Alkaloids: PDF

ALKALOIDS LSB Lecture 4  Introduction “alkaloid” (alkali-like) - commonly used to designate basic heterocyclic nitrogenous compounds of plant origin that are physiologically active A precise definition of the term 'alkaloid' (alkali-like) is somewhat difficul...

ALKALOIDS LSB Lecture 4  Introduction “alkaloid” (alkali-like) - commonly used to designate basic heterocyclic nitrogenous compounds of plant origin that are physiologically active A precise definition of the term 'alkaloid' (alkali-like) is somewhat difficult because there is no clear-cut boundary between alkaloids and naturally occurring complex amines In addition to carbon and nitrogen, alkaloids may contain oxygen, sulphur, chlorine, bromine, and rarely phosphorus  Introduction – Deviations from Definition Basicity: Some alkaloids are not basic e.g. Colchicine, Piperine, Quaternary alkaloids. Nitrogen: The nitrogen in some alkaloids is not in a heterocyclic ring e.g. Ephedrine, Colchicine, Mescaline. Plant Origin: Some alkaloids are derived from Bacteria, Fungi, Insects, Frogs, Animals Better definition?? Alkaloids are cyclic organic compounds containing nitrogen in a negative state of oxidation with limited distribution among living organisms.  Introduction Typical alkaloids are derived from plant sources, they are basic, they contain one or more nitrogen atoms (usually in a heterocyclic ring) and they usually have a marked physiological action on man or other animals. Morphine Cinchonine Vincristine  Introduction The name 'proto-alkaloid' or 'amino-alkaloid' is sometimes applied to compounds such as hordenine, ephedrine and colchicine which lack one or more of the properties of typical alkaloids. They lack nitrogen in a heterocycle ring. Ephedrine Hordenine Colchicine  Introduction Pseudo alkaloids that are not derived from amino acids but have nitrogen in a heterocyclic ring. e.g Caffeine False alkaloids are non alkaloids give false positive reaction with alkaloidal reagents. Example?? Caffeine  Brief History The term alkaloid was coined by Meissner, A German Pharmacist, in 1819. Alkaloids have been used for various purposes like poisons, medicines, poultices, teas etc. The French chemist, Derosne in 1803, isolated Narcotine. Sertürner further investigated opium and isolated morphine (1806, 1816). A significant contribution to the chemistry of alkaloids in the early years of its development was made by the French researchers Pierre Joseph Pelletier and Joseph Bienaimé Caventou, who discovered quinine (1820) and strychnine (1818). Several other alkaloids were discovered around that time, including xanthine (1817), atropine (1819), caffeine (1820),coniine (1827), nicotine (1828), and cocaine (1860). Coniine was the first alkaloid to have its structure established (Schiff, 1870) and to be synthesized (Ladenburg,1889) For others, such as colchicine, took over a century before structures were elucidated  Occurrence in Plants Rare in lower plants. Dicots are more rich in alkaloids than monocots. Families rich in Alkaloids: Apocynaceae, Rubiaceae, Solanaceae and Papaveracea. Families free from Alkaloids: Rosaceae, Labiatae  Distribution All Parts e.g. Datura Barks e.g. Cinchona Seeds e.g. Nux vomica Roots e.g. Aconite Fruits e.g. Black pepper Leaves e.g. Tobacco Datura Latex e.g. Opium  Function in Plants They may act as protective agents against insects and herbivores due to their bitterness and toxicity. They are, in certain cases, the final products of detoxification (waste products). Source of nitrogen in case of nitrogen deficiency. They, sometimes, act as growth regulators in certain metabolic systems. They may be utilized as a source of energy in case of deficiency in carbon dioxide assimilation.  Alkaloid Effect in Humans High biological activity Produce varying degrees of physiological and psychological responses – largely by interfering with neurotransmitters In large doses- highly toxic – fatal In small doses – many have therapeutic value muscle relaxant, pain killers, tranquilizers, mind altering drugs, chemotherapy Tubocurarine – Muscle relaxant Vincristine – Chemotherapy Reserpine – Antipsychotic Arrow Poison  Forms of Alkaloids Free bases Salts with Organic acids e.g. Oxalic, acetic acids Salts with inorganic acids e.g. HCl, H2SO4. Salts with special acids such meconic acid in opium and quinic acid in cinchona Glycosidal form e.g. Solanine in Solanum.  Nomenclature Trivial names should end with "ine". These names may refer to: The genus of the plant, such as Atropine from Atropa belladona. The plant species, such as Cocaine from Erythroxylon coca. The common name of the drug, such as Ergotamine from ergot. The name of the discoverer, such as Pelletierine that was discovered by Pelletier. The physiological action, such as Emetine that acts as emetic, Morphine acts as narcotic. A prominent physical character, such as Hygrine that is hygroscopic.  Nomenclature Prefixes: "Nor-" designates N-demethylation or N-demethoxylation, e.g. norpseudoephedrine and nornicotine. "Apo-" designates dehydration e.g. apomorphine. "Iso-, pseudo-, neo-, and epi-" indicate different types of isomers. Suffixes: "-dine" designates isomerism as quinidine and cinchonidine. "-ine" indicates, in case of ergot alkaloids, a lower pharmacological activity e.g. ergotaminine is less potent than ergotamine.  Physico-Chemical Properties Most alkaloids are well-defined crystalline Strychnine Phosphate substances which unite with acids to form salts, hence sharp melting point In the plant they may exist in the free state, as salts or as N-oxides. Cinchonine In addition to the elements carbon, hydrogen and nitrogen, most alkaloids contain oxygen. A few, such as coniine from hemlock and nicotine from tobacco, are oxygen-free and are liquids. Although colored alkaloids are relatively rare, Berberine berberine, for example, is yellow and the salts of sanguinarine are copper-red.  Physical Properties - State Most alkaloids are crystalline solids. Emetine Few alkaloids are amorphous solids e.g. emetine. Some are liquids that are either: Volatile e.g. nicotine and coniine, or Non-volatile e.g. pilocarpine and hyoscine. Hyoscine Hyoscine Butylbromide  Physical Properties - Color The majority of alkaloids are colorless but some are colored e.g.: Colchicine Colchicine and berberine are yellow. Canadine is orange. The salts of sanguinarine are copper- red. Berberine  Physical Properties - Solubility As a general rule, alkaloids as bases are not soluble or are sparingly soluble in water, soluble in apolar or only slightly polar organic solvents, and are soluble in concentrated hydroalcoholic solutions. Exceptions Bases soluble in water: caffeine, ephedrine, codeine, colchicine, pilocarpine and quaternary ammonium bases. Bases insoluble or sparingly soluble in certain organic solvents: morphine in ether, theobromine and theophylline in benzene. Salts are usually soluble in water and, insoluble or sparingly soluble in organic solvents.  Physical Properties - Isomerism Optically active isomers may show different physiological activities. l-ephedrine is 3.5 times more active than d-ephedrine. l-ergotamine is 3-4 times more active than d-ergotamine. d-Tubocurarine is more active than the corresponding l- form. Quinine (l-form) is antimalarial and its d- isomer quinidine is antiarrythmic. The racemic (optically inactive) dl-atropine is physiologically active.  Chemical Properties - Nitrogen All alkaloids do contain a nitrogen atom. Could be primary, secondary, tertiary or quaternary alkaloid Primary – Norephedrine (I) Secondary – Ephedrine (II) I II Tertiary – Atropine (III) III IV Quaternary – Sanguinarine (IV)  Chemical Properties - Basicity Basicity depends on availability of lone pair of electrons: 1. Electron donating or electron withdrawing neighbors. Electron-withdrawing groups in close proximity to the nitrogen atom decrease the basicity, whereas electron-donating groups enhance the basicity 2. Type of hybridization. 3. Aromaticity. For alkyl amines, order of basicity is Primary = Tertiary < Secondary (WHY??)  Chemical Properties - Basicity The basic character of the heterocyclic ring itself varies: In a molecule of pyridine, with 6  electrons, and in the case of quinoline and isoquinoline, the lone pair of electrons on the nitrogen atom is available and the basicity is clear.  Chemical Properties - Basicity N In the case of pyrrole or indole, the lone H Pyrrole pair of electrons on the nitrogen atom plays a role in the aromatic character, and the compounds are not basic (they are N acidic). Indole H Another example is pyrrolidine, which is N saturated, and is a strong base. H Pyrrolidine Chemical Properties - Basicity  Chemical Properties Oxygen Stability Effect of heat: Most alkaloids contain oxygen Most alkaloids are decomposed by heat. and are solid in nature e.g. Exceptions are strychnine and caffeine. Atropine. Some alkaloids are free from Reaction with acids: oxygen and are mostly liquids Leads to salt formation. Dilute acids hydrolyze ester alkaloids e.g. eg Nicotine, coniine. Atropine Strong acids can cause: Dehydration: Atropine → Apoatropine Morphine → Apomorphine Atropine Demethoxylation: e.g. Codeine  Classification Ephedrine Generally, there are two broad divisions: Heterocyclic or typical alkaloids, divided into various groups according to their ring structure. Non-heterocyclic or atypical alkaloids, sometimes called ‘proto-alkaloids’. Atropine Sanguinarine Skeletal Structures of Alkaloids Found in Medicinal Plants Pyrrole Pyrollidine Pyrrolizidine Pyridine Piperidine Imidazole Aporphine Quinolizidine Quinoline Isoquinoline Tropane Indolizidine Indole Purine Pyrrole and Pyrrolidine Stachydrine  Pyrrolizidine Echimidine Pyridine and Piperidine  Tropane (piperidine/ N -methyl-pyrrolidine) Cocaine  Quinoline Quinine Cinchonine Isoquinoline Narcotine Aporphine Boldine Quinolizidine Indole  Indolizidine Swainsonine Imidazole  Purine Caffeine Theobromine  Steroidal Funtumine Terpenoid  Qualitative Tests for Alkaloids Precipitation Reagents: General precipitate reactions based on the ability of alkaloids as bases to give simple or complex salt with different, more often complex acids, salts of heavy metals and others. These products are usually water insoluble, so called precipitate. They are used to: 1- Indicate the absence or presence of Alkaloids 2- Test for complete of extraction Disadvantages: Some non-alkaloids interfere such as proteins, lactones, coumarins  Classification of Alkaloidal Precipitating Agents 1. Reagents that form double salts: Mayer’s Reagent: Potassium Mercuric Iodide. Dragendorff’s Reagents: Potassium Iodobismethate. Gold Chloride. 2. Reagents Containing Halogens: Wagner’s Reagent: Iodine/ Potassium Iodide. Classification of Alkaloidal Precipitating Agents 3. Organic Acids: Hager’s Reagent: Picric Acid Tannic Acid. 4. Oxygenated High Molecular Weight Acids: Phosphomolybdic acid Phosphotungestic acid Silicotungestic Acid  Qualitative Tests for Alkaloids - Colour Reagents 1- Froehd’s Reagent: Phosphomolybdic acid 2- Marqui’s Reagent: Formaldehyde/ Conc. H2SO4 3- Mandalin’s Reagent: Sulphovanidic acid 4- Erdmann’s Reagent: Conc. HNO3/Conc. H2SO4 5- Mecke's Reagent: Selenious acid / conc. H2SO4 6- Shaer's Reagent: Hydrogen peroxide / conc. H2SO4 7- Rosenthaler's Reagent: Potassium arsenate / conc. H2SO4 8- Conc. HNO3  Extraction, Purification and Isolation of Alkaloids from Powdered plants Extraction and purification Method I: The powder is treated with alkalis to liberates the free bases that can then be extracted with water immiscible organic solvents. Method II: The powdered material is extracted with water or aqueous alcohol containing dilute acid. Alkaloids are extracted as their salts together with accompanying soluble impurities. Method III: The powder is extracted with water soluble organic solvents such as MeOH or EtOH which are good solvents for both salts and free bases.  Plant material and solvent Organic solvent dissove Alkaloids Organic solvent dissove Impurities Extract Concentration Acidification Alkalinization Acidified Extract (Alk. as salts) Alkaline aqueous layer  Purification of the Crude Alkaloidal Fractions: Repeated Acid-Base procedures: Render extract Acidic, extract with organic solvent (dissolve non alkaloidal impurities), Alkalinize and extract again with organic solvents (Dissolve Alkaloids). Precipitation with alkaloidal precipitating agent. Convert to crystalline salts.  Identification of Alkaloids Melting point Colour test Optical Rotation Microcrystal test HPLC, GC, GC-MS UV, IR, NMR, MS. Skeletal Structures of Alkaloids Found in Medicinal Plants Pyrrole Pyrollidine Pyrrolizidine Pyridine Piperidine Imidazole Aporphine Quinolizidine Quinoline Isoquinoline Tropane Indolizidine Indole Purine  Alkaloid Biosynthesis Alkaloids are derived from amino acids (for typical alkaloids and proto – alkaloids) and other plant amines (for pseudo alkaloids) Other precursors, e.g. terpenes or steroids, are often also built into the final alkaloidal skeleton. The amino acids that most often serve as alkaloidal precursors include: phenylalanine, tyrosine, tryptophan, histidine, anthranilic acid, lysine and ornithine.  TERM PAPER Identify a local plant in your area For each plant, conduct an ethnobotanical survey Local indications (what they are used for) how they are used (part of plant etc) their preparation (method of extraction) their admixtures, if any knowledge of fine differences between them (closely related plants, plants that resemble each other at certain stages of the year) Based on an extensive literature search, identify secondary metabolites isolated from plant Established linkages between isolated secondary metabolites and local indications Deposit voucher specimens of plant sample at the Department of Herbal Medicine herbarium. Obtain a voucher specimen