Glycosides Lecture Notes (PDF)

GLYCOSIDES Lecture (8) Lecture Content; Phenolic Glycosides: E- Flavonoid glycosides F- Coumarin glycosides Non-glycosidic organo-sulfur drugs Cyanogenic Glycosides Glucosinolates Assoc. Prof. Noha Swilam  E- Flavonoid Glycosides - One of the...

GLYCOSIDES Lecture (8) Lecture Content; Phenolic Glycosides: E- Flavonoid glycosides F- Coumarin glycosides Non-glycosidic organo-sulfur drugs Cyanogenic Glycosides Glucosinolates Assoc. Prof. Noha Swilam  E- Flavonoid Glycosides - One of the most diverse and widespread group of natural products Distribution - In fruits, vegetables, nuts, seeds, stems, flowers as well as tea, and are one of the most important constituents of the human diet - Free or in glycosidal form, more common in higher plants - Seeds of family Leguminosae (isoflavonoids), - Members of family Polygonaceae (flavan-3-ols, anthocyanins) Skeleton Diphenyl propane derivatives 7 CH2 B 4′ A [ C6-C3-C6 ] 15 carbons CH2 CH2 2 Role in plant 1- Role in plant defense mechanism is very limited. Production of phytoalexins (isoflavones or isoflavanones) or other plant phenolics in response to fungal infection or other external stimuli. 2- Pigments in flowers, attract pollinating birds and insects. 3- Plant growth regulators, inhibiting or activating enzymes. Pharmacological activities: - Binding to enzymes and cell membranes. - Chelation of heavy metal ions. - Electron transfer in enzyme systems, e.g. oxido-reductases. - Free radical scavenging (antioxidant). Therapeutic uses: Procyanidins in Crateagus sp. → Cardiotonic Catechins in Tea. → Anticancer Flavonoids in Licorice → Antiviral Daidzin & Genistin in Soybeans → Anticancer Rutin in Citrus → Prevent capillary fragility Flavonoids in Buchu → Diuretic Tinctormine in Safflower → Treat angina “Ca antagonist” Astilbin in Smilax, → Anti-hepatotoxic 3 Silybin in Silybium marianum  Identification 1- Reaction with AlCl3 Yellow 2- Shinoda’s test: Alc. soln. + Mg metal/HCl Orange, red or violet color 3- Lead subacetate test: Alc. soln. + Pb subacetate Yellow ppt. 4- UV spectral absorption: UV spectra of flavonoids show 2 absorption maxima: Band I (due to cinnamoyl system of ring B + C4=O) Band I Band II Band II (due to benzoyl system of ring A, + C4=O) 220-280 nm 300-400 nm O Hydroxylation pattern B A - Hydrophilicity, acidity Phenolic OH 4 - UV & visible light absorption O 4 - Chemical reactivity  O Ring B O Ring B O Ring B 2 2 2 A A 3 A 3 3 4 OH O O Flavanone Flavanol Flavane O Ring B O Ring B O 2 A A A 3 OH Ring B O O O Flavone Flavonol Isoflavone + OH Ring B OH Ring B O Ring 2 B A A A 3 4 O O 5 Chalcone Dihydrochalcone Anthocyanin Flavone glycosides OH OMe 1-2 Apiose- Glc-O O Rh1-6Glc-O O OH rutinose OH O OH O Apigenin Diosmetin Apiin Diosmin Apiin Diosmin (or Barosmin) In leaves & seeds of * in Buchu leaves, Celery (Apium graveolens) Conium and Dahlia Parsley (Petroselinum sativum) * Acid H.OH → Diosmetin + Rh + Glc * Acid H.OH → Apigenin + Ap + Glc MOA : treatment of capillary fragility and increase the venous tone. Uses: (prophylactic in varicose veins & acute hemorrhoids) 6 7  OH Flavonol glycosides HO O OH Rutin OR (Quercetin-3-rutinoside) OH O Nicotiana tabacum, rutinose Sophora japonicum Quercetin (R=H) Rutin (R=-Glc6-1Rh) Quercitrin (R=Rh) Acylated deriv. (R=Rh4-Glc6-p-coumaroyl) Hydrolysis: (in Ginkgo biloba) Reflux Improves blood circulation Rutin + 1N H2SO4 Quercetin + Glc + Rh (in cerebrovascular insufficiency) MOA: Prevents capillary fragility, permeability and bleeding. (strengthen the capillaries) Antioxidant and anti-inflammatory. Uses : Varicose veins, hemorrhoids and internal bleeding. 8 9 Rutin Quercetin-3-O-rhamnoglucoside (Rutinose) File:Rutin structure.svg Rutinose Glc 6 → 1Rh 6 1 Ginkgo biloba Acylated flavonoid Coumaroyl 10 Flavanone glycosides General characters 1- have a reactive C=O + hydroxylamine → Oxime (c.f. flavone deriv.) 2- with strong alkali → benzaldehyde + acetic acid + phenol (c.f. Flavone deriv. + strong alkali → cinnamic acid + phenol) Alkali Alkali 3- Flavanone Chalcone Flavone H+ OMe Hesperidin Rutinose-O O (Hesperitin-7-rutinosde) OH -In the peel of unripe Citrus fruits (5-14% in Bitter orange, up to 8% in OH O dry peel), which gradually disappears Hesperitin on ripening. Hesperidin 11  OMe OMe OMe Rutinose-O OMe Rutinose-O O Rutinose-O OH OH OH OH alkali methylation OH O OH O acid OH O Hesperidin Hesperidin chalcone Stable methyl derivative MOA: - necessary for the absorption of vitamin C. - prevents capillary fragility in cerebro-and cardiovascular diseases & hypertension. Uses: - used for blood vessel conditions such as hemorrhoids, varicose veins, and poor circulation (venous stasis). 12  Bioflavonoids: Bioflavonoids collective name given to rutin, hesperidin and quercetin. Bioflavonoids are often used in vitamin C formulas because they enhance the absorption and action of this vitamin C. Bioflavonoids help maximize the benefits of vitamin C by inhibiting its breakdown in the body. vitamin C maintain collagen. Collagen helps keep our skin healthy, elastic, and firm. Collagen breakdown has been attributed to wrinkles and lines. 13 Naringin OH (naringenin-7-neohesperidoside) Neohesperidose-O O (Rh1-2Glc) - in the peel of Grapefruit, Citrus paradisi, (rich in immature fruits). OH O -The main bitter component of grapefruit juice - sol. in hot H2O Naringenin Naringin (very bitter) Uses: Bitter stomachic, anti-inflammatory OMe Neohesperidose O O OH OH NaOH H2/Pd OH O O O Naringin Naringin chalcone Naringin Intensely bitter dihydrochalcone very sweet > Sucrose (1000 times) 14 Liquiritin OR (liquiritigenin-4-glucoside) HO O in Licorice roots The main constituent of DGL (Deglycyrrhizinated Licorice extract) O Uses: in the treatment of gastric & duodenal Liquiritin R= Glc ulcer, & anti-inflammatory. Liquiritigenin R= H OH Flavanol glycosides HO O Astilbin 2 OH Neoastilbin 3 O-Rh in the roots of Astilbe sp., Smilax glabra OH O -Astilbin is not sweet, (Neoastilbin is sweet) Astilbin (2R,3R) -Astilbin + acid → taxifolin + Rh Neoastilbin (2S,3S) -Neoastilbin + acid → neotaxifolin + Rh Action and Uses: 15 Antioxidant, hepatoprotective, prevent cataract formation in diabetic patients. Isoflavonoid glycosides - Dietary phytoestrogens - Cancer-protective compounds (effective in preventing breast and prostate cancer) - Aid in the treatment of osteoporosis Daidzin and Genistin Daidzin in soya beans meals, Glycine max, Medicago sativa Genistin in Genista, lupinus, Prunus Glc-O O HO O Intestinal bacteria R O R O OH (−glucosidase) OH - Glucose Daidzin (R=H) Daidzein (R=H) Genistin (R=OH) Genistein (R=OH) 16 Anthocyanidins and their glycosides - Name: from the Greek antho (flower) and kyanos (blue) - Anthocyanidins are hydroxylated cations, their glycosides are anthocyanins - Colored compounds, pH dependent, blue “alkaline” Red “acidic” - Color is due to the same anthocyanin, cyanidin 3, 5-diglucoside. - Sugar part is usually attached to C-3, (rarely to C-5). monosacch. (Glc, Gal, Rh), disacch (Rh-Glc) or trisacch. -Sol. in water, acidic soln., MeOH -insol in ether, acetone & CHCl3 **Precipitated from aq. / or alc. solns. R as blue Pb salts + (sol. in glacial acetic acid) HO O OH 3 5 OH R` OH R R' Pelargonidin H H Pelargonium Cyanidin OH H Cornflower, Rose sp. Delphenidin OH OH Delphenium, Viola sp. 17 Flavan-3-ols - Catechin, epicatechin, epigallocatechin - Proanthocyanidins (polyflavanoids, of catechin or epicatechin units) Catechin & Epicatechin - in Green tea, leaves of Camellia sinensis OH (Epigallocatechin & its gallate deriv.) - in Rhubarb tannins HO O (Epicatechin and its gallate, and its polymers) OH - in Hawthorn (Crataegus sp.) - in Black tea (Theaflavins) OH OH Pharmacological action and uses: - Antioxidant. axial (+)-Catechin (-OH) - lipid-oxidation (Fat burning → slimming ) equatorial (-)-Epicatechin (-OH) - Anticancer, Antiviral & Antibacterial. - Rhubarb ext. is effective against renal failure. “Epicatechin and its 3-O-gallate derivative were found to contribute mainly to its antiuremic action” 18 - Procyanidins in Crataegus are effective in the treatment of heart diseases.  Green Tea Epigallocatechin 3-O gallate Black Tea Proanthocyanidins (condensed tannin) 19 Proanthocyanidins (condensed tannin) Condensation products (dimeric, trimeric or tetrameric) of flavan-3-ol & flavan-3, 4-diols /or flavan skeleton - on heating with HCl → anthocyanidins - They may possess anti-HIV activity Biflavones Amentoflavone HO O in Amentotaxus OH OH Bark of Chrozophora sp. O Pharmacological action and uses: OH O HO Cardiotonic Prevents cataract formation in diabetic patients OH O 20 Flavonoid-containing compounds Flavanolignans Silymarin (a mixture of various flavanonol or flavanol derivatives) - The principal components are: 1-Silybin 2-Silychristin 3-Silydianin - in the fruits of Silybum marianum O CH2OH O HO O OH O HO O Oxeran ring OCH3 OH OH CH2OH OCH3 OH OH O OH O Taxifolin Coniferyl alcohol Silychristin Silybin Uses: -Hepatoprotective -Prophylactic from liver damage caused by metabolic toxins. -in liver dysfunction and after hepatitis treatment. -in chronic degenerative liver condition (liver cirrhosis, fatty liver) 21 *Silymarin, or its major constituent, silybin has a very poor bioavailability i.e. When taken orally, the majority of silymarin is not absorbed from the digestive tract. *This problem has been solved by 1- Complex formation of silybin with a soy phospholipid known as phosphatidyl-choline →Silymarin Phytosome® 2- Complex formation of silybin with cyclodextrin 3- Glycoside formation *This complex has lipophilic properties, and pharmacokinetic studies have demonstrated substantially improved bioavailability (up to 10 times), *probably due to improved absorption across the gastrointestinal mucosa. CH2OH O HO O O Oxeran ring OH OH OH O OCH3 Taxifolin Coniferyl alcohol 22 Silybin  F- Coumarins - Derivatives of benzo--pyrone, or lactones of o-hydroxycinnamic acid - Free & in glycosidic “classified as phenolics just for convenience” - Some are toxic “Aflatoxins”, but other are imp. as anticoagulant & antibiotic - Have fragrant odor & bitter aromatic, burning taste, sol. in alc Coumarin aglycones Coumarin glycosides Coumarin (benzo--pyrone) Aesculin - in Dipteryx odorata, D. oppositifolia, in Aesculus & Fraxinus sp. Melilotus albus (sweet clover), M. officinalis & Trifolium pratense (red clover) GlcO HO O O O O Coumarin Aesculin *H.OH (acid/or enz): → asculetin +Glc Uses: Uses: -Flavoring agent in tobacco, Treatment of varicose veins and butter and perfumery industries 23 hemorrhoids. -Insecticide Coumarin derivatives of pharmaceutical importance (4-Hydroxycoumarins) -Anticoagulants Bishydroxycoumarin (Dicoumarol) phytoalexin → from Melilotus officinalis (infected leaves) -Coumarin antibiotics Novobiocin & coumermycin OH → from Streptomyces sp. OH H2 C 4 4 O O O O Dicoumarol - Anticoagulant (Bishydroxycoumarin) Poisonous coumarins (Aflatoxins) Toxins produced by fungi & are Hepatotoxic or carcinogenic OCH 3 OCH 3 O O O O O O O O O O 3 AFB1 O 3 AFG1 24 2 2 Non-glycosidic organo-sulfur drugs Alliin (1.2% in fresh garlic) : (+)-S-allyl-L-cysteine sulfoxide H.OH (alliinase enzyme) after crushing → Allicin (diallyl thiosulfinate) Allicin in air + H2O → dially disulfide, trisulfide & poly… (strong smell) O O S COOH S Uses: Alliinase + H2O H S NH2 Antibacterial Alliin Allicin Anti-hyperlipidemic (odorless) (odor & flavor of Garlic) Cyanogenic Glycosides (Cyanogenetic or Cyanophore glycosides) - plants containing these compounds are used as flavoring agents - considered as O-glycosides on H.OH → HCN gas - for plants, “chemical defense” against organisms damaging or feeding on plant tissues and lead to release of HCN gas, which is toxic 25 Amygdalin in: bitter almond seeds (Prunus amygdalus), kernels of apricots (Prunus armeniaca), peaches, plumes - H.OH by emulsin (mix of 3 enzymes) → benzaldehyde + HCN NC NC CH CH O O Amygdalin + Glucose Glc-(1 - 6)-Glc hydrolyase Glc (Gentiobiose) Amygdalin Prunasin Prunasin CHO NC hydrolyase CH Mandelonitrile lyase HO + Glucose HCN + Benzaldehyde (R)-Mandelonitrile Volatile oil of bitter almond 26  Glucosinolates (Thioglycosides or Isothiocyanate glycosides) S-glycosides - anions having Glc. & sulfate (S atom conjugated to Glc, & S in sulf.oxime gp) - in mustard family (Cruciferae) & Liliaceae. - rich sources: oilseeds (rapeseed), condiments (mustard and horseradish) & vegetables (broccoli, cabbage). **Black mustard is a local irritant & emetic, *Externally, rubefacient, *Commercially, condiment Pharmacological action & Uses (same as white mustard) -Anticarcinogenic Sinigrin in seeds Brassica nigra (black mustard) Sinalbin in seeds of Brassica alba (White mustard) -myrosinase enz. → p-hydroxybenzyl isothiocyanate + 27 sinapine acid SO4 + Glc