesic. − glycyrrhizinic acid Uses Starting materials for partial (50 times sweeter than sucrose.( synthesis of adreno- corticosteroids Anti-inflammatory action. − ttt peptic ulcer. Uses of and sex hormones by the use of improve appetite. appropriate micro- organism − natural corticosteroid & anti-inflammatory ‫الجزئ‬ ‫ي‬ ‫يستخدم يق صناعة المواد الخاصة بالتكيب‬ due to structure similarity to cortisone. ‫للكورتيكوستتويدات األدرينية والهرمونات الجنسية‬ ‫ر‬ ‫باستخدام الكائنات الحية الدقيقة المناسبة‬ − Its metabolites in the body can induce sodium and fluid retention leading to hypertension 5  Glycosides Cyanophore Glycosides Definition They are glycosides which on hydrolysis yield HCN as one of the products. Detection Guignard test (Specific test) : HCN as hydrolysis product + HCl + Na picrate paper → the paper is (in plants) turned from yellow into brick red, which is due to the formation of sodium iso-purpurate. Amygdalin ( Aromatic Cyanogenic Glycosides ) Occurrence Most widely distributed of cyanophore glycosides. > occurs in bitter almond Total hydrolysis → 2 glucose + benzaldehyde + HCN. Controlled hydrolysis by 3 enzymes in 3 steps: 1- Amygdalase: Liberation of one mole of glucose and one mole of mandelonitrile hydrolysis glycoside (Prunasin 2- Prunase: Liberation of a second mole of glucose and one mole of mandelonitrile 3- B-Hydroxy-nitrilase: Mandelonitrile breaks down to give HCN and benzaldehyde Linamarin ( Aliphatic Cyanogenic Glycosides ) Occurrence linseed. Hydrolysis Thioglycosides (Thiocyanate – glucose enolate - sulfurated glycosides.) Sinigrin Sinalbin Occurrence black mustard. white mustard. → Allyl isothiocyanate (volatile oil of mustard) → Acrinyl isothiocyanate (non volatile oil) Hydrolysis + glucose + potassium acid sulfate. + glucose + potassium hydrogen sulfate. Black and white mustard seeds are used as (attributed to their contents of thioglycosides.) : rubefacients counter irritants Anti-cancer Prevent cancer of the colon. Anti-bacterial cause pre-cancerous cells to die (apoptosis). Uses Anti-fungal Anti-oxidant Anti-inflammatory wound healing 6