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Pharmacognosy-I PHG 251 Introduction to Pharmacognosy A brief history of natural products in medicine Value of natural drug products Production of natural drug products The role of natural products in drug discovery General principles of botany: morphology and systematics I. The history of natural products in medicine A great proportion of the natural products used as drugs The study of drugs used by traditional healers is an important object of pharmacognostical research Sumerians and Akkadians (3rd millennium BC) Egyptians (Ebers papyrus, 1550 BC) Authors of antiquity Hippocrates (460-377 BC) “The Father of Medicine” Dioscorides (40-80 AD) “De Materia Medica” (600 medicinal plants) The Islamic era Ibn Altabari (770850) “” فردوس الحكمه )Ibn Sina (980-1037 ”القانون في الطب“ )Ibn Albitar (1148-1197 ”الجامع لمفردات األدوية واألغذية“ The era of European exploration overseas (16th and 17th century) The 18th century, Pharmacognosy Johann Adam (1759-1809) Linnaeus At (naming and classifying plants) the end of the 18th century, crude drugs were still being used as powders, simple extracts, or tinctures The era of pure compounds (In 1803, a new era in the history of medicine) Isolation of morphine from opium Strychnine Quinine (1817) and caffeine (1820) Nicotine (1828) Atropine (1833) Cocaine (1855) In the 19th century, the chemical structures of many of the isolated compounds were determined In the 20th century, the discovery of important drugs from the animal kingdom, particularly hormones and vitamins. microorganisms have become a very important source of drugs Definitions Pharmacognosy: It is the science of biogenic or nature-derived pharmaceuticals and poisons Crude drugs: It is used for those natural products such as plants or part of plants, extracts and exudates which are not pure compounds Ethnobotany: It is a broad term referring to the study of plants by humans Ethnomedicine: It refers to the use of plants by humans as medicine Traditional medicine: It is the sum total of all non-mainstream medical practices, usually excluding so called “western” medicine Natural products: they can be 1. Entire organism (plant, animal, organism) 2. Part of an organism (a leaf or flower of a plant, an isolated gland or other organ of an animal) 3. An extract or an exudate of an organism 4. Isolated pure compounds Types of drugs derived from plants 1. Herbal drugs, derived from specific parts of a medicinal plant 2. Compounds isolated from nature 3. Nutraceuticals, or “functional foods” II. Value of natural products 1. Compounds from natural sources play four significant roles in modern medicine: They provide a number of extremely useful drugs that are difficult, if not impossible, to produce commercially by synthetic means 2. Natural sources also supply basic compounds that may be modified slightly to render them more effective or less toxic 3. Their utility as prototypes or models for synthetic drugs possessing physiologic activities similar to the originals H3C COOH COOH COOH Ibuprofen H3 C HO O O Salicylic Acid Aspirin CH3 CH3 4. Some natural products contain compounds that demonstrate little or no activity themselves but which can be modified by chemical or biological methods to produce potent drugs not easily obtained by other methods Baccatin III Taxol III. Production of natural drug products 1. 2. 3. 4. 5. 6. Collection (wild) Cultivation (commercial), collection, harvesting, drying, garbling, packaging, storage and preservation e.g. ginseng, ginkgo, peppermint Fermentation (Recombinant DNA technology or Genetically engineered drugs) Cell-culture techniques Microbial transformation Biologics (prepared from the blood of animals) IV. The role of natural products in drug discovery 1. Combinatorial chemistry 2. High-throughput screening of natural products 3. Combinatorial biosynthesis 4. Ethnopharmacology V. General principles of botany: morphology and systematics How to define a pharmaceutical plantderived drug from the botanical point of view ? a botanical drug is a product that is either: Derived from a plant and transformed into a drug by drying certain plant parts, or sometimes the whole plant, or 1. Obtained from a plant, but no longer retains the structure of the plant or its organs and contains a complex mixture of biogenic compounds (e.g. fatty and essential oils, gums, resins, balms) • isolated pure natural products are thus not “botanical drugs”, but rather chemically defined drugs derived from nature. 1. 2. 3. 4. 5. 6. 7. 8. the following plant organs are the most important, with the Latin name that is used, for example in international trade, in parentheses: Aerial parts or herb (herba) Leaf (folia) Flower (flos) Fruit (fructus) Bark (cortex) Root (radix) Rhizome (rhizoma) Bulb (bulbus) The large majority of botanical drugs in current use are derived from leaves or aerial parts. A plant-derived drug should be defined not only in terms of the species from which it is obtained but also the plant part that is used to produce the dried product. Thus, a drug is considered to be adulterated if the wrong plant parts are included (e.g. aerial parts instead of leaves) Taxonomy It is the science of naming organisms and their correct integration into the existing system of nomenclature The names of species are given in binomial form: the first part of the name indicates the wider taxonomic group, the genus; the second part of the name is the species. Papaver somniferum L. Species: somniferum, here meaning ‘sleepproducing’ Genus: Papaver (a group of species, in this case poppies, which are closely related) Family: Papaveraceae (a group of genera sharing certain traits) L.: indicates the botanist who provided the first scientific description of the species and who assigned the botanical name Morphology of higher plants 1. Flower It is the essential reproductive organ of a plant. For an inexperienced observer, two characteristics of a flower are particularly noteworthy: the size and the color Although the flowers are of great botanical importance, they are only a minor source of drugs used in phytotherapy or pharmacy e.g. chamomile, Matricaria recutita L. (Asteraceae ) 2. Fruit and seed The lower plants, such as algae, mosses and ferns, do not produce seeds Gymnosperm and Angiosperm Gymnosperm: they are characterized by seeds that are not covered by a secondary outer protective layer, but only by the testa – the seed’s outer layer Angiosperm: the seeds are covered with a specialized organ (the carpels) which in turn develop into the pericarp. Drugs from the fruit thus have to be derived from an angiosperm species Fruits and seeds have yielded important phytotherapeutic products, including: Fruit Caraway, Carum carvi L. (Umbelliferae) Seed (white) mustard, Sinapis alba L. (Brassicaceae) 3. Leaves 1. 2. 3. 4. 5. The function of the leaves, as collectors of the sun’s energy and its assimilation, results in their typical general anatomy with a petiole (stem) and a lamina (blade) A key characteristic of a species is the way in which the leaves are arranged on the stem, they may be: Alternate Distichous Opposite Decussate Whorled The form and size of leaves are essential characteristics e.g. oval, oblong, obovate, rounded, linear, lanceolate, elliptic, spatulate, cordate, hastate or tendril The margin of the leaf is another characteristic feature e.g. entire, serrate, dentate, sinuate, ciliate or spinose Numerous drugs contain leaf material as the main component. e.g. Deadly nightshade, Atropa belladonna L. (Solanaceae) 4. Bark The bark as an outer protective layer frequently accumulates biologically active substances e.g. Red cinchona, Cinchona succirubra L. (Rubiaceae) No stem-derived drug is currently of major importance 5. Rhizome and root drugs Underground organs of only a few species have yielded pharmaceutically important drugs e.g. 1. Sarsaparilla, Smilax regelii (Smilacaceae) 2. Korean ginseng, Panax ginseng (Araliaceae) 6. The bulbs and exudates 1. Garlic, Allium sativum L. (Liliaceae) 2. Aloe vera L. (Asphodelaceae) S1 L1 Introduction to Pharmacognosy Anna Drew with slide contribution from Bob Hoffman & grateful acknowledgement for inspirational teaching received at the School of Pharmacy, University of London ‘Pharmacognosy’ – pharmakon ‘a drug’ (Greek) – gignosco ‘ to acquire knowledge of’ (Greek) – OR cognosco ‘to know about’ (Latin) Johann Adam Schmidt (1759-1809) – Lehrbuch der Materia Medica – Published Vienna 1811 – Beethoven’s physician Naturally occurring substances having a medicinal action: Surgical dressings prepared from natural fibres Flavourings and suspending agents Disintegrants Filtering and support media Other associated fields: – Poisonous and hallucinogenic plants – Raw materials for production of oral contraceptives – Allergens – Herbicides and insecticides Pharmacognosy is related to: – Botany – Ethnobotany – Marine biology – Microbiology – Herbal medicine – Chemistry (phytochemistry) – Pharmacology – Pharmaceutics Skills & techniques valuable elsewhere: Analysis of other commodoties Foods, spices, gums, perfumes, fabrics, cosmetics Used by Public analysts, forensic sciences, quality-control scientists Role in pure sciences Botany, plant taxonomy, phytochemistry Botanists and chemists looking at: Chemical plant taxonomy, genetic/enzymatic studies involving 2y metabolites Artificial and tissue culture Effects of chemicals on plant metabolites Induction of abnormal syntheses Bioassay-guided isolation techniques Vegetable drugs can be arranged for study: – Alphabetical – Taxonomic** botanical classification – Morphological Organised drugs: leaves, flowers, fruit, seeds etc Unorganised drugs: extracts, gums, resins, oils etc – Pharmacological/therapeutic* Increasingly used with screening Constituents of one drug may fall into several groups – Chemical/biogenetic Constituents or biosynthetic pathways CLASS SUBCLASS Angiospermae (Angiosperms) Plants which produce flowers Gymnospermae (Gymnosperms) Plants which don't produce flowers Dicotyledonae (Dicotyledons, Dicots) Plants with two seed leaves Monocotyledonae (Monocotyledons, Monocots) Plants with one seed leaf SUPERORDER A group of related Plant Families, classified in the order in which they are thought to have developed their differences from a common ancestor. There are six Superorders in the Dicotyledonae (Magnoliidae, Hamamelidae, Caryophyllidae, Dilleniidae, Rosidae, Asteridae), and four Superorders in the Monocotyledonae (Alismatidae, Commelinidae, Arecidae, Liliidae) The names of the Superorders end in -idae ORDER Each Superorder is further divided into several Orders. The names of the Orders end in -ales FAMILY Each Order is divided into Families. These are plants with many botanical features in common, and is the highest classification normally used. At this level, the similarity between plants is often easily recognisable by the layman. Modern botanical classification assigns a type plant to each Family, which has the particular characteristics which separate this group of plants from others, and names the Family after this plant. The number of Plant Families varies according to the botanist whose classification you follow. Some botanists recognise only 150 or so families, preferring to classify other similar plants as sub-families, while others recognise nearly 500 plant families. A widely-accepted system is that devised by Cronquist in 1968, which is only slightly revised today. The names of the Families end in -aceae SUBFAMILY The Family may be further divided into a number of sub-families, which group together plants within the Family that have some significant botanical differences. The names of the Subfamilies end in -oideae TRIBE A further division of plants within a Family, based on smaller botanical differences, but still usually comprising many different plants. The names of the Tribes end in -eae SUBTRIBE A further division, based on even smaller botanical differences, often only recognisable to botanists. The names of the Subtribes end in -inae GENUS This is the part of the plant name that is most familiar, the normal name that you give a plant - Papaver (Poppy), Aquilegia (Columbine), and so on. The plants in a Genus are often easily recognisable as belonging to the same group. The name of the Genus should be written with a capital letter. SPECIES This is the level that defines an individual plant. Often, the name will describe some aspect of the plant the colour of the flowers, size or shape of the leaves, or it may be named after the place where it was found. Together, the Genus and species name refer to only one plant, and they are used to identify that particular plant. Sometimes, the species is further divided into sub-species that contain plants not quite so distinct that they are classified as Varieties. The name of the species should be written after the Genus name, in small letters, with no capital letter. VARIETY A Variety is a plant that is only slightly different from the species plant, but the differences are not so insignificant as the differences in a form. The Latin is varietas, which is usually abbreviated to var. The name follows the Genus and species name, with var. before the individual variety name. FORM A form is a plant within a species that has minor botanical differences, such as the colour of flower or shape of the leaves. The name follows the Genus and species name, with form (or f.) before the individual variety name. CULTIVAR A Cultivar is a cultivated variety, a particular plant that has arisen either naturally or through deliberate hybridisation, and can be reproduced (vegetatively or by seed) to produce more of the same plant. The name follows the Genus and species name. It is written in the language of the person who described it, and should not be translated. It is either written in single quotation marks or has cv. written in front of the name. Example Linnaeus (1707-1778), Swedish biologist Division Class Subclass Order Suborder Family Subfamily Tribe Genus Species Varieties Angiospermae Dicotyledoneae Sympetalae Tubiflorae Verbenineae Labiatae (Lamiaceae) Stachydoideae Satureieae Mentha Mentha piperita Linnaeus (peppermint) Mentha piperita var. officinalis Sole (White Peppermint); Mentha piperita var. vulgaris Sole (Black Peppermint) Contribution of plants to medicine and pharmacy 18th century drugs plant based 19th century a range of drugs was isolated: 1805 morphine 1817 emetine 1819 strychnine 1820 quinine Famous plants/plant drugs? Quinine Cinchona bark, South American tree Used by Incas; dried bark ground and mixed with wine First used in Rome in 1631 Extracted 1820 Large scale use 1850 Chemical synthesis 1944 Actual tree remains the most economic source Belladonna -> atropine Anticholinergic syndrome: Hot as hell Blind as a bat Red as a beet Dry as a bone Mad as a hatter Physostigma venosum Calabar bean Efik People Efik Law Trial by ordeal “A suspected person is given 8 beans ground and added to water as a drink. If he is guilty, his mouth shakes and mucus comes from his nose. His innocence is proved if he lifts his right hand and then regurgitates” (Simmons 1952) Deadly esere Administration First of the Calabar bean observed by WF Daniell in 1840 Later described by Freeman 1846 in a Communication to the Ethnological Society of Edinburgh Physostigmine or Eserine First isolated in 1864 by Jobst & Hesse ‘Taxol’ Pacific Yew tree, Taxus brevifolia, bark 1964 activity discovered at NCI 1966 paclitaxel isolated Mitotic inhibitor – interferes with normal microtubule growth during cell div Used for cancer chemotherapy 1969 1200kg pure 1975 bark -> 28kg crude extract -> 10g active in another in vitro assay 1977 600g 7000 pounds bark requested to make 1978 Mildly active in leukaemic mice 1979 Horowitz; unknown mechanism involved stabilising of microtubules 1980 20,000 pounds of bark needed 1982 Animal studies completed 1984 Phase I trials 12,000 pounds for Phase II to go ahead 1986 Phase II trials began Recognised 60,000 pounds miniumum needed Environmental concerns voiced 1988 An effect in melanoma RR of 30% refractory ovarian cases Annual destruction of 360,000 trees to treat all US cases 1989 NCI handed over to BMS Agreed to find alternative production pathway 1992 BMS given FDA approval & 5yrs marketing rights Trademark ‘Taxol’ Generic paclitaxel 2000 sales peaked US$1.6 billion Now available as generic Alternative production – 1967-1993 all sourced from Pacific Yew – Late 1970s synthetic production from petrochemical-derived starting materials – 1981 Potier isolated 10-deacetylbaccitin from Taxus baccata needles – 1988 published semi-synthetic route – 1992 Holton patented improved process improving yield to 80% – 1995 use of Pacific Yew stopped – Now plant cell fermentation (PCF) technology used – Also found in fungi – Race for synthetic production -> docetaxel Why do we need plants? 1. Source of drug molecules Most drugs can be synthesised Still more economical to use the plant Papaver opium -> morphine, codeine (strong medicinal pain) Ergot fungus –> ergotamine (headache), ergometrine (direct action on uterine muscle) Digitalis foxglove -> digoxin (acts on cardiac muscle) 2. Source of complex molecules that can be modified to medicinal compounds Examples: Droscera yam: molecule -> steroids Soya: saponins -> steroids 3. Source of toxic molecules To study the way the body responds to their pharmacological use Investigating pharmacological mechanisms picrotoxin – nerve conduction 4. Source of compounds to use as templates for designing new drugs Morphine: No better painkiller. Once structure worked out wanted to improve it. What is required? Diacetylmorphine (heroin): OH group -> O-O-diacetyl. Still addictive? Codeine: Methylate hydroxyl phenolic; O-Me. 1/5 analgesic capacity of morphine, useful to suppress cough reflex Dihydromorphinone: Reduced =, oxidised 2y alc. Potential analgesic. Dihydrocodeine: Me-ether of previous. More powerful than codeine, less than morphine. Dextromethorphan: Good against cough reflex Is lower ring necessary? Is middle ring needed? Pentazocin Pethidine Phenazocine Methadone 5. Source of novel structures these might never be thought of Catharanthus periwinkle -> vincristine (alkaloid dimer) 6. Source of plant drugs As a powder or extract The pure compound is often not isolated because: Active ingredient is unknown Active ingredient is unstable Isolation process is too costly 250,-500,000 species of higher plants on earth <10% investigated and only for one activity Huge potential in plant kingdom Future: intense screening Anticancer - NCI Antimicrobial Antiviral Antimalarial Insecticidal Hypoglycaemic Cardiotonic Antiprotozoal Antifertility - WHO Screening – Pharmacological – in vitro testing – Chemical – certain constituents Eg alkaloids Failed screening work – Incorrect identification of plant material – Plants exist in chemical races – different constituents – Low yield of active compound – Solubility – have to find correct solvent Future 80% world population rely on natural remedies Westernization of societies (‘traditional’ knowledge) Extermination of species conservation, Natural retain gene pools resources exhausted cultivation, artificial propogation Conclusion Natural products very important to medicine Exist in range of structures that one wouldn’t think of synthesizing Can act as templates for new drug development Untapped reservoir of new compounds
