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Shikimic Acid Pathway H O O OH OH OH Shikimic Acid Illicium anisatum L. Illicinaceae {Shikimino-ki in Japanese} (1885) E. coli mutant strains pathway intermediate Shikimic Acid Pathway • Important for aromatic compounds • Precursor of aromatic amino acids (Phe, Tyr, Try) biosynthesis in bacteria, fungi & higher plants. ANIMALS! HUMAN! • Building block for other compounds: certain alkaloids, coumarins, phenyl propanes, vol. oils,.. • Starting point for tannins in all plants • Provide protection of plants against microorganisms Biosynthesis of shikimic acid Scheme of the conversion of shikimic acid to cinnamic acid Shikimic acid → Chorismic acid → Prephenic acid → p-OH-phenylpyruvate ↓ ↓ Anthranilic acid ↓ Tryptophan ↙ ↓ ↙ p hytohormones (indol-3- ↓ Phenylpyruvate ↓ Phenylalanine Tyrosine→alkaloids ↓ p-coumaric acid ↓ ↘ Cinnamic acid ↘ ace tic acid Alkaloids alkaloids Possibilities of derivatives of cinnamic acid • 1-Substitution in aromatic ring • 2-State of the oxidation of the side chain • -CH=CH-COOH →Propenic acid, cinnamic acids • • • • • -CH=CH-CH2OH → Propenol, coniferylalcohols CH2-CH=CH2 →Allyl, Eugenol (volatile oil) -CH=CH-CH3 → Propenyl, Anethol (volatile oil) -CH2-CH2-CH3 →n-propyl 3- Shortening of the side chain Formation of phenol carboxylic acids and simple phenols Cinnamic acids Cinnamic acid p-coumaric acid Caffeic acid Ferulic acid Sinapic acid 5-OH-ferulic acid Tri-OH-cinnamic acid Formation of Phenylpropane Derivatives with Shorter Side Chain: Shortening of side chain by β-oxidation and subsequent decarboxylation (simple phenols) which might be linked to oxidation→hydroquinone → quinone COOH O O H OH O OH p-Coumaric acid OH p-Hydroxybenzoic acid OH Hydroquinone O Quinone Benzoic acids related to cinnamic acids Cinnamic acid ………………...Benzoic acid p-coumaric acid……………….p-OH-benzoic acid Caffeic acid………………........Protocatechuic acid Ferulic acid………………………Vanillic acid Sinapic acid……………………..Syringic acid Tri-OH-cinnamic acid……….Gallic acid Derivatives of dehydroshikimic acid Vanilla planifolia (Orchidaceae) • • Vanillin produced from eugenol (in plants) or lignin is a degradation by-product of paper from wood (large scale preparation of vanillin) H O H O Fermentation under blankets in the sun fermentation OCH3 OCH3 O-Glucose Eugenol Coniferylalcohol (lignin) Vanilloside Vanilloside (odourless ) is liberated during fermentation & oxidized to vanillin CH2OH fermentation OCH3 O-Glucose Vanilloloside • CH2OH H O fermentation OCH3 OH Vanillyl alchohol OCH3 OH Vanillin Fine aroma and taste is due to other compounds better than pure vanillin OH Vanillin 5 6 4 3 2 1 O O 5,6-Benzopyran-1-one isocoumarin 5 Coumarins 4 1 6 O 3 2 O 5,6-Benzopyran-2-one coumarin Name derived from Coumarouna (local Guyana name) for the seeds of Dipteryx odorata (Fabaceae) common name for Tonka bean Seeds as spirits spice (not used now, hepatotoxic & carcinogenic) Characteristic new mown hay smell Commonly used as sun UV protector Absorb short wave UV 230-315 nm & transmit longwave UV 315 - 400 nm resulting in brown sun tan Characters of Coumarins • Free coumarins are organic solvents-soluble • Derivatives of α-chromone, differ in benzene ring substitutions (OH, OCH3, CH3) • Common in Apiaceae, Asteraceae, Fabaceae, Lamiaceae, Poaceae, Moraceae, Rutaceaea & Solanaceae • • • • • Characteristic UV (blue, yellow & purple) enhanced by ammonia Umbelliferone R1=OH, R2=H R1 6 Aseculetin R1=R2= OH R2 7 O O Scopoletin R1=OCH2, R2= OH Aseculus hippocastanum (horse-chestnut) (Hippocastanaceae) rich in aesculin (6β-D-glucosyloxyl-7-OH-coumarin ); used in sun tan preparations (both glycoside & aglycone) • Symptomatic Rx of cutaneous capillary fragility Biosynthesis of the coumarins OH OH Dicoumarol O O O O • Melilotus officinalis (Fabaceae) mould-infected sweet clover • Discovered by studying grazing cattle coagulation pattern (sweet clover disease) • Dicoumarol replaces vitamin K in prothrombin result in anticoagulant effect • Prevention of thrombosis • Pharmaceutical industry: synthetic derivatives for p.o preparations • Extract: p.o & topically to Rx minor vascular disorders & acute attacks of piles Furanocoumarins (Photosensitizers) 6 O 7 O O Furnaocoumarin Furan ring is derived from isopentyl pyrophosphate (mevalonic acid pathway) 6,7 or 7,8 furanocoumarins Furanocoumarins-rich plant families: Apiaceae, Fabaceae, Moraceae & Rutaceae Roots, fruits or seeds Furanocoumarin Natural Derivatives R1 • Psoralea corylifolia (Fabaceae) fruits 4' 5' 6 5 7 O 4 1 8 O 3 2 O R2 Ammi majus (Apiaceae) fruits الخلّة الشيطاني Ammi visnaga !!! Cause dermatitis after consumption or direct contact of skin with such plants followed by exposure to sun (only 6,7furanocoumarins; 7,8-furanocoumarin derivatives are inactive) Medicinal value: 1) Photo chemotherapy: Rx of vitiligo as part of PUVA for repigmentation of skin 2) UVA= 320nm + p.o+ topical psoralen or derivatives Psoriasis: abnormal epidermal production of scaly skin • • • Example of Medicinally-valuable Furanocoumarins R1 4 • Commonly known as Psoralens 5 4' 6 3 • Psoralen R1=R2= H 5' 7 2 1 O O O • Bergapten R1= OCH3, R2=H [5-MOP] 8 R2 • *Xanthotoxin R1= H , R2= OCH3 * Xanthotoxin= Methoxsalen = 8-MOP nat. or semisynthetic derivative of psoralen p.o medication • Imperatorin R1=H , R2 = CH2-CH=C(CH3)2 • Trioxalon = TMP 4,5,8-trimethylpsoralen (synthetic) topical or bath sol. Then exposure to UVA @ 320-380 nm MOP of PUVA & Toxicity 1. Interfere with DNA by forming bridges between its base pairs (pyrimidine part) 2. Double bonds of furanocoumarin are activated by UV radiation 3. Inhibits replication & transcription of DNA & synthesis of RNA & cell division 4. Rx of psoriasis is based on the basis of DNA synthesis, inhibitory effect by furanocoumarins Photosensitization Mechanism: Binding of activated 3,4double bond in furanocoumarin with 5,6-double bond of pyrimidine base pair in DNA Binding of 4’,5’-double bond of psoralen molc. with a second molecule of pyrimidine base of another base pair Sug ar Adenine N N N N Sugar P H N Cytosine P O N H O N O N Sugar Thymine P CH3 N 4` 5` O 4 6 7 O OCH3 Xanthotoxin 3 O Lignin & Lignans • Lignin is plant polymer acting as strengthening material for plant cell wall & matrix for cellulose micro-fibrils • Represent a large no. of aromatic material based on C6C3 building unit • Lignins formed by oxidative coupling of hyroxycinnamyl alcohol monomers by peroxidase enzymes [p-coumaryl-, coniferyl- and sinapyl-alcohol] • Lignans are dimeric phenylpropanes (C-18) coupled at the central carbon of the side chain [via their ßcarbon of the side chain] 20 Formation of the lignans • Dimers of cinnamic acid linked via their ß-carbons and further modifications; i.e. Podophyllotoxin ↓ ↓ Podophyllotoxin: 2 C6C3 [Coniferylalcohol] via several intermediates • Dried root & rhizhome of Podophyllum peltatum [May apple, mandrake] (Berberidaceae) USA & Canada • Structure elucidated in 1930’s; planar structure with 4 chiral centers • C2H5OH extract = Podophyllin (20% podophyllotoxin, 10% βpeltatin, 5% α-peltatin) • Traditionally as cathartic, purgative, antiviral, warts remedy • Trans lactone ring is essential for anti-tumor action; aromatization of ring C↓activity. Too toxic to be used clinically! • [OH-] converts into inactive isomer (e.g.epi-podophyllatoxin) • Classified as microtubule inhibitor [inhibits polymerization of tubulin and stop cell division at the beginning of metaphase] 22 Etoposide and teniposide • As semisynthetic anticancer agents developed from 4’demethylepipodophyllotoxin • They act as Topo II inhibitors (prevention of DNA synthesis and replication) • Etoposide : small cell lung cancer, breast cancer, leukemia & Hodgkin’s disease,… Teniposide : brain and bladder cancer,… • Glycosides < active than genins < side effects Podophyllotoxin & Peltatins • Lignans formed by oxidative coupling of 2 cinnamic acid residues (dimeric phenylpropane derivatives) known as LIGNANS R3 H R2 O O O H H3CO O Podophyllotoxin Alpha-Pelatin Beta- Pelatin R1=CH3 R2= OH R1= H R2= H R1= CH3 R2= H R3= H R3= OH R3= OH OCH3 OR1 24 Tannins & Gallic acid • Gallic acid is the building block of many tannins COOH COOH COOH Tannins HO OH OH Shikimic acid O OH OH 3-Dehydroshikimic Acid HO OH OH Gallic acid Properties of Tannins: • H2O solubility !! (colloidal aq. Solution in A` PH) • Binds proteins to form indigestible complex (leather tanning) • Amorphous • Astringent taste (unripe fruits, in all organs or organ-specific) • Fe+2 salts binding producing dark blue or greenish black sol. Complexes (ink) • Ppt with metals e.g. Cu, Pb (acetate salts to separate tannins from extracts); ppt gelatin and alkaloids; • Large MW (1000-5000) • Pseudotannins (MW~500) Hydrolysable tannins • Possibilities of condensation of the gallic acid OH OH HO HO OH O COOH O COOH HO OH OH HO COOH HO HO COO HO OH O Hexahydroxydiphenic acid OH HO O 3-galloyl-gallic acid Ellagic Acid Classification of Tannins Hydrolysable Condensed H+ or enzymes Rx produce • H+ or Enzymes Rx simple molecules produce complex insoluble compounds A) Ellagitannins • Complex polymers • Biosynthesis from acetate or shikimate pathway B) Gallotannins • Building units are catechins + flavonoids estrefied with gallic acid OH O Ellagitanins O OH H+ Enzymes + HO O O HO O OH CO2H H+ Enzymes + Sugar HO OH OH Gallic Acid OH Sugar OH Ellagic Acid Gallotannins OH OH Catechin Medicinal Value of Tannins Limited Application: Based on ability to bind proteins to form indigestible complex 1. Diarrhea 2. Bleeding gums 3. Skin injuries preparations Plant Material H2O/Alc Ether Tannins (sugar + gallates) + Free Gallic A` Hamamelis • Dried leaves of Hamamelis virginiana L. COOH (Hamamelidaceae) • North America & Canada HO OH • Gallotanins OH Uses: Gallic acid 1. Infussions & extracts in haemorrhoids (topical pharmaceuticals) R'O 2. Topically skin inflammation H O R= GALLIC ACID OR H 3. Face lotions as astringent OR H OH R' = TRIGALLIC ACID H OH Galls • • Vegetable growths as a result of insect infections of the leaves & twigs of Quercus infetoria (Fagaceae) 70-80% tannins from Turkey, Syria, Greece & Iran COOH O O O Uses: O OH HO HO 1. Rx of catarrh & infection OH HO TRIGALLIC ACID OH 2. Stop bleeding locally 3. Alkaloid poisoning remedy (insoluble comlex) 4. Ink preparation R'O O H 5. Textiles dyeing esp. leather R= GALLIC ACID OR HO OH OR H H H OH R' = TRIGALLIC ACID