Glycosides.pdf

Glycosides  Glycosides General Introducion Terpenoid Glycosides : * Introduction a. Steroid Glycoside i. Cardiac Glycosides ii. Saponin Glycosides b. Triterpenoid Glycoside : - Saponin Glycosides  Phenolic Glycosides - Introduction - Anhraquinone Gl...

Glycosides  Glycosides General Introducion Terpenoid Glycosides : * Introduction a. Steroid Glycoside i. Cardiac Glycosides ii. Saponin Glycosides b. Triterpenoid Glycoside : - Saponin Glycosides  Phenolic Glycosides - Introduction - Anhraquinone Glycsides - Tannin Glycosides - Coumarin Glycosides - Chromone Glycosides - Flavvonoid Glycosides Miscellaneous Glycosides * Cyanogenetic Glycosides * Glucosinolate Glycosides Resin and Resin Combination  Introduction -Definition of glycosides - Classification of glycosides - Sugar moiety (part) - Glycoside bonds (linkage) - Type of glycoside bonds - General biosynthesis of glycosides - Hydrolysis of glycosides - General properties of glycosides  Glycosides The term glycoside is very broad term which embraces all the many and varied combination of sugar and non- sugar parts, however, it can be defined as a group of naturally occurring compounds characterized by consisting of sugar and non-sugar part. Sugar part glycone e.g. glucose Non-sugar part aglycone e.g. Diosgenin (..... genin) The most characteristic feature of glycoside is their tendency to be hydrolyzed by water in acidic , alkaline or enzymatic media.  Classification of Glycosides : There are several modes for classification of glycosides, since it compose of two distinct parts.  General Classification : 1. Homoside or holoside when the two parts are sugars. i.e. both glycone and aglycone are sugars e.g.;sucrose& starch CH2OH CH2OH O O OH OH O HO CH2OH OH OH SUCROSE CH2OH CH2OH CH2OH O O O OH OH OH O O OH HO OH OH OH Starch Heterosides : When the glycone is sugar and the aglycone is non-sugar Laloab : Balanite aegyptiacu. Family Balnitaceae Fenugreek : trigonella foenum gracum , family Leguminosae Tacca :tacca leontopetaloids , family Taccacae Classification based on sugar part: 1. Glucoside Glucose 2. Rhamnoside Rhamnose 3. Schillabiose (Rhamnose +glucose) 4. Pentoside Pentose sugar  CLASSIFICATION BASED ON NON-SUGAR PART : A. Classification based on chemical structure : 1. Aliphatic glycoside e.g. saponin glycoside 2. Phenolic glycoside e.g. Flavonoid glycoside 3. Alkaloidal glycoside e.g. Solanidine.  B) Classification based on functional groups 1. Alcohol glycoside (Salicin). 2.Aldehyde glycoside (Glycovanillin). 3.Anthraquinone glycoside (Sennoside).  HOME WORK Write brief report on the following glycosides 1-Salicin 2-Glcovanilline 3-Sennoside including the following A-Natural source B-Structure C-Hydrolysis D-Biological importance  C)Classification based on biosynthetic origin : 1. Acetate mevalonate pathway - Terpenoid glycoside 2. Acetate-malonate and Shikimic acid pathways - Phenolic glycosides. 3. Shikimic acid followed by trans-amination pathways : - Alkaloidal glycosides - Cyanogenetic glycoside. 4. Acetate mevalonate followed by transamination and then by transulphation : - Glucosinolate glycoside.  Miscellaneous classification : 1. Classification based on Physiological properties - cardiac glycoside 2. Classification based on Physiochemical properties - saponin glycoside The classification adopted in pharmacognostical chemistry is based on combination of two or more of these classifications & include : 1. Terpenoid glycosides. 2. Phenolic glycosides. 3. Miscellaneous glycosides.  i. Terpenoid glycosides : Further divided into two groups A. Steroidal glycosides : The aglycone contain steroidal nucleus. R G HO 1. Steroidal saponin glycosides. 2. Cardiac glycoside. b. Triterpenoid glycoside HO G Triterpenoid Saponin Glycoside  ii. Phenolic glycosides. The aglycone consist of phenolic group and include G HO 1. Anthraquinone glycosides. 2. Flavonoid glycosides. 3.Tannin glycoside. 4. Coumarin glycosides. 5. Chromone glycosides.  iii. Miscellaneous glycosides 1. Cyanogenetic glycosides. The aglycone characterized by the presence of cyanide group R O G C R C N 2. Glucosinolate glycoside N - OS O2OX R -C S -G X = K + or C ATION  SUGAR PART H O CH2OH C O H H- C - OH H H HO - C - H OH H H - C - OH HO OH H - C - OH H OH H2- C - OH *CYCLIC SUGAR OPEN CHAIN SUGAR  NORMAL SUGAR Glucose - Rhamnose Arabinose -Fructose etc… RARE SUGAR Xylose Fucose SPECIAL SUGAR -Digitoxose - Cymarose- Aminosugar ACID DRIVATIVES* Glucuronic acid Galacturonic acid  Glycoside Bond (Linkage) : It is the link or bond which connect or join the glycone and aglycone (sugar part to the non- sugar part). It is very characteristic feature of this type of natural products, and give them their physiological and physiochemical properties. It is virtually or generally formed by the condensation or reaction of the OH group of the glycone and that of the aglycone whether the last one is aliphatic or phenolic (OH)`  It look like an ether bond but actually it is an acetal bond which is usually formed after the formation of hemicetal bond, the latter is a characteristic of aldehyde (carbonyl )functional group ; this result in the formation of cyclic sugar which preceded it is involvement in glycoside bond formation.  GLYCOSIDIC BOND (Linkages) OH O-G HO-G OH O-G H H R-CHO + 'R-OH R C O'R +'R-OH R C O"R OH 'R + H2O HEMICETAL BOND ACETAL BOND  CHO - CH2OH H- C - OH O HO - C - H OH C H - C - OH OH H OH H - C - OH OH CH2 - OH F OLDE D GLUCOSE OPE N CHAIN GLUCOSE H5 HEMICETAL BOND H H CH3OH CH2OH O O OH OH HO OH HO CH2OH OH OH GLUCOPYRANOSE GLUCOFORANOSE  Holoside SUCROSE CH2OH CH2OH O O OH OH O HO CH2OH OH OH ACETAL GLUCOSIDE ACETAL BOND CH2OH CH2OH CH2OH O O O OH OH OH O O OH HO OH OH OH ACETAL BOND IN STARCH  Heteroside CH2OH O OH O HO TERPENOID OH ACETAL CH2OH GLYCOSIDE O OH O HO PHENOLIC OH GLUCONE AGLYCONE  Type of Glycoside Bond 1. O-GLYCOSIDE Laloab : Balanite aegyptiacu. Family Balnitaceae Fenugreek : Trigonella foenum gracum , family Leguminosae Tacca :tacca leontopetaloids , family Taccacae  2. C-GLYCOSIDE Vitexin Vitex leucens ,family. Verbenaceae  3. N-GLYCOSIDE NH2 N N HO N N O CH 2OH OH OH Crotonoside Croton tiglium family Euphorbiaceae  4. S-GLYCOSIDE N-O-SO3- K+ H2C=CH-CH(OH)CH2C S-glucose Progoitrin Brassica species Salvadora perisica, family Salvadoracea  General Biosynthesis of Glycosides : The formation of glycosides from two distinct parts impart some complexity over the study of their biosynthesis, since each part is formed via different biosynthetic pathways. Glycone or sugar moiety or part is known to be biosynthesized via sugar metabolic pathways. The aglycone on the other hand, comprises compounds of different biosynthetic origins, therefore, the most important step is the one in which the aglycone and glycone are linked together to form the glycoside.  Available information believed that this reaction takes place in 2 steps and catalysed by the enzyme Glycosyl transferase or glycosidase enzyme. Step I involve activation of the glycone or sugar by UTP. Glycone + UTP glycone – UDP + Pi Step II involve condensation of the active glycone with aglycone. Glycone-UDP + aglycone glycone – aglycone + UDP ` Once the first sugar is linked to the aglycone further sugar can be added using the same mechanism. This reaction can be applied to all type of sugar  STARTING FROM ( CO2+H2O) SHOW HOW WE CAN BIOSYNTHESISED STEROIDAL GLYCOSIDES ???  Example: Biosynthesis of steroidal glycoside CO2 + H2O Photosynthesis Carbohydrate glycolysis glucose Pyruvate UTP glucose-UDP Acetyl CoA steroid glycoside glycosyl transferase MVA steroid IPP cycloartenol GPP SQUALENE (FPP)2  Hydrolysis of Glycosides There are three types of glycoside hydrolysis depending on the hydrolytic reagent : 1-Acid hydrolysis : It is the type of choice for glycoside hydrolysis, Mineral acids, (hydrochloric acid, nitric acid, sulphuric acid) can hydrolyze glycoside bond at room temperature, however, the hydrolysis process can be enhanced by heat : R’- O – R” H+/H2O R’-OH + HO – R” Heat Glycoside glycone aglycone Some organic acids such as, acetic acid, can also hydrolyze glycoside bond.  2-Alkaline hydrolysis : glycoside can also be hydrolyzed in alkaline media but it’s disadvantage is the formation of artifact compounds, and therefore, should be avoided. e.g. lactones' ring in cardiac glycoside can be rapture in alkaline media to give the corresponding acid salt and alcohol  Production of artifact O O O O HCl + glucose HO natural glucose O O O HO C O Na+ NaOH + glucose glucose HO artifact  3-Enzymatic hydrolysis : Certain glycosides are usually hydrolyzed by certain enzymes which is usually found in the same plant but in different cells or tissues and any even such as injury may bring the enzyme in contact with the glycoside and hydrolysis may take place and therefore, crushing of fresh plant material for extraction purpose should be preceded by inhibition of the enzyme using hot alcohol or water. The hydrolysis by the enzyme is very specific and each enzyme can hydrolyze only one glycoside bond or type e.g. enzyme emulsin which is found in the bitter almond seed. Myrosinase enzyme found in black mustard seed  Total and Partial hydrolysis : In glycoside having more than one sugar, acid hydrolysis result in complete separation of the glycone from the aglycone and at the same time separate the monosaccharide from each other. This is known as total hydrolysis Partial hydrolysis involve stepwise separation of the monosaccharide using specific enzyme. This type of hydrolysis is very useful in the study of sugar sequence.  CH 2OH O TOTAL HYDROLYSIS OH CH 2OH O OH PARTIAL HYDROLYSIS OH STEP CH 2OH PARTIAL HYDROLYSIS WISE O OH PARTIAL HYDROLYSIS PARTIAL OH HYDROLYSIS HO OH  General Properties of Glycosides : * Solubility : Glycosides are fairly soluble in H2O but more soluble in aqueous alcohol. On hydrolysis the glycone remain soluble in water but the aglycone is soluble in organic solvents. Colourless compound Odourless compound. Solid compound usually amorphous sometimes crystalline.  Summary Introduction Organic natural compounds consist of sugar and non-sugar part * Definition : Hydrolysis : Classification General Classification - Holoside - Heteroside Classification based on : Sugar part ; glucoside Non-sugar part Glycoside Bond - ROH-HO-R R-O-R - Physiological and physiochemical properties - Hemicetal and acetal bond - Type of glycoside bond : - O-glycoside - C-glycoside - N-glycoside - S- glycoside * General Biosynthesis : Glycone + UTP glycone - UDP + Pi Glycone - UDP + aglycone glycone – aglycone + UDP  Hydrolysis of glycoside - Acid hydrolysis - Alkaline hydrolysis - Enzymatic hydrolysis -Total and Partial hydrolysis General Properties of glycosides : - Solubility - Colour - Odour - State  Glycoside Miscellanous Phenolic Terpenoid 1. Anthraquinones Triterpenoids Steroids 1. Cyanogenine 2. Flavonoids Glycoside 3. Tannins Saponin 2. Glucosinolates 4. Coumarins Cardiac Saponin glycoside 5. Chromones Glycosides Glycosides  Terpenoid Glycoside The aglycones are biosynthesised via acetate-mevalonate pathway. Belong to triterpenoid class and divided into : a. Steroid glycosides - Cardiacglycosides - Seroidal Saponin glycosides b. Triterpenoid glycosides - Triterenoid Saponin glycosides  Glycoside Terpenoid Triterpenoids Steroids Saponins Cardiac Saponin Glycosides Glycosides Chemistry of Cardiac Glycosides : Terpenoid Steroidal Glycoside Cardiac glycoside :  Introduction Distribution General Chemical properties Structural Variation Sugar Moiety Physiochemical Properties D rug Containing Cardiac Glycosides Cardiac aglycone (Cardiogenin) Digitalis Leaves : - Purpurea glycoside A and B Digitalis Lanata : - Lanatoside A, B, C, D, and E Strophanthus Seeds : - Strophanthus kombi * K-strophanthoside - Strophanthus gratus * Ouabain - Squil bulb * Schillaren A  Introduction Some of the steroidal compounds naturally occurring in the plant kingdom are characterized by highly specific and powerful action on the cardiac muscles, they form a well defined and homogenous chemical group from structural and pharmacological point of view and usually occurs as glycosides. Despite the narrow margin of safety )‫ (هامش السالمة‬and the emergence of new synthetic drug possessing similar pharmacological activity on the heart, the cardiac glycoside remain the drug of choice in the treatment of cardiac insufficiency or heart failure.  SUMMARY steroidal compounds naturally occurring plant kingdom highly specific powerful action cardiac muscles. –  well defined and homogenous group structural and pharmacological occurs as glycosides narrow margin of safety emergence of new synthetic drug drug of choice cardiac insufficiency or heart failure.  Distribution : Cardiac glycoside have specifically limited distribution in nature and only scattered in a dozen of families the most known are : 1. Scrophularaiceae: which include digitalis leaves 2. Apocynaceae : which include strophanthus seed. 3. Liliaceae : which include squill bulb.  Among Sudanese medicinal plants which is known to contain cardiac glycoside is Scelopiadiaceae (calatropis) )‫(العُشر‬. These compounds are also found exceptionally in some animals e.g. toad skin???.  General Chemical Properties : The cardio-tonic activity is essentially linked with the aglycone, however, the presence of sugar is very important to modify the polarity and hence the solubility to assist absorption, transportation and distribution in the target organ. The common chemical feature of the aglycone include 1.The presence of steroidal nucleus (C17 ring structure). R 17 C D 14 A B 3 HO P erhydro 1,2,C yclopentano phenonthrene ring structure 2. The presence of OH group at C3 (2˚ alcohol), and OH group at C14 (3˚ alcohol) 3. Unsaturated lactones ring at C17. 4. Ring fusion (configuration) should be : A/B cis B/C trans C/D cis There are 2 types of unsaturated lactone rings : 1. 5 membered unsaturated lactones ring O O 2. 6 membered unsaturated lactones ring O O And therefore, there are 2 types of cardiac glycoside (according to the substitution of R at C17) 5 membered ring cardinolide 6 membered ring bufadienolide For optimum cardio tonic activity the above requirements 1, 2, 3, and 4 should be satisfied or fulfilled  Structural variation : O O O O R2 CH3 CH3 12 R1 CH 11 3 CH3 1 10 OH OH HO 5 HO SCILLARENIN A Structural variations in cardiac glycosides are rather limited and consist of additional oxygenated functional group at C1, C5, C11, C12 these are mainly hydroxide (OH) groups.The methyl group at C10 is sometimes oxygenated in the form of aldehyde or alcohol.  In general the addition of any oxygenated functional group will affect the polarity and hence solubility, transportation and distribution and this in turn will affect the potency of the biological activity. The effect of additional oxygenated functional group on the steroidal nucleus is always positive, and the positive effect rise with the increase of oxygenated functional groups.  Sugar Moiety : Glucose is the common sugar in cardiac glycoside, however, the majority of sugar in cardiac glycosides are deoxygenated sugar. The sugar moiety is usually linked with the OH at C3.  CH2OH CH3 CH3 O O O OH OH OH HO OH HO OH HO OH OH GLUCOSE OH RHMNOSE DIGITOXOSE  CH3 O CH3 HO OH O O-COCH 3 ACETYL DIGITOXOSE HO OH CH3 OH O OH DIGITOXOSE HO OCH3 CYMAROSE  Physiochemical Properties : In general cardiac glycosides are fairly soluble in H2O, slightly soluble in absolute alcohol and chloroform and highly soluble in aqueous alcohol. After hydrolysis the cardiogenin (aglycone) is soluble in organic solvents and the sugar is soluble in water. The presence of lactones ring render the molecule labile and likely to open in alkaline media.  Assignment Write brief report on cardiac glycosides containing plants including : – 1. Scientific name – Pharmacognostical description – 2. Historical background – 3. Active chemical constituent using chemical structures. – 4. Pharmacological properties and medicinal uses  DRUG CONTAINING CARDIAC GLYCOSIDES FOX GLOVE LEAVES ‫أصبع‬ ‫العذراء‬ DigitaIis purpurea Digitalis lanata Family Scrophulariaceae  STROPHANTHUS SEED ‫بذور األستروفانتوس‬ - Strophanthus kombe, - Strophanthus gratus Family Apocyaceae SQUILL ‫بصل العنصل‬ - Urginea maritima, Family Liliaceae Cardiotonic activity is linked with the aglycone, below are the different aglycones found in digitalis cardiac glycoside COMPOUND R1 R2 O O R2 Digitoxigenin H H CH3 R1 Digoxigenin H OH CH3 OH Gitoxigenin OH H HO Gitaloxigenin OCHO H Diginattigenin OH OH  O O O O R2 HO CH3 OH H2C H O R1 HO C OH OH HO HO OH STROPHANTHIDIN OH OUABIGENIN O O CH3 CH3 OH HO SCILLARENIN A  Digitalis leaves (Fox glove leaf) The drug is the dried leaves of Digitalis purparea and Digitalis lanata family Schrophulariaceae The aglycone in digitalis is cardinolide type. Digitalis purpurea purple fox glove. Digitalis lanata Grecian fox glove DigitaIis purpurea Purple Fox glove Digitalis lanata Grecian Fox Glove  Common features : of the aglycon 1. Steroidal nucleus. 2. β)OH( at C3, C14.. 3. 5-membered unsaturated lactone ring i.e cardinolide type  O O R2 CH3 R1 CH3 OH HO Substitutions in R1, R2 give different aglycones. COMPOUND R1 R2 DIGITOXIGENIN H H DIGOXIGENIN H OH GITOXIGENIN OH H GITALOXIGENIN OCHO H DIGINATIGENIN OH OH  Digitalis purpurea contain 2 main cardiac glycosides 1. Purpurea glycoside A. 2. Purpurea glycoside B. The sugars mainly are the same in both glycoside but different in aglycone.  Hydrolysis : 1. Purpurea glycoside A Digitoxigenin + 3 digitoxose + glucose 2. Purpurea glycoside B Gitoxigenin + 3 digitoxose + glucose The sugars moiety, which are usually at C3, are the same in both glycoside and consist of 3 digitoxose sugar and glucose  Purpurea glycoside A O O CH3 O OH DIGITOXOSE HO OH OH CH3 CH2OH O O O DIGITOXIGENIN OH GLUCOSE CH3 HO OH O O OH OH CH3 O O OH CH2OH O O DIGITOXINE 2° OH OH HO OH PURPUREA GLYCOSIDE A 1° HYDROLYSIS : Purpurea glycoside A(1˚) T.H Digitoxigenin + 3–Digitoxose + Glucose H+/OH- Purpurea glycoside A(1˚) P. H Digitoxin (2˚) + Glucose Enzyme Digitoxin (2˚) Total hydrolysis Digitoxigenin + 3-Digitoxose  Purpurea glycoside B HYDROLYSIS : Purpurea glycoside B(1˚) T.H ??? H+/OH- Purpurea glycoside B(1˚) P. H ??? Enzyme Gitoxin (2˚) Total hydrolysis ???? 2. Digitalis lanata family schrophulariaceae also known as Grecian fox glove O O R2 R1 OH CH 3 O O CH 3 O O CH 3 O O OH CH 2OH O O O O-C-CH 3 OH HO OH COMPOUNDS R1 R2 LANATOSIDE A H H LANATOSIDE B H OH LANATOSIDE C OH H LANATOSIDE D OCH H LANATOSIDE E OH OH  O O R2 R1 OH CH 3 O O CH 3 O O CH 3 O O OH CH 2OH O O O O-C-CH 3 OH HO OH  HYDROLYSIS : Lanotoside A(1˚) Total hydrolysis Digitoxigenin + 2 –Digitoxose + Acetyl digitoxose +Glucose Lanotoside A(1˚) Partial hydrolysis Acetyl Digitoxin + Glucose Acetyl Digitoxin (2˚) Total hydrolysis Digitoxigenin + 2-Digitoxose + Acetyl digitoxose Initial dose 1500-2000 mg/ 24/48hrs Maintainance dose 100-200 mg/8hrs 1. Purpurea glycoside A Digitoxigenin + 3 digitoxose + glucose 1-Lanotoside A(1˚) Digitoxigenin + 2 Digitoxose + Acetyl digitoxose +Glucose  Other constituent : - Saponins glycosides - Volatile oils. - Amino acid (Digitalosmine) - Enzyme oxidase.  Strophanthus seeds : The drug is the dried seed of Strophanthus kombi family Apocynaceae, it contain a number of cardinolides (5 membered unsaturated lactone ring) the main one is the k-strophanthoside The aglycone is strophanthidine. the sugar mainly are cymarose, β-glucose, α-glucose Strophanthus kombi  O O O H C OH O O CYMAROSE K-STROPHANTHDIN CH 2OH O O ß-GLU. OCH 3 2° CYMARIN OH CH 2OH O O OH 2° -K-STROPHANTHIN B α-GLU.. HO OH OH 1° -K-STROPHANTHOSIDE HYDROLYSIS : 1. K-Strophanthoside Total hydrolysis ?? 2. K-Strophanthoside Partial hydrolysis ?? 3. k-Strophanthin B Total hydrolysis ?? 4. Cymarin Total hydrolysis ??  O O 12 17 CHO 16 OH 3 O OH 5 K-Strophanthidin Cymarose Cymarin -Glucose K-Strophanthin  -Glucose K-Strophanthoside  O O Strophanthus H2C OH gratus HO HO O O HO OH OH H2C HOCH 2 O HO OHOH O HOCH 2 O OUABIGENIN OH O OH HO OH OUABIGENIN HO OUABAIN OUABAIN STROPHANTHUS GRATUS STROPHANTHUS APOCYNACEAE GRATUS APOCYNACEAE Initial dose 500mg Maintainance dose ? Initial dose 500mg Maintainance dose ?  Squill bulb : The drug consist of sliced and dried scale leaves of several species of the genus Uriginea, Uriginea martima family liliaceae, the plant is indigenous in Mediterranean region. There are two type of Squill bulb, white squill and red squill. The white squill consist of up to 4% of cardiac glycoside of bufadienolide type. The chief constituent is scillarenA Squill bulb  Scillaren A O O OH CH 3 O O Rhaminose OH SCHILLARENIN CH 2OH O O OH PROSCHILLARIDINA 2° Glucose OH HO OH SCILLAREN A 1° RHAMNOSE (RH) + GLUCOSE (GL) SCHILLABIOSE  Cardio tonic, Diuretic, Expectorant, emetic Normal dose 100mg. Hydrolysis : ?? Squill in addition to the cardio-tonic activity possess expectorant and diuretic activity and also characterized by having an emetic property. The red squill containing no cardiac glycoside and mainly use as pesticide and rodenticide Biological importance of Cardiac Glycosides Is the drug of choice in congestive heart failure )‫)وهن القلب االحتقاني‬ What is congestive heart failure ?  is a syndrome that occurs because the heart is failing as a pump. The left ventricle no longer functions as an adequate pump to maintain normal cardiac output (normal ejection fractions). This may be due to: 1- disease of the heart muscle, ischemic heart disease which leads to myocardial infarctions affecting left ventricular function. 2- chronic long term untreated hypertension. 3- bacterial endocarditic..etc. Therapeutic effects Use of cardiac glycosides in therapeutic stem from the ability of this compounds to increase the force of systolic contraction ( positive isotropic effect) and increasing contractility of the failing heart results in a more complete emptying of the ventricle and shorting in the late systole. Thus the heart has more time to rest between contraction. In addition, the improved circulation tend to improve the performance of the renal system which relief the oedema often associated with congestive heart failure  Saponin Glycosides : Introduction : Definition General properties Distribution Classification of saponins Steroidal saponin glycoside Biosynthesis of Steroidal saponin glycoside Potentiality of steroidal saponin Synthesis of steroidal drug from diosgenin glycoside  Steroidal saponin containing drugs Nitrogenous analogue of steroidal sapogenin Triterpenoid saponin glycosides ❖ - Introduction ❖- General chemical properties ❖- Some Important sapogenin in triterpenoid saponin ❖- Triterpenoid saponin containing drugs. ❖-Monodesmosidic and bidesmosidic saponin ❖Biological importance of saponin glycoside  Saponin Glycosides Definition : These are organic natural products of complex nature, widely distributed in higher plant, but can also be produced by lower organism and some animal e.g. fish saponins. They are mostly terpenoid in nature of triterpenoid class and therefore, polycyclic structure.  General properties : 1.Their aqueous extract produce persistent foam on shaking. 2. Form colloidal solution in water 3. Irritant to mucous membrane. 4. Possess bitter taste. 5. Destroy red blood cells in a process called haemolysis and they are specially very toxic to cold blooded animal e.g. fish and snails. 6. Very toxic intravenously (I.V) but non-toxic orally. Why?. 7. Reduce the surface tension of water and therefore, useful as emulsifying agent, How?. 8. Can combine with the cholesterol of the cell membranes and therefore, produce general toxicity, How?. 9. On hydrolysis, saponin give an aglycone known as sapogenins. 10. They are mostly amorphous and difficult to separate as crystalline products, however, their acetyl derivatives can produce very nice crystals.  Distribution : They are widely distributed in higher plants and characterize some plant families e.g. 1. Liliaceae. 2. Dioscoreaceae. 3. Leguminosae. 4. Balanitacace. 5. Taccaceae. 6. Phytollacaceae. 7. Scrophulariaceae.  Classification of Saponins : Based on the aglycone part (sapogenin), saponin glycosides are classified into two broad class : 1. Steroidal saponin glycosides. 2. Triterpenoid saponin glycosides.  Steroidal saponin are further divided into two subclass : O N F EO O C D A B HO HO Neutral steroidal saponin Basic steroidal saponin  Triterpenoid saponin are also divided into two classes. Tetracyclic triterpene pentacyclic triterpene  Steroidal saponin glycosides : Widely distributed in monocotyledons e.g. Liliaceae and some of the them occur in dicotyledons e.g. Leguminosae O F EO C D A B HO According to the shape of ring E and F, they are divided into 4 class.. 1- Spirotan group 2- Furostan group 3- Furospirostan 4- Miscellaneous  (i) Spirostan group O F E O C D A B HO 1- C27 Sapogenin Skeleton 2- steroidal nucleus. 3- Spiroketal structure at C22 4- OH at C3 5 - C=C Δ5-6 6- Furan ring E 7- Pyran ring F (ii) Furostan group HO F E O C D A B HO 1- C27 Sapogenin Skeleton 2- steroidal nucleus. 3- No Spiroketal structure 4- OH at C3 and C26 5- C=C Δ5-6 6- Furan ring E 7- Open ring F  (ii) Furostan group In the plant Furostan usually found as biglycoside, a monoglycosides produce easily during extraction giving Spirostan group (Pyran ring F) selective hydrolysis (iii) Furospirostan O F CH2OH E O C D A B HO 1- C27 Sapogenin Skeleton 2- steroidal nucleus. 3- Spiroketal structure C22 4- OH at C3 and C26 5- C=C Δ5-6 6- Furan Both ring E and F.  (iv) Miscellaneous (A) Solanoids O E O C D A B HO OH 1- C22 Sapogenin Skcleton 2- Steroidal nucleous 3- OH at C3 and C6 4- Ring E Lactone 5- Loss OF ring F  (B) Kryptogenin HO F EO O C D A B HO 1- C27 Sapogenin Skeleton 2- Steroidal nucleolus 3- Both ring E and F open 4- C= O at C16 and C22 5- OH at C3 6- C=C Δ5-6  Steroidal saponin containing drugs : 1. Yams : Dioscorea spp. Dioscorea composite Family: Dioscoreaceae Steroidal sapogenin Diosogenin and Yamogenin O O 25 25 O O Diosogenin (25α) HO Yamogenin (25β) HO  Other drugs containing Diosogenin and Yamogenin a) Fenugreek : Trigonella foemum-gracum,Family : Leguminosae b) Balanite :[Laloab] Balanite aegyptica, Family: Balanitaceae c) Kagorae (Tacca) C)Tacca leontopetaloides Family :Taccaceae  2. Sisal Agave sislana, Agavaceae O O 25 O O O HO HO Hecogenin 3. Solanum (Potato) : Solamum tuberosum,Family Solanaceae H N O HO Solasodine Basic sapogenin  O O 21 22 24 26 20 23 25 17 27 cholesterol 16 O HO O F E O CH2OH O steroidal saponin O OH HO OH Biosynthesis of Steroidal Saponins  Biosynthesis of Steroidal Saponins ✓Cholesterol was proved to be the direct precursor of steroidal sapogenin. ✓The spiroketal functional group is derived from cholesterol side chain.  Requirements : Selective oxygenation. Ring formation Glycosidation  Procedure : I. Selective hydroxylation C16 , (CH3) at C26 II. Introducing keto function (C = 0) at C22. III. Reaction between (OH) at C16 and keto (C = 0) at C22 give 1st. ring closure (hemicetal bond). IV. Glycosidation of (OH) at C26 followed by hydrolysis give 2nd ring closure (see furostan group). V. Glycosidation of (OH) at C3 give steroidal saponin.  CHO - CH2OH H- C - OH O HO - C - H OH C H - C - OH OH H OH H - C - OH OH CH2 - OH F OLDE D GLUCOSE OPE N CHAIN GLUCOSE  (ii) Furostan group In the plant Furostan usually found as biglycoside, a monoglycosides produce easily during extraction giving Spirostan group (Pyran ring F) selective hydrolysis  22 26 O 25 O 27 H 16 OH O H H H HO OH H H + + HO OH O OH OH H H O H.. OH H H H H H HO HO UDPGlu OGle Steroidal H OH O H+ H O H O Saponin H H H H H HO Diosgenin (sapogenin) HO UDPGlu O H O H H H H CH2OH O O OH Diosgenin glycoside(saponin) HO OH UDP- G UDP Glu  Potentiality of steroidal Saponin : Research on saponin glycosides specially steroidal saponins become an interesting field for phytochemist and pharmaceutical industries, since the steroidal nucleus can provide a cheap raw starting materials for the production of steroidal drugs e.g 1-sex hormones and 2-anti-inflammatory (cortison)  OH O O OH TESTOSTERONE ESTERONE C 19 C 18 O O HO CH3 C=O OH O O CORTISON ANTI-INFLAMMTORY Synthesis of Steroidal Drugs from Diosgenin Glycoside ACoA O H O H H H H CH 2OH O O Diosgenin glycoside (saponin) HO 21 O HO OH 20 H 25 22 E O H Diosgenin (sapogenin) H H HO Ac O / Ac O H O Ac O H O O C rO3 H H O H AcO H H AcO Hydrolysis O O H H H Progeste rone O HO Pre gne nolone  AC2O CrO3 hydrolysis  Synthesis of cortisone O Progesterone O CH2OH CH2OH O O HO OH OH O O Hydrocortisone O Certisone Synthesis of sex hormone O Progesterone O OH 18 O 19 O Testosterone HO ♂ ♀Oesterone Nitrogenous analogues of Steroidal saponin N O N HO HO Solasodine Solanidine  Triterpenoid saponin Glycosides Organic natural products of terpenoid origin, belong to triterpenoid class, they are characterized by polycyclic ring skeleton and compose of 2 form : 1. Tetracyclic triterpenoid 2. Pentacyclic triterpenoid Tetracyclic triterpene pentacyclic triterpene The pentacyclic skeleton are also found into 2 forms : 30 29 30 29 Oleanane structure Ursane structure β-Amyrin α-Amyrin  These compounds are usually found in acidic form 29 17 COOH COOH 28 Oleanolic acid Urosolic acid Acidic Sapogenin Acid can also form glycoside bond but in Easter form rather than the normal ether form.  29 17 COOH COOH 28 Oleanolic acid Urosolic acid O N F EO O C D A B HO HO Neutral steroidal saponin Basic steroidal saponin  30 29 E 25 C D 28 26 A B 27 23 24  30 29 E 25 C D 28 COOH 26 A B 27 HO 23 24 1) 8-methyl group * 3-α-methyl group C23, C27, C29. * 5-β-methyl group C24, C25, C26, C28, C30 2) 2 geminal dimethyl groups (23-24) (29-30). 3) Unsaturated bond ∆11-12 4) OH group at C3 5) COOH group a C17 (C28) 6) Sugar moiety. * Usually at C3 (Ether) * Sometimes at C28 (Ester)  Some Important sapogenin in Triterpenoid Saponins COOH COOH OH HO HO Hedergenin CH2OH Oleanolic acid O CO-C-CH 3 OH COOH COOH HO HO O CH3-C-O HO CH2OH HO CH2OH Phytollaccagenin Bayogenin Triterpenoid saponin containing drugs 1. Liquiric Root Glycyrrheza glabra,Family Leguminose COOH O Glycyrrhetic acid CH2OH O O OH HO D-Glucronic acid COOH O O D-Glucronic acid HO OH OH Glycyrrhetic acid Glycyrrhetine = K' or salt of Glycyrrhetic acid  2.Soap bark Quillaia bark QuillaiaSaponins Quillaja Saponaria Family Rosaceae Rhaminose COO-Fucose Xylose-Apiose O Glacronic acid Xylose Galactose 3.Phytollacea dodecandra, Family Phytollacaeae COOCH 3 COOH HO HO CH2OH Phytollaccagenin Monodesmosidic and Bidesmosidic Saponin 1. Triterpenoid Saponin COOH COOG GO GO Monodesmosidic Bidesmosidic 2. Steroidal Saponin  Biological Importance of Saponin Glycoside : General : - Emulsifying agent. - Molluscicidal agent. Triterpenoid Saponin : - In peptic ulcer - Sweetening agent. - Expectorant. Steroidal Saponin : - Anti-flammatory. - Source of steroidal drugs.  Cont. Ass. No.6 HO F E O C D A B HO Name the group represented by the above structure and discuss its chemical properties Enumerate the biological importance of saponins  Glycoside Miscellanous Phenolic Terpenoid 1. Anthraquinones Triterpenoids Steroids 1. Cyanogenine 2. Flavonoids Glycoside 3. Tannins Saponin 2. Glucosinolates 4. Coumarins Cardiac Saponin glycoside 5. Chromones Glycosides Glycosides C , H ,O N &S C,H,O  Glycoside Terpenoid Triterpenoids Steroids Saponins Cardiac Saponin Glycosides Glycosides Phenolic Glycosides Definition : They are organic natural products characterized by the presence of phenolic group. The parent compound is phenol, however, most of these compounds occur as polyphenols e.g. OH OH OH O OH Quercetin OH OH Phenolic glycosides are characteristic of plant tissues, however, some of them occur in animal tissues. The presence of phenolic compound in any specimen may determine the origin of that specimen More than 8000 compounds have been isolated and chemically characterized, flavonoid constitute the largest groups, other groups also occur in large number such as : - Xanthins - Tannins - Anthraquinones - Lignins.  Phenol can exist in different forms : - Monomeric phenols, - Dimeric phenols - Polymeric phenols, phenolic polymers. The last one is the usual form in plant tissues e.g. - Melanin pigment (black pigment) - Lignin The lignin form with cellulose the wood tissues : Lignin + Cellulose wood tissues. -  OH OH HO O OH OH OH O SIMPLE PHENOL FLAVONOL QUERCETIN OH HO COOH O [ NH2 TYROSIN Tetrahydrocannabinol  LEGNIN UNIT OH HO OH HO HO OH OH O HO OH O O MELANIN UNIT OH O O OH  General Properties 1. Acid in reaction : O- H+ This property is used in their isolation from plant extract i.e. form sodium phenolate with sodium bicarbonate. 2, High affinity to form H-bonding, both intermolecular and intramolecular H-bonding  3. React with heavy metals e.g. Mg, Mn, Fe to form salt-like known as chelates in a process called chelation, this is very important in biological system e.g. – i. Haemoglobin, – ii. Chlorophyll – iii. Cyanocobalmin [Vit. B12]. 4. Ease of oxidation Monophenol biphenol polyphenol OH OH O Quinones [O] [O] OH O  Biological importance of phenolic glycoside 1. Give some traditional foods and drinks their characteristic flavour. 2. Protect some plants from herbivorous animals. 3. Play important role in N-fixation 4. Play some role in the process of parasitism. 5. Occur in lower plants and usually in a form of antibiotic e.g. Grisiofulvin from OCH3 OCH3 Grisiofolvum penicillium culture O O CH3O Cl  Classification of Phenolic Glycosides : Phenolic glycosides are classified according to chemical structure into 5 important groups : Quinone pigments Tannins Flavonoids Coumarins Chromones Each group is represented by a parent structure  O 1. QUINONES STRUCTURE 6-6 O COOH 2. TANNINS STRUCTURE 6-1 HO OH OH O O O O FLAVONOIDS FLAVONE STRUCTURE iso-FLAVONOIDS 6-3-6 COUMARINS STRUCTURE 6-3 O O O CHRMONE STRUCTURE 6-3 O  OH HO CALVIN SHIKIMATE CYCLE COOH PATHWAY CH 2-CH-COOH NH2 OH PHENYLALANIN General Biosynthesis SHIKIMIC ACID -NH2 of Phenolic Glycoside PHENOLS HO OH [O] HYDROXYCOUMARIN HYDROXY CH BENZOIC + 3MALONATE COOH ACID p-HYDROXY CINNAMIC ACID Xanthones REDUCTION QUIONES + Stibenes FLAVONOIDS HO CH=CH-CH 2-OH p-HYDROXYCINNAMYL iso-FLAVONOIDS ALCOHOL POLYMERIZATION POLYMERIZATION -O REDUCTION LIGNIN DIMERIZTION FLAVOLANS PHENYLPROPENS LIGNAN  Quinone Pigments : These are organic natural products, coloured compound, ranging from pale yellow to black. Over 450 structures have been known although they are widely distributed in plant kingdom and exhibited great structural variation, they make a relatively small contribution to plant colour, since they are mostly found in tissue such as root and bark. They are characterized by the quinone group For identification and detection purposes quinones can be divided into 4 groups according to quinone nucleus : – Naphthaquinones are involve in cellular respiration. – Ubiquinones or co-enzyme Q, are found in almost all organisms and function as electron carrier in electron transport chain in mitochondria. – Plastoquinones play an important role in photosynthesis process as electron carrier in electron transport chain in green plants. – The most important group of quinones is the Anthraquinones which are cited in all pharmacopoeias as laxative compounds.  O O 1.BENZOQUINONES O O p-BENZOQUINONES p-BENZOQUINONES RED PIGMENTS YELLOW PIGMENTS O O OH 2. NAPHTHOQUINONE O OH O LAWSONE JUGLONE YELLOW  O O CH3 CH3O 4. isoPRENOID QUINONES [ ] [ ] CH3 n CH3O n O O PLASTOQUINONES UBIQUINONES n = 3-9 n = 1-12  O O CH3 CH3O 4. isoPRENOID QUINONES [ ] [ ] CH3 n CH3O n O O PLASTOQUINONES UBIQUINONES n = 3-9 n = 1-12  Anthraquinones : Long before any information was known about their chemistry, some herbal drugs, e.g Senna, Rhubarb, Cascara were traditionally used as laxative or purgative. They are of great economic important before the introduction of synthetic dyestuffs.  Their structures were elucidated later found to be based on anthraquinone nucleus. They are found in both free state and as glycosides. The anthraquinone is the oxidized form, however, studies showed that both the oxidized and reduced form occur together in most natural products.  OH O H H H Anthranol Anthrone +4H -2H O O O Anthraquinone +2H O O Dianthrone Oxidized and reduced form H OH of Anthraquinone Oxanthrol Anthraquinone containing Drugs : Senna leaves and fruits. Cascara bark Frangula bark. Aloe SENNA LEAVES AND FRUITS Source Cassia acutifolia Cassia angustifolia Family : Leguminosae Indigenous source Sudan, Egypt, India, Saudia Aarabia Commercial source : Sudan, India  Chemical constituents : The drug contain phenolic glycoside of anthraquinone group and characterize by a dianthrone structure. On hydrolysis give aglycones of dianthrone structure Sennoside A. Sennoside B Sennoside C Sennoside D  R 10,10- Sennoside A COOH trans Sennoside B COOH meso Sennoside C CH2OH trans Sennoside D CH2OH meso  On hydrolysis each glycoside give the corresponding aglycone 1. Sennoside A Sennosidine A + glucose 2. Sennoside B Sennosidine B + glucose 3. Sennoside C Sennosidine C + glucose 4. Sennoside D Sennosidine D + glucose  Cascara Bark Cascara Sagrada Christ thorn ‫القشرة المقدسة السدر‬ ‫النبق‬ –Rhamnus purshina, Family : Rhamnaceae Indigenous source : Pacific coast of North America. The bark is stripped of the trunk of older branches, dried and stored for at least one year before it can be used for medicinal purposes, during such time slow hydrolysis take place. Cascara Bark  Chemical constituents : 6.8% of anthraquinone glycoside the major glycoside are cascaroside group A,B.C and D. cascaroside represent best example of O and C glycoside  CH 2OH O OH OH HO O O OH CH 2OH R O OH OH OH C10 R CASCAROSIDE A 10β H CASCAROSIDE B 10α H CASCAROSIDE C 10β OH CASCAROSIDE D 10α OH  Frangula ‫قشرة العوسج‬ Alder Buck thorn ‫النبق المسهل‬ Source Rhamnus frangula Family Rhamnaceae Indigenous source : South East Europe. The bark is also should be stored for one year before use  Chemical constituents : 6% of anthraquinone –o-glycosides, the major are 1- glucofranguloside A 2- glucofranguloside B. On slow hydrolysis. OR1 O OH OR2 CH3 O Glucofranguloside R1 = Glucose, ‘R2 =Rhaminose Franguloside (Frangulin A) R1 = H, R2 = Rhaminose  Hydrolysis : Glucofranguloside A (1˚( Franguline A (2˚( + glucose Glucofranguloside B (1˚( Franguline B (2˚( + glucose Franguline A (2˚( emodine + Rhamanose Franguline B(2˚( emodine + Apinose Glucofranguloside A (1˚) T H emodine + Rhamanose + glucose Glucofranguloside B (1˚( emodine + Apinose + glucose Aloes )‫) شجرة الزقوم‬ ‫الصبار‬ The drug consist of the dried juice from the leaves of various Aloes species : Aloes Africana (cape Aloe) Barbados Aloes (Curacao Aloe) Aloes Perryi (Socotrine Aloe) Family : Liliaceae.  Indigenous source : Africa, South East Asia, South America Chemical constituents : 10-30% of anthraquinone glycosides, the major one is barbaloin. OH O OH HO CH 2OH CH 2OH O OH OH OH Barbaloin  Continuous assessment NO. 10 Give the natural sources of the following compounds ?? 1. Frangulin A 2. Sennoside C 3. Cascaroside D Tannins  Introduction : These are organic natural compounds of complex nature characterized by high molecular weight and high ability to react with amino acids and proteins to form water insoluble polymers, which are resistant to enzymes and fermentation by micro- organism. This process convert skin into leather and known as tanning ‫ الدباغة‬and hence the term tannins. In case of living tissues the process known as stringent Occurrence of Tannins : In vascular plant tannins usually occur in woody parts of the stem, however, they are found in some unripe fruits e.g. dates, ficus, which disappear completely in ripe fruits, thus some scientist believe that tannins are used as a source of energy for ripening process General Properties : 1. Amorphous, none crystalline compounds. 2. Form colloidal solutions in water with stringent taste and acid reaction. 3. Form precipitate with protein and gelatin solution. 4. Give coloured solution with FeCl3 ranging from blue to reddish to black. 5. Give red colour with potassium ferricyanide and ammonia (KFe(CN)4 + NH3) 6. Give precipitate with solution of heavy metals e.g., Cu, Zn, and Pb. 7. Give yellow colour with potassium dichromate (K2Cr2O7) and chromic acid solution. The precipitated protein is resistant to protolytic enzyme, such reaction when take place in living tissues known as stringent, and form the basic of therapeutic application of tannin.  Uses : 1. The property of protein precipitation have been utilized in : i. protection of tissues from digestive enzyme. ii. Protection of exposed tissues e.g.in injuries and burns from infection (N.B. : The precipitated protein form a protective layer under which the new tissues can be regenerated.) 2. Used as stringent for GIT e.g. in diarrhea HOW ?? 3. Production of leather. Different tannin compounds produce different type of leather both in colour and touch or texture. 4. Colour with FeCl3 is used for production of inks. 5. Used as reagent or detector in medical laboratories for the detection of protein and gelatin in various body fluids e.g. urine and plasma. 6. Used as antidote for alkaloid over dose and poisoning. HOW ??  General Chemical Properties : 1. Complex chemical structure. 2. Polyphenolic structure. 3. Difficult in isolation into individual compound, phytochemist prefer the use the term tannin extract rather than tannin compound. 4. Form phenolic polymers from simple phenols.  Simple phenols COOH COOH OH OH OH OH OH Gallic acid Protocateuchic acid OH O C=O Ellagic acid HO OH C O OH O  COOH OH OH X2 OH OH O C=O OH HO COOH HO OH HO OH C O OH O HOOC OH OH Ellagic acid Hexahydroxy diphenic acid  Classification of tannins 1. Pseudotannins. 2. True tannins. 1-Pseudotannins :.1 These are simple phenolic compounds which are under certain condition can give reaction similar to that of true tannins e.g. : 1. Gallic acid 2. Catechin 3. Chlorogenic acid.  OH COOH OH OH OH O OH O OH OH OH O OH OH Catechin Chlorogenic acid  True tannins : These are further devided in two classes according to: a. Type of polymerization nucleus. b. Mode of polymerization : 1. Hydrolysable tannin.. 2. Condensed tannin. Hydrolysable Tannins : The nucleus here is glucose molecule and surrounded by a number of gallic acid molecules, known as galloyl glucose depside.  There are two types of hydrolyzable tannins: 1. Monomeric galloyl glucose depside. 2. Polymeric galloyl glucose depside.  OH O C OH OH O OH O OH CH 2 OH C O O O C OH OH O OH O OH OH OH C O O C OH OH O OH Monomeric galloyl glucose depside  OH OH OH OH C O OH O O CH 2 OH C O O O C OC OH OH O O OH O O OH C OH C O O OH OH OH OH Polymeric galloyl glucose depside Condensed Tannins : This type is very difficult to hydrolyze, hence the old term, non-hydrolysable tannin. However, can be hydrolyzed using drastic conditions, by addition of FeCl3 and use of high temperature, The hydrolytic product showed the presence catechin as main product which concluded that catechin is the nucleus of polymerization.  OH OH O OH Condensed tannin HCl/FeCl3 ∆ OH OH catechin  OH R OH O OH OH OH OH OH O OH OH OH OH OH O OH OH OH R Flavolan (Proanthocyanidine condensed tannin) Practical tests to differentiate between hydrolysable and condensed tannins in the lab : Test Hydrolysable Condensed tannin Heat (Destructive, heat without H2O OH OH OH OH OH Pyragallol Catechol Heat + HCl Gallic acid + Ellagic Insoluble matter acid (Red phlobaphen) FeCl3 Blue colour Green colour Bromine water No precipitate precipitate Tannin containing drugs : Hydrolysable Tannin : Clove, redrose petals, eucalypyus leaves, hammalis leaves. Condensed Tannin : Cinnamon ; Tea, Kola, hammamlis.  Coumarins These are natural compounds derived from benzo-α-pyrone. α O O α benzo-α-pyrone. They are biosynthesized in the plants from cinnamic acid via hydroxylation at position ortho to the side chain followed by lactone formation.  COOH COOH (OH) COOH OH OH Cinnamic acid Cyclozation (OH) cinnamic acid OH (OH) O O (OH) OH Umbelliferone O O O O OH Aesultin coumarin CH3O CH3O OH O O O O O Scopoletin Scopolin G Biosynthesis of coumarins  R1 R2 O O Compound R1 R2 Coumarin H H Umbelliferone H OH Aesultin OH OH Scopoletin OCH3 OH Scopolin OCH3 O-G Of the well known drugs containing Coumarin nucleus : 1. Dicoumarol 2. Warfarin OH O O O O O. Dicoumarol (Natural) O O Warfarin synthetic Antidote of vitamin K Dicoumarol is a natural product, used as an oral anticoagulant when the risk of blood clots become life threatening. Warfarin is a synthetic development from the natural compounds and initially used as rodenticides. Of the most interesting drug contain coumarin nucleus, the antibiotic novobiocin which is obtained from the streptomyces neveus culture, act on Gram +ve bacteria. a. Sugar metabolic pathway.+ Trans amination b. Acetate malonate c. Shikimic acid + Trans amination d. Aetate malonate e. Acetate mevalonate * Contain rare amino sugar (amide {NH2C=O})  Chromones Organic natural products derived from benzo-δ-pyrone O O O O benzo-δ-pyrone drugs benzo-α-pyrone. Of the well Known drug which contain chromone nucleus are : 1. Khellin. 2. Visnagin  OCH3 O O O CH2R2 R1 Compound R1 R2 Vsnagin H H Khellin OCH3 H Khellol (glycoside) H O-G These compounds are obtained fom Ammi visnaga, family Umbelliferace and used as coronary vasodilators. VISNAGIN KHELLIN KHELLOL Flavonoid Glycosides These are organic natural products. They are virtually universal plants, pigments responsible for the color of flowers, fruits and sometimes leaves. The common color is the yellow and the terms flavonoids itself come from the latin word flavus which means yellow. Flavones Aurones Yellow Chalcones Red Anthocyanins Blue Purple When they are not directly visible, they contribute to color by acting as co-pigment, e.g. colorless flavone and flavonols co-pigment protect anthocyanin In some cases the molecule absorb near UV radiation which is only perceived by insect eyes and function to ensure pollination and hence, play a role in plant species conservation. Flavonoids are also ubiquitous in the leaf cutile and epidermal cell they ensure tissue protection against the damaging effects of UV radiation. Chemically, flavonoids are characterized by common basic skeleton Flavone 2-phenyl-4-chromone. O CC C O Flavone 2-phenyl-4-chromone General Biosynthesis : Flavonoids are classified as compound of mixed biosynthetic origin, thus both shikimic acid and acetate malonate pathway contribute in their formation. (see structure)  C C C Shikimate pathway Acetate malonate pathway O O SCoA 3(HOOC-CH2COSCoA) O 3-[MALONYL-SCoA ] CINNAMYL-SCoA  OH OH HO OH HO O OH O OH O Chalcone Flavonone  Occurrance : No flavonoid have been found in Algae, but they are common in mosses. However, they are highly distributed in higher plants. Pro-antho-cyanins are remarkably ubiquitous in Gymnosperms, while the majority of flavonoids are found in Angiosperms, the common flavonoid families include : Polygonaceae, Leguminosae, Rutaceae and Compositae. Free flavonoids, aglycone are usually concentrated in the leaf cuticle while the glycoside form are water-soluble and accumulate in vacuoles of the epidermis or mesophyll.  Flavonoids Glycoside : 2' 3' OH 1' HO 8 O 4' 7 1 6' OH 2 5' 3 6 4 5 OH OH O  Sugar moiety can be mono, di or polysaccharide, homogeneous or heterogeneous, in straight chain or branched. All (OH) group can involve in glycoside bond, however, usually at C7 (flavonoids) or C3 (flavonols)  Recently some flavonoid esters have been detected with fatty acids such as malonic acid, acetic acid or tiglic acid and sometimes with aromatic acid or phenolic acid such as benzoic acid and gallic acid. Beside the normal O-glycoside, C-glycoside are also common among flavonoids e.g. vitexin, Some S-glycoside have also been detected.  Classification of Flavonoids : Chemistry of flavonoids are so diverse and subject to a lot of modification more than 20000 compounds have been detected so far comprises about 400 different structures, recently it has been grouped into 10 classes (see structure). `  1' O B A C O  OH OH OH OH HO O HO O Dihydrochalcone OH O Flavonone OH O Flavones OH OH HO OH HO O O OH OH OH O Aurones OH O Chalcone Dihydroflavonols OH + HO O OH O OH OH O Anthocyanine O iso-Flavonoid OH OH HO O HO O OH OH OH OH O Flavan3,4-diols  OH HO OH OH O Dihydrochalcone (colourless) On the other hand chemical studies showed that this diversely focused on the oxidation level of ring C and based on this, it has been summerized into 4 groups. (see structure)  OH AR A O Chalcone O AR A O Aurones  OH OH HO OH HO OH OH O OH O Chalcone (Yellow) Dihydrochalcone (colourless)  Chalcones : This is the first product in the biosynthetic pathway of flavonoids and represent the parent compounds of all flavonoids. They are common in certain families e.g. Leguminosae, Labiatae and Compositae and contribute to the yellow colour of their flowers. Some colourless chalcones have also been obtained from plant and named α (OH) chalcone  OH OH HO OH HO OH  OH OH O OH O Chalcone (Yellow)  -(OH) chalcone (colourless) Example : Butea monosperma, Leguminosae OH Butein : R = H Coreopsin R = Glucose  Flavonones : These are obtained from chalcone by isomerization : OH OH RO OH RO O OH O OH O Chalcone Flavonone They are highly distributed in the plant kingdom specially in the Rutaceae members.  OH OH RO O OH O Naringenin R=H Naringin R = O-G-O-Rh, Rh = Rhaminose, G = Glcose. This compound is the cause of the bitter taste of citrus fruits, specially grape fruits Citrus paradise, Rutaceae.  Flavones :. This is produced from flavonone by addition of double bond at position 2-3 i.e oxidation of flavonone OH OH HO O HO O OH O OH O Flavonone (Naringenin) Flavone (Apigenin) Example : Vitexin, Vitex leucene, Verbenaceae (C-glycoside) O OH O OH CH2OH O OH HO OH OH  Flavonols : This is characterized by an additional OH group at C3 Example :Quercetin OH OH HO O insect vision. Sugar moiety usually at C3 OH They are thought to be very important for OH O They are thought to be very important for insect vision. Sugar moiety usually at C3  isoFlavonoids : These are characteristic of Leguminosae family and thought to have important role for the physiological function of both plant s and animals. HO O 1 2 3 4 OH OH O Flavonoid iso-flavonoid  Anthocyanidine : These are groups of water soluble pigments responsible for the red, pink and blue colour of most flowers and fruits. The term come from the Greek antho (flower) and kuonos (blue). Usually occur as glycoside (Anthocyanin) and derived from the 2-phenyl benzopyrylium cation and commonly known as flavylium cation. OH + HO O OH OH  Usually found in the cell sap and the type of colour and its intensity depend on pH. They are of great important in plant species conservation by attracting insects and birds for the process of pollination and seed dispersal.  Biological Importants of flavonoids : 1. There is strong believe that flavonoids play a very important roles for the plants and animals. However, the mechanism and details of this role still unknown, but some of them can be summarized as follow : 2. Growth regulations. 3. Enzyme inhibition. 4. Species conversation (pollination and seed dispersal) 5. Photo-protective against toxic UV radiation (act as filter) 6. Chemo-protctive (used in insecticides and pesticides formulae). 7. Fish poison and molluscicides.  Therapeutic uses : Veno-activity : Flavonoids are essentially used to treat capillary and venous disorders (They decrease capillary permeability and fragility) it can be used alone or in combination with other ingredients of vascular protective agents and venous tonics. Like other phenolic compounds, it is recommended as antioxidant : however, these two therapeutic uses of flavonoid still ambiguous, require more investigations and research. Name the following structure  Cyanogenitic glycosides : These are a group of oganic natural product and mainly plant derived compounds characterized by liberation of hydrocyanic acid on hydrolysis and thus of great important as natural toxicants e.g. Amygdalin a constituent of Prunus amygdalus var amara, Family Rosacease (bitter almond ‫ )اللوز المر‬and other prunus species e.g. Apricot ‫المشمش‬, peaches ‫الخوخ‬, cherries ‫ الكرز‬and plums ‫البرقوق‬.  The hydrocyanic acid is released when the plant is crushed and the glycosidase enzymes{ usually found in the same tissues but in different cells} are brought into contact with glycosides, however, the kernel of the sweat almonds Prunus amygdalus var, dulcis containing the enzyme but did not produce HCN since it contain no cyanogentic glycoside : Amygdalin (1◦ ) β-glycosidase Prunasin (2◦) β-glycosidase Mandelonitrile (aglycone) Enzyme Benzaldehyde + HCN (toxic)  C N O CH2OH beta-glycoside O OH Glucose HO HO Prunasin (2˚( beta-glycoside Amygdalin C N CHO + Enzyme HCN C H2O OH Benzaldehyde Mandelonitrile Cyanogenic glycoside are biosynthesized from a range of amino acids depending on the plant spcies. In bitter almond the prunasin is produce from phenylanine.  COOH COOH O2 NH2 NADPH NH2 OH L-phenyl alanine NADPH O2 N(OH)phenyl alanine COOH COOH N N OH E-aldoxime OH OH N,N(OH) phenyl alanine N H2O C phenyl acetonitrile N NADPH OH Z-aldoxime O2 G O H HO H C N N C UDP Glucose Prunasine Mandelonitrile  Cyanogenic glycoside are biosynthesized from a range of amino acids depending on the plant spieces. In bitter almond the prunasin is produce from phenylanine. Different amino-acids produce different cyanogenic glycoside Amino acid Cyanogenic glycoside Source 1. Phenylanaline Prunasin Bitter almond ‫اللوز المر‬ 1. Tyrosin Durrin Sorghum ‫الذرة‬ 1. Valine Linamarin Flax ‫الكتان‬ 1. Leucine Heterodandrin