PHYTOCHEMISTRY AND NATURAL PRODUCTS CPPH403 Dr. Dima MUHAMMAD 2018-2019 1 -Trease and Evans Pharmacognosy, William C. Evans, Saunders Elsevier, 2009, sixteenth edition., ISBN 978-0 -7020 -2934 9 2- Textbook of pharmacognosy & phytochemistry, Biren Shah & A.K. Seth, Elsevier, 2010, 1st edition, ISBN: 978-81- 312-2298-0 3-Medicinal Natural Products: A Biosynthetic Approach. Paul M Dewick, John Wiley & Sons, 2009,3rd edition, ISBN 978-0-470-74168-9. 4- Pharmacognosy. Phytochemistry, medicinal plants. Bruneton Jean, Lavoisier; 2009 4th edition; ISBN 978- 2743011888. 1 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS PRIMARY AND SECONDARY METABOLISM All organisms need to transform and interconvert a vast number of organic compounds to enable them to live, grow, and reproduce. They need to provide themselves with energy in the form of ATP, and a supply of building blocks to construct their own tissues. An integrated network of enzyme-mediated and carefully regulated chemical reactions is used for this purpose, collectively referred to as intermediary metabolism, and the pathways involved are termed metabolic pathways. Despite the extremely varied characteristics of living organisms, the pathways for generally modifying and synthesizing carbohydrates, proteins, fats, and nucleic acids are found to be essentially the same in all organisms, apart from minor variations. These processes demonstrate the fundamental unity of all living matter, and are collectively described as primary metabolism. In contrast to these primary metabolic pathways, which synthesize, degrade, and generally interconvert compounds commonly encountered in all organisms, there also exists an area of metabolism concerned with compounds which have a much more limited distribution in nature. Such compounds, called secondary metabolites, are found in only specific organisms, or groups of organisms, and are an expression of the individuality of species. Secondary metabolites are not necessarily produced under all conditions, and in the vast majority of cases the function of these compounds and their benefit to the organism are not yet known. Some are undoubtedly produced for easily 2 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS appreciated reasons, e.g. as toxic materials providing defense against predators, as volatile attractants towards the same or other species, or as colouring agents to attract or warn other species, but it is logical to assume that all do play some vital role for the well-being of the producer. It is this area of secondary metabolism which provides most of the pharmacologically active natural products. It is thus fairly obvious that the human diet could be both unpalatable and remarkably dangerous if all plants, animals, and fungi produced the same range of compounds. Figure 1.1: Origins of secondary metabolites in relation to the basic metabolic pathways of plants 3 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS THE MEVALONATE AND METHYLERYTHRITOL PHOSPHATE PATHWAYS 1. TERPENOIDS Terpenoids comprise the largest group of natural products, with over 35000 known members. Terpenoids form a large and structurally diverse family of natural products derived from C5 isoprene units (Figure 1.2) joined in a head-to-tail fashion. Typical structures contain carbon skeletons represented by (C5)n, and are classified as hemiterpenes (C5), monoterpenes (C10), sesquiterpenes (C15), diterpenes (C20), sesterterpenes (C25), triterpenes (C30), and tetraterpenes (C40). Figure 1.2: Isoprene structure. 4 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS Figure 1.3: Terpenoids derivatives. Isoprene itself was known as a decomposition product from various natural cyclic hydrocarbons, and had been suggested as the fundamental building block for Terpenoids, also referred to as ‘isoprenoids„. 5 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS methyl-erythrol-4-phosphate, MEP -2 Figure 1.4: Isporene bio-origin. The biochemically active isoprene units were subsequently identified as the diphosphate (pyrophosphate) esters dimethylallyl diphosphate (DMAPP) and isopentenyl diphosphate (IPP) (Figure 1.5). O P P O P P I PP D M A PP Figure 1.5: active isoprene forms Isoprenoid synthesis then proceeds by the condensation of isopentenyl pyrophosphate with the isomeric dimethylallyl pyrophosphate to yield geranyl pyrophosphate. Further C5 units are added by the addition of more isopentenyl pyrophosphate. 6 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS Figure 1.6: Preliminary stages in the biosynthesis of isoprenoid compounds. Figure 1.7: Terpenoid derivatives of linear combination of isoprene units. Relatively few of the natural terpenoids conform exactly to the simple concept of a linear head-to-tail combination of isoprene units as seen with geraniol (C10), farnesol (C15), and geranylgeraniol (C20) (Figure 1.6). Squalene (C30) andphytoene (C40), although formed entirely of isoprene units, display a tail-to-tail linkage at the centre of the molecules. Most terpenoids are modified further by cyclization reactions. 7 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS Many other natural products contain terpenoid elements in their molecules, in combination with carbon skeletons derived from other sources, such as the acetate and shikimate pathways. Many alkaloids, phenolics, and vitamins are examples of this. 1.1. MONOTERPENES (C10) Enzyme-catalysed combination of DMAPP and IPP yields geranyl diphosphate (GPP). Figure 1.8: Geranyl diphosphate synthesis GPP and its isomers (Linalyl PP and neryl PP), by relatively modest changes, can give rise to a range of linear monoterpenes found as components of volatile oils used in flavouring and perfumery. The resulting compounds may be hydrocarbons, alcohols, aldehydes, or perhaps esters. Figure 1.9: Simple Monoterpenes formation 8 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS The range of monoterpenes encountered is extended considerably by cyclization reactions, and monocyclic or bicyclic systems can be created. Figure 1.10: monocyclic or bicyclic monoterpenes 1.1.1. IRIDOIDS (C10) The iridane skeleton (Figure 1.11), found in iridoids, is monoterpenoid in origin and contains a cyclopentane ring which is usually fused to a six-membered oxygen heterocycle. The iridoid system arises from geraniol by a type of folding. Iridane Iridoids Geraniol Figure 1.11: Iridane skeleton and iridoid based structure. The name derives from Iridomyrmex, a genus of ants which produces these compounds as a defensive secretion . Most occur as glycosides; some occur free and as bis compounds; Of pharmaceutical significance is their presence in Valerian, Gentian and Harpagophytum. 9 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS 1.1.1.1. GENTIAN, Gentiana lutea L. Gentian (Gentian Root BP, EP, BHP) consists of the dried fermented rhizomes and roots of the yellow gentian, Gentiana lutea L. (Gentianaceae). - Description: Gentian is a perennial herb about 1m high found in the mountainous districts of central and southern Europe and Turkey. Important districts for its collection are the Pyrenees, the Jura and Vosges Mountains, the Black Forest and former Yugoslavia. - Collection and preparation: When the plants are 2–5 years old, the turf is carefully stripped around each and the rhizomes and roots are dug up. This usually takes place from May to October, collection in the autumn being more difficult on account of the hardness of the soil, although possibly preferable from the medicinal point of view. The commercial drug consisting of ‘red„ or fermented gentian; Usually, the drug is made into heaps, which are allowed to lie on the hillside for some time and may even be covered with earth. After it is washed and cut into suitable lengths the drug is dried, first in the open air and then in sheds. Prepared in this way the drug becomes much darker in colour, loses some of its bitterness and acquires a very distinctive odour. - Constituents: Gentian contains bitter glycosides, alkaloids, yellow colouring matters, sugars, pectin and fixed oil. The secoiridoid gentiopicroside (about 2%, also known as gentiopicrin and gentiamarin). 11 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS The yellow colour of fermented gentian root is due to xanthones. - Uses: Gentian is used as a bitter tonic, it is also reported to have choleretic, antioxidative and hepatoprotective. In traditional medicine it has been employed to treat various gastrointestinal conditions, as an anti-inflammatory and wound- healing agent. Figure 1.12: Gentiana lutea 1.1.1.2. VALERIAN ROOT Valerian consists of the rhizome, stolons and roots of Valeriana officinalis L.s.l. (Valerianaceae), collected in the autumn and dried at a temperature below 40°C. - Description: The plant is a perennial about 1–2 m high. It is obtained from wild and cultivated plants in The Netherlands, Belgium, France, Germany, eastern Europe and Japan. It is also cultivated in the USA. 11 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS Figure 1.13: Valeriana officinalis - Constituents: The drug yields about 0.5–1.0% of volatile oil, sesquiterpen derivatives (valerenic acid derivatives), in addition to epoxy-iridoid esters called valepotriates. Seasonal variations in the constituents of valerian raised in the Netherlands have been reported. Thus the accumulation of valerenic acid and its derivatives together with valepotriates reached a maximum in February to March whereas the volatile oil remained essentially constant during the period of study. H O, air, 2 tº>41 ºC Figure 1.14: Valerian roots constituents.