Pharmacognosy and Phytochemistry (Coumarins/Chromones) - PDF

Pharmacognosy and Phytochemistry Shikimic acid pathway (Coumarins/furanocoumarins/chromones) By Dr. Farah Al-Mamoori  Shikimic Acid Pathway H O O...

Pharmacognosy and Phytochemistry Shikimic acid pathway (Coumarins/furanocoumarins/chromones) By Dr. Farah Al-Mamoori  Shikimic Acid Pathway H O O OH OH OH Shikimic acid is isolated from plants of Illicium species (Japanese ‘shikimi’, Japanese star anise).  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 micro- organisms Oseltamivir phosphate ( Tamiflu) Star anise‫اليانسون النجمي‬ (Illicium verum) Shikimic acid is currently the raw material for synthesis of the antiviral drug oseltamivir (Tamiflu), in demand as a defence against avian influenza (bird flu)  Oseltamivir phosphate (Tamiflu) is an orally active neuraminidase inhibitor developed for the treatment and prophylaxis of influenza viruses A and B  The starting material for the oseltamivir synthesis is (−)-shikimic acid  an important biochemical intermediate in plants and microorganisms.  Previously, shikimic acid was extracted solely from the fruits of the shikimi tree (Illicium verum Hook.f.), also known as star anise, which contains a large amount of this compound. Later on, shikimic acid was obtained from the fermentation of genetically engineered Escherichia coli strains, which are deficient in the shikimate kinase gene.  Currently, Roche, the drug manufacturer still relies on both extraction and fermentation methods to obtain ton quantities of shikimic acid Coumarins  4 4 5 3 5 3 1 O 2 2 6 1 6 O O *Hepatotoxic O 5,6-Benzopyran-1-one 5,6-Benzopyran-2-one isocoumarin coumarin Name derived from Coumarouna (local Guyana name) for the seeds of Dipteryx odorata ‫( حبوب التونكا‬Fabaceae), common named for Tonka bean.Sweet odor, used in perfumes and fabric conditioners Characters of Coumarins Free coumarins are organic solvents-soluble Derivatives of α-chromone, differ in benzene ring substitutions (OH, OCH3, CH3) Common in Apiaceae, Fabaceae & Rutaceaea Umbelliferone R1=H, R2=OH Aesculetin R1=R2= OH Scopoletin R1=OCH2, R2= OH R1 6 R2 7 O O  Scheme of the conversion of shikimic acid to cinnamic acid Shikimic acid → Chorismic acid → Prephenic acid → p-OH-phenylpyruvate ↓ ↓ ↓ Anthranilic acid Phenylpyruvate Tyrosine→alkaloids ↓ ↓ ↓ Tryptophan Phenylalanine p-coumaric acid ↙ ↓ ↓ ↘ ↙ Cinnamic acid ↘ p hytohormones (indol-3- ace tic acid Alkaloids alkaloids Coumarins Aesculus hippocastanum (horse- chestnut)‫كستناء الحصان‬ (Hippocastanaceae)  Leaves / bark seeds rich in aesculin  Symptomatic Rx of cutaneous capillary fragility  Coumarins exhibit anti-inflammatory effect(reduce swelling) Aesculin, is a coumarin glucoside that naturally occurs in the trees horse chestnut aesculin Examples from pharmaceutical market *Aescin is a mixture of saponins with anti- inflammatory, vasoconstrictor and vasoprotective effects found in Aesculus hippocastanum (the horse chestnut) Aescin  Cinnamon Cassia cinnamon contains high amounts of coumarin, which can cause liver toxicity and damage if consumed in high amounts 4 5 3 2 1 6 O O 5,6-Benzopyran-2-one coumarin 2-4 grams of powder a day. Some studies have used between 1 gram and 6 grams of cinnamon. Warfari & coumarins Warfarin was the first anticoagulant rodenticide, but today its use is declining as many rodents have grown resistant to it.  Bleeding  Dicoumarol is present in sweet clover (Melilotus officinalis).‫البريسم الحلو‬  This agent interferes with the effects of vitamin K in blood coagulation, the blood loses its ability to clot, and thus minor injuries can lead to severe internal Sweet Clover bleeding. Aflatoxins Aflatoxins are a group of mycotoxins produced by the fungus Aspergillus and are potent hepatotoxins and carcinogens in the liver. Structurally all aflatoxins contain a coumarin ring and an unsaturated lactone moiety.  Furanocoumarins (Photosensitizers)  Commonly known as psoralens  Plants containing psoralens have been used internally and externally to promote skin pigmentation and suntanning.  The psoralen, because of its extended chromophore, absorbs in the near UV and allows this radiation to stimulate formation of melanin pigments. 6 O 7 O O Furnaocoumarin  Furan ring is derived from isopentyl pyrophosphate (mevalonic acid pathway)  Psoralens Found in plants (Psoralea corylifolia and Ammi majus) Psoralea corylifolia Ammi majus ‫الخلة الشيطانية‬ Medicinal value: Photo chemotherapy: Rx of vitiligo and psoriasis as part of PUVA for repigmentation of skin. PUVA = Psoralen or derivatives (p.o + topical) + UVA (320nm).  Reaction with psoralens inhibits DNA replication and reduces the rate of cell division.  Also, methoxsalen (xanthotoxin; 8-methoxypsoralen) is a constituent of the fruits of Ammi majus.  It is used medically to facilitate skin repigmentation where severe blemishes exist (vitiligo).  Grapefruits (Citrus paradisi) The major furanocoumarins found in grapefruits (Citrus paradisi) include bergamottin, and 6',7'-dihydroxybergamottin  Grapefruit juice is a potent inhibitor of CYP3A4-mediated drug metabolism Organic compounds that are derivatives of furanocoumarin interfere with liver and intestinal enzyme CYP3A4 and are believed to be primarily responsible for the effects of grapefruit on the enzyme. Cytochrome isoforms affected by grapefruit components also include CYP1A2, CYP2C9, and CYP2D6 Furanochromones Ammi visnaga ‫الخلة البلدية‬  The dried ripe fruits of Ammi visnaga have a long history of use in the Middle East as an antispasmodic and for the treatment of angina pectoris.  It contain high amounts of furochromones (khellin, visnagin, khellol, and khellol glucoside).  Khellin is coronary vasodilators and spasmolytic agents.  Khellin has been used in the treatment of angina pectoris and bronchial asthma.  A mixture made of khellin, piperazine and hexamine is used as antibacterial drug for urinary tract infections.  In the early 20th century, researchers searched for khellin analogs with lower toxicity and better efficacy. A number of drugs were discovered through this research, such as amiodarone and cromolyn sodium, which are used in current medical practice.