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Transcript
Phytochemistry 2nd Semester – 2016/2017 Dr. Jehad Almaliti 1 Part (1) Introduction to phytochemistry 2 Introduction - Natural products, especially those derived from plants, have been used for medicinal purposes since ancient times - Clay tablets of the Babylonian, Assyrian, and Sumerian eras dated 2600 - 4000 BC are thought to be the earliest recordings of plant usage as herbal remedies - Egyptians also had many paintings of medicinal plants on their tomb walls dated around 2200 – 2700 BC. The Ebers papyrus, which dates from around 1550 BC, is the most famous medical document of ancient Egypt and contains more than 800 medicinal recipes using medicinal plants - This centuries-old usage of natural products certainly continues into the present, as half of prescription drugs in the market today contain plant-derived ingredients 3 Some important natural products 1785:William Withering used foxglove extract to treat heart patients, and he published this application. Digoxin was discovered due to this treatment; Glaxo Smith Kline markets this drug as Lanoxin, and it is used to treat arrhythmia and congestive heart failure 1803: Sertϋrner isolated morphine from opium. 1817: Isolation of strychnine from strychnine tree (Strychnos nux-vomica). 1820: Isolation of caffeine (from Coffee beans) and quinine from Cinchona (C. officinalis) bark. 1828: Isolation of nicotine from tobacco (Nicotiana tabacum) leaves. 1833: Isolation of atropine from Atropa belladonna leaves and roots. 1855: Isolation of cocaine from coca (Erythroxylum coca) leaves. 1868: Isolation of digitaline from foxglove (Digitalis purpurea) leaves. 1897: Arthur Eichengrün and Felix Hoffmann at Bayer Company created aspirin. Aspirin was the first semi-synthetic drug synthesized from a natural product, salicylic acid, extracted from the willow (Salix spp.) bark. 1928: Alexander Fleming discovered Penicillin from penicillium mold, and this discovery changed modern medicine and the treatment and understanding of infectious disease. 4 Importance of Natural Products in Drug Discovery 5 Phytochemistry The study of chemicals involved in the activity of medicinal plants which are usually secondary metabolites. Many are known to provide protection against biological attacks and plant diseases. They also exhibit a number of protective functions for human consumers. Techniques commonly used in the field of phytochemistry include extraction, isolation, structural determination using different spectroscopic methods (MS, UV, IR, 1D & 2D NMR) as well as various chromatography techniques (HPLC, LC-MS) 6 • • • • How drugs of natural origin can be used? Industrial feasibility? Isolated and purified natural products: Cardiac glycosides, morphine, antibiotics,… Derivatives of natural products : Steroids (sex hormones, contraceptives, corticosteroids,…) Total chemical synthesis of natural products: Tubocurarine, caffeine,…. Partial synthesized / modified natural products Different anticancer drugs (vinblastine, taxol,…) 7 Production of drugs based on natural products • Ethnopharmacology/ethnobotany/traditional medicine • Isolation from natural resources (cost, limited access to raw materials) • Total synthesis (complex structures) • Combination enzymatic and chemical synthesis (advances in molecular biology) • Transgenic plants (genetic engineering) • Cell and tissue culture (expensive and tedious) 8 Some reasons for the interest in natural compounds in the 20th /21st century • Search for chemicals from natural sources as curative agents, especially for chronic diseases (diabetes, hyperlipidemia, hypertension) or for diseases the synthetic chemistry was not successful (cancer) • Increased interest in the chemical compounds from the viewpoint of pure science • Worldwide interest in the different traditional medicines (“back to the nature”-trends) • Interest in the use of chemical constituents as an aid in plant taxonomy (chemotaxonomy) 9 Classification of natural products Based on: • Chemistry (Chemical structures): e.g. carbohydrates, steroids, alkaloids,… • Physiological effect(s)/Pharmacological activity: e.g. vitamins, antibiotics, anticoagulant, hypotensive,… • Taxonomic: e.g. family , genus, species,… • Morphological: part used e.g. flower, leaves, roots,… • Biosynthetic Pathway: e.g. shikimic acid derivatives, mevalonic acid derivatives, acetate-malonate derived 10 Primary and Secondary Metabolites • Primary metabolites: Compounds produced during the fundamental pathways; essential for the plant life (H2O, CO2 → Photosynthesis): carbohydrates, fats, proteins, nucleic acids →primary activity of green plants • Are essentially the same in all organisms, apart from minor variations. – Kingdom Plantae – Kingdom Animalia – Kingdom Fungi – Kingdom Bacteria • These processes demonstrate the fundamental unity of all living matter, and are collectively described as primary metabolism, with the compounds involved in the pathways being termed primary metabolites 11 Secondary Metabolites • Are assembled from (pieces of) primary metabolites • May be more prevalent or unique to certain genus, species, and similar compounds occur within genuses and families • Not necessarily involved in the essential metabolism of the cell, but exert physiologic activity for the plant, its environment and human (phyto-hormones, plant-protection, plant-insect-, plant-animal interactions, source of drugs); • May have useful nutritional benefits to humans/other organisms • The genes and enzymes guiding biosynthesis vary from one organism to the next (condition and species sensitive) • Most pharmacologically active natural products are 2ry metabolites The biosynthesis of the secondary metabolites • Acetate-malonate pathway • Acetate-mevalonate pathway (mevalonic acid pathway) • Shikimic acid pathway • “Amino acid “pathway 13 14 Acetate-derived Natural Products Acetate formed from carbohydrate via pyruvic acid Produce large no. of imp. natural products (flavonoids, anthraquinones, macrolides, terpenes & steroids) 2 main routes originate with acetate pathway: 1.Acylpolymalonate pathway leading to FA & polyketides 2.Mevalonic acid pathway producing terpenes & steroids 15 Acetate malonate pathway A-Non-aroamtic derivatives (polyacetylenes, polyynes) B-Aromatic polyacetates (polyketides) B1-Monocyclic compounds: -Cannabinoids -Phenylchromane derivatives (Flavonoids) B2-Polycyclic compounds: -Anthracenes -Chromones -Antibiotics from acetate metabolism 16 Acetate mevalonate pathway (Mevalonic acid p.w.) • Isoprenoid compounds • Terpenes (mono-, sesqui-, di-, tri-, tetra-, polyterpenes( • Cardiac glycosides • Saponin glycosides • Steroids • Vitamin D 17 Shikimic acid pathway • • • • • • • Aromatic biosynthesis: Phenols Phenolic glycosides Phenyl-propane-derivatives Lignins/Lignans Aromatic amino acids Tannins 18 “Amino acid” pathway Includes all biogenetic drugs containing “N”.: -Alkaloids -Cyanogenic glycosides -Glucosinolates -Alliines -Antibiotics from amino acid metabolism -Anticancer drugs from amino acid metabolism 19 General Biosynthesis Pathway CO2 + H2O + Light PO4 Photosynthesis Carbohydrates Glycolysis Nucleic acids Tannins Shikimic acid Phenyl propanes Chorismic acid Aromatic Amino acids Pyruvic acid N2 Via citric acid cycle Amino acids Acetic acid Proteins Peptides Alkaloids Fatty acids & Polyketides Mevalonic acid Terpenes Steroids Purines 20 Construction Mechanisms Despite living organisms variations, pathways for synthesis & modification of 1ry metabolites essentially same (minor variations) Carbohydrates glycolysis Energy [O*] Fats FA’ [O*] Energy Proteins AA’ Energy The number of building blocks are few Structural diversity from mix. of building units H ry Most imp. building blocks in biosynthesis of 2 met. O Derived from following intermediates SCoA O 1 HO2C 6 HO 5 OH OH OH Shikimic Acid Mevalonic acid (MVA) 21 2 Acetyl Enzyme CoA OH O 3 4 Most important building blocks SCoA O 1 HO2C 2 Acetyl Enzyme CoA SCoA O 6 H OH 3 4 O 5 OH Mevalonic acid (MVA) SCoA O HO OH OH Shikimic Acid O CO2H Malonyl-CoA Maonyl-CoA Acetyl-CoA CO2H CO2H NH2 HO 1 HO2C 6 2 OH 3 4 Tyrosine Phenylalanine 5 C6C2 5 OH Mevalonic acid (MVA) 1 2 NH2 4 3 Isoprene Unit C6C1 C6C3 22 Most frequent Building Units 8 blocks are basic, many are natural chemicals 1) C1 unit: CH3 Simplest Derived from S-methyl of L-methionine ( e.g. OCH2O (methylene dioxy gp.) 2) C2 unit: usually part of long alkyl chain e.g. fatty acid OR part of aromatic system SCoA O SCoA ) O CO2H Acetyl-CoA Maonyl-CoA 23 Most frequent Building Units cont. 3) C5 Unit: e.g. Isoprene unit formed from MA 1 HO2C 6 2 OH 3 5 5 OH 4 1 Mevalonic acid (MVA) 4 2 3 Isoprene Unit 4) C6C3 Unit: refers to phenylpropyl gp Derived from shikimate-derived AA` L-phenylalanine OR L-tyrosine. (sat. or unsat. C3 Side chain) CO2H CO2H NH2 HO Tyrosine NH2 Phenylalanine C6C2 C6C1 C6C3 24 Most frequent Building Units cont. 5) C6C2N Unit: derived from L-phenylalanine OR L-tyrosine (common) through decarboxylation 6) Indole-C2N Unit: derived from L-tryptophan CO2H NH2 N L-Tryptophan -CO2H NH2 N Indole-C2N 7) C4N Unit: Usually as heterocyclic pyrollidine CO2H H2N NH2 L-Ornithine -CO2H H2N -NH2 C4N N Pyrolidine 8) C5N Unit: Usually found as piperidine ring H2N CO2H L-Lysine NH2 -CO2H -NH2 H2N C5N N Piperidine ring 25 Building Natural Products from the Blocks 26