Phytochmistry PDF

Phytochmistry By : Fatima Elmehdawi "Bioside" redirects here. For the poisonous substance or microorganism, see Biocide. Salicin, a glycoside related to aspirin Chemical structure of oleandrin, a cardiac glycoside In chemistry, a glycoside /ˈɡlaɪkəsaɪd/ is a molecu...

Phytochmistry By : Fatima Elmehdawi "Bioside" redirects here. For the poisonous substance or microorganism, see Biocide. Salicin, a glycoside related to aspirin Chemical structure of oleandrin, a cardiac glycoside In chemistry, a glycoside /ˈɡlaɪkəsaɪd/ is a molecule in which a sugar is bound to another functional group via a glycosidic bond. Glycosides play numerous important roles in living organisms. Many plants store chemicals in the form of inactive glycosides. These can be activated by enzyme hydrolysis, which causes the sugar part to be broken off, making the chemical available for use. Many such plant glycosides are used as medications. Several species of Heliconius butterfly are capable of incorporating these plant compounds as a form of chemical defense against predators. In animals and humans, poisons are often bound to sugar molecules as part of their elimination from the body. In formal terms, a glycoside is any molecule in which a sugar group is bonded through its anomeric carbon to another group via a glycosidic bond. Glycosides can be linked by an O- (an O-glycoside), N- (a glycosylamine), S- (a thioglycoside), or C- (a C-glycoside) glycosidic bond. According to the IUPAC, the name "C-glycoside" is a misnomer; the preferred term is "C-glycosyl compound". The given definition is the one used by IUPAC, which recommends the Haworth projection to correctly assign stereochemical configurations. Many authors require in addition that the sugar be bonded to a non-sugar for the molecule to qualify as a glycoside, thus excluding polysaccharides. The sugar group is then known as the glycone and the non- sugar group as the aglycone or genin part of the glycoside. The glycone can consist of a single sugar group (monosaccharide), two sugar groups (disaccharide), or several sugar groups (oligosaccharide). The first glycoside ever identified was amygdalin, by the French chemists Pierre Robiquet and Antoine Boutron-Charlard, in 1830. Related compounds Molecules containing an N-glycosidic bond are known as glycosylamines. Many authors in biochemistry call these compounds N-glycosides and group them with the glycosides; this is considered a misnomer and is discouraged by the International Union of Pure and Applied Chemistry. Glycosylamines and glycosides are grouped together as glycoconjugates; other glycoconjugates include glycoproteins, glycopeptides, peptidoglycans, glycolipids, and lipopolysaccharides.[citation needed] Glycans are involved in various biological processes, including disease pathways. C-glycosides are un- natural glycan analogues where the glycosidic oxygen is replaced with a carbon substituent. C- glycosides are cyclic ethers and not acetals as their parent O-glycosides. They are more stable to chemical and enzymatic hydrolysis since the anomeric position is now a carbon substituent. So, they are extensively used as mechanistic probes and potential therapeutics. They have different conformational and receptor binding properties than their O-glycosidic counterpart. In most cases they have higher efficacy and are better drugs like the example show.If you need to be convinced take for example the case of alpha galactose ceramide, the famous anticancer drug, alphagalactose ceramide. The c- analogue was comparied with its parent o-glycoside In treatment of the mouse malaria and melanoma model. In both cases the c-glycoside shoes to have better drug efficacy then the o-glycoside. In the mouse malaria model, they treated sporozoites with both the c-glycoside and the o-glycoside and after 42 hours the c-glycoside was significanly better at treating the sporozoited then theoglycoside.Similirly, in the melanoma model, skin treated with the c-glycoside showed much better results than treatment with the o-glycoside at the same dosage. Schmieg, et al. J. Exp. Med. 2003, 198, 1631–164 Dall’Olio, F.; Pucci, M.; Malagolini, N. et.al Cancers. 2021, 13 (21), 5273. Chemistry Much of the chemistry of glycosides is explained in the article on glycosidic bonds. For example, the glycone and aglycone portions can be chemically separated by hydrolysis in the presence of acid and can be hydrolyzed by alkali. There are also numerous enzymes that can form and break glycosidic bonds. The most important cleavage enzymes are the glycoside hydrolases, and the most important synthetic enzymes in nature are glycosyltransferases. Genetically altered enzymes termed glycosynthases have been developed that can form glycosidic bonds in excellent yield.[citation needed] There are many ways to chemically synthesize glycosidic bonds. Fischer glycosidation refers to the synthesis of glycosides by the reaction of unprotected monosaccharides with alcohols (usually as solvent) in the presence of a strong acid catalyst. The Koenigs-Knorr reaction is the condensation of glycosyl halides and alcohols in the presence of metal salts such as silver carbonate or mercuric oxide.[citation needed] Classification Glycosides can be classified by the glycone, by the type of glycosidic bond, and by the aglycone. By glycone/presence of sugar If the glycone group of a glycoside is glucose, then the molecule is a glucoside; if it is fructose, then the molecule is a fructoside; if it is glucuronic acid, then the molecule is a glucuronide; etc. In the body, toxic substances are often bonded to glucuronic acid to increase their water solubility; the resulting glucuronides are then excreted. Compounds can also be generally defined based on the class of glycone; for example, biosides are glycosides with a disaccharide (biose) glycone. By type of glycosidic bond  Depending on whether the glycosidic bond lies "below" or "above" the plane of the cyclic sugar molecule, glycosides are classified as α-glycosides or β-glycosides. Some enzymes such as α-amylase can only hydrolyze α-linkages; others, such as emulsin, can only affect β-linkages. There are four type of linkages present between glycone and aglycone: C-linkage/glycosidic bond, "nonhydrolysable by acids or enzymes" O-linkage/glycosidic bond N-linkage/glycosidic bond S-linkage/glycosidic bond By aglycone Glycosides are also classified according to the chemical nature of the aglycone. For purposes of biochemistry and pharmacology, this is the most useful classification. Alcoholic glycosides An example of an alcoholic glycoside is salicin, which is found in the genus Salix. Salicin is converted in the body into salicylic acid, which is closely related to aspirin and has analgesic, antipyretic, and anti- inflammatory effects. Anthraquinone glycosides These glycosides contain an aglycone group that is a derivative of anthraquinone. They have a laxative effect. They are mainly found in dicot plants except the family Liliaceae which are monocots. They are present in senna, rhubarb and Aloe species. Anthron and anthranol are reduced forms of anthraquinone. Coumarin glycosides Here, the aglycone is coumarin or a derivative. An example is apterin which is reported to dilate the coronary arteries as well as block calcium channels. Other coumarin glycosides are obtained from dried leaves of Psoralea corylifolia. Chromone glycosides In this case, the aglycone is called benzo-gamma-pyrone. Cyanogenic glycosides Amygdalin In this case, the aglycone contains a cyanohydrin group. Plants that make cyanogenic glycosides store them in the vacuole, but, if the plant is attacked, they are released and become activated by enzymes in the cytoplasm. These remove the sugar part of the molecule, allowing the cyanohydrin structure to collapse and release toxic hydrogen cyanide. Storing them in inactive forms in the vacuole prevents them from damaging the plant under normal conditions. Along with playing a role in deterring herbivores, in some plants they control germination, bud formation, carbon and nitrogen transport, and possibly act as antioxidants. The production of cyanogenic glycosides is an evolutionarily conserved function, appearing in species as old as ferns and as recent as angiosperms. These compounds are made by around 3,000 species. In screens they are found in about 11% of cultivated plants but only 5% of plants overall; humans seem to have selected for them. Examples include amygdalin and prunasin which are made by the bitter almond tree; other species that produce cyanogenic glycosides are sorghum (from which dhurrin, the first cyanogenic glycoside to be identified, was first isolated), barley, flax, white clover, and cassava, which produces linamarin and lotaustralin. Amygdalin and a synthetic derivative, laetrile, were investigated as potential drugs to treat cancer and were heavily promoted as alternative medicine; they are ineffective and dangerous. Some butterfly species, such as the Dryas iulia and Parnassius smintheus, have evolved to use the cyanogenic glycosides found in their host plants as a form of protection against predators through their unpalatability. Flavonoid glycosides Here, the aglycone is a flavonoid. Examples of this large group of glycosides include: Hesperidin (aglycone: hesperetin, glycone: rutinose) Naringin (aglycone: naringenin, glycone: rutinose) Rutin (aglycone: quercetin, glycone: rutinose) Quercitrin (aglycone: quercetin, glycone: rhamnose) Among the important effects of flavonoids are their antioxidant effect. They are also known to decrease capillary fragility.[citation needed] Phenolic glycosides Here, the aglycone is a simple phenolic structure. An example is arbutin found in the Common Bearberry Arctostaphylos uva-ursi. It has a urinary antiseptic effect. Saponins Main article: Saponin These compounds give a permanent froth when shaken with water. They also cause hemolysis of red blood cells. Saponin glycosides are found in liquorice. Their medicinal value is due to their expectorant, corticoid and anti-inflammatory effects. Steroid saponins are important starting material for the production of semi-synthetic glucocorticoids and other steroid hormones such as progesterone; for example in Dioscorea wild yam the sapogenin diosgenin, in the form of its glycoside dioscin. The ginsenosides are triterpene glycosides and ginseng saponins from Panax ginseng (Chinese ginseng) and Panax quinquefolius (American ginseng). In general, the use of the term saponin in organic chemistry is discouraged, because many plant constituents can produce foam, and many triterpene- glycosides are amphipolar under certain conditions, acting as a surfactant. More modern uses of saponins in biotechnology are as adjuvants in vaccines: Quil A and its derivative QS-21, isolated from the bark of Quillaja saponaria Molina, to stimulate both the Th1 immune response and the production of cytotoxic T-lymphocytes (CTLs) against exogenous antigens make them ideal for use in subunit vaccines and vaccines directed against intracellular pathogens as well as for therapeutic cancer vaccines but with the aforementioned side-effect of hemolysis. Saponins are also natural ruminal antiprotozoal agents that are potential to improve ruminal microbial fermentation reducing ammonia concentrations and methane production in ruminant animals. Steroid glycosides (cardiac glycosides) Main article: Cardiac glycoside In these glycosides, the aglycone part is a steroid nucleus. These glycosides are found in the plant genera Digitalis, Scilla, and Strophanthus. They are used in the treatment of heart diseases, e.g., congestive heart failure (historically as now recognised does not improve survivability; other agents[example needed] are now preferred[medical citation needed]) and arrhythmia. Steviol glycosides Main article: Steviol glycoside These sweet glycosides found in the stevia plant Stevia rebaudiana Bertoni have 40–300 times the sweetness of sucrose. The two primary glycosides, stevioside and rebaudioside A, are used as natural sweeteners in many countries. These glycosides have steviol as the aglycone part. Glucose or rhamnose-glucose combinations are bound to the ends of the aglycone to form the different compounds. Iridoid glycosides These contain an iridoid group; e.g. aucubin, geniposidic acid, theviridoside, loganin, catalpol. Thioglycosides As the name contains the prefix thio-, these compounds contain sulfur. Examples include sinigrin, found in black mustard, and sinalbin, found in white mustard. Chapter 11 Synthesis, role and usage of lipids. Oils and waxes The majority of lipids dissolve in nonpolar solvents (chloroform, ether, CCl4), because they are hydrophobic. 11.1 Biological functions (1) reserve sources of energy (2) building stones of cell membranes (3) isolation and mechanical protection (4) hormones, vitamins → regulation of metabolic processes 11.2 Classification on the basis of their reaction with bases (alkali) (1) not saponifiable lipids  terpene- and carotenoid hydrocarbons  steroids (stigmasterine and sytosterine)  liposoluble vitamins (D, E, K, A)  prostaglandins (2) saponifiable lipids  simple lipids: neutral fats, plant oils, waxes  combined lipids: phosphoglycerides, sphyngolipids, glycolipids the special transformation of fatty acids results polyalkines (polyacetylenes) 201 Pharmacognosy 1 Saponifiable combined lipids (1) Phosphoglycerides  fundamental compound: L-α-phosphatidic acid (Figure 11.1) ester bond O α1 O CH2 O C R1 ß2 R2 C O C H O α3 CH2 O P OH acidic group OH acidic group ester bond Figure 11.1 L-α-phosphatidic acid  further alcohol components can bind to the phosphoric acid molecule part by ester bonds  if the alcohol is cholamine (ethanolamine = 1-amino-2-hydroxy-ethan, Figure 11.2), the forming phosphoglyceride is cephaline (phosphatidyl-ethanol-amine, Figure 11.3) 2 1 HO CH2 CH2 NH2 Figure 11.2 Cholamine O α1 O CH2 O C R1 ß2 R2 C O C H O basic group α3 CH2 O P O CH2 CH2 NH2 OH acidic group Figure 11.3 Cephaline 202  Synthesis, role and usage of lipids. Oils and waxes  if the alcohol component is choline (trimethyl-2(or β)-hydroxyethyl-ammonium- hydroxide, Figure 11.4), the forming phosphoglyceride is lecithin (Figure 11.5) [ ] + CH3 2 1 - HO CH2 CH2 N CH3 OH ß α CH3 Figure 11.4 Choline O α1 O CH2 O C R1 ß2 R2 C O C H O CH3 α3 + CH2 O P O CH2 CH2 N CH3 O CH3 - subst. phosphation Figure 11.5 Lecithin  cephaline and lecithin: the main building stones of membranes in animal and plant cells  cephaline occurs in the lipoid materials of the brain  the egg-yolk contains lecithin in high quantities  from soybean oil: soya-lecithin → it is used by food- and pharmaceutical industry as emulgent and emulsion stabilizing material  if the alcohol component is serine (α-amino-β-hydroxy-propionic acid, Figure 11.6), phosphatidyl-serine (Figure 11.7) will be formed ß α HO 3CH2 CH 2 COOH 1 NH2 Figure 11.6 Serine 203 Pharmacognosy 1 O O CH2 O C R1 R2 C O C H O acidic group CH2 O P O CH2 CH2 COOH OH NH2 basic group acidic group Figure 11.7 Phosphatidyl-serine  if the alcohol component is inositol (Figure 11.8), phosphatidyl-inositol (Figure 11.9) will be formed OH OH H OH H H OH H HO H H OH Figure 11.8 Inositol (hexa-hydroxy-cyclohexane) O O CH2 O C R1 OH OH R2 C O C H O H OH H H CH2 O P OH H O H OH H OH Figure 11.9 Phosphatidyl-inositol  phosphatidyl-serine and phosphatidyl-inositol: building blocks of cell membranes  phosphatidyl-inositol: important role in signal transformation, activated by hormone receptors → secondary messenger molecules will be formed (2) Sphyngolipids  occurrence: in the membrane of plant and animal cells; a fundamental compound is sphyngosine = unsaturated amino-diol with long (C18) carbon-chain (Figure 11.10) 204  Synthesis, role and usage of lipids. Oils and waxes 1 CH2 OH 2 H2N C H 3 4 5 18 H C CH CH (CH2)12 CH3 OH Figure 11.10 Sphyngosine (3) Glycolipids  sugar- or sugaralcohol-molecules connect to one of the OH groups of glycerol by ether-bond; the other two OH groups are esterified by long-chain fatty acids  mono- and digalactosyl-diglycerols: components of photosynthetic membranes Saponifiable simple lipids (1) Fats and fatty oils  esters of fatty acids formed with glycerol  solid state of matter (fat): the esterifying acid components are saturated  liquid state of matter (fatty oil): the esterifying acid components are unsaturated  place of biosynthesis: chloroplast, but the enzymes elongase and desaturase work in the cytoplasm  fatty acids are formed from acetyl-CoA and malonyl-CoA (Figure 11.11), and they are always even- numbered: O CO 2 O H3C C S CoA biotine HOOC H2C C S CoA acetyl-coensyme A (vitamin H) malonyl-coensyme A Figure 11.11 Acetyl-CoA and malonyl-CoA, precursors of fatty acids  malonyl-CoA can be formed also from oxalacetic acid; the reaction is catalysed by the enzyme peroxydase in the presence of Mn2+ ions; malonic acid is formed as intermedier (Figure 11.12) 205 Pharmacognosy 1 oxalyl-group COOH COOH O C O peroxydase CH2 HOOC H2C C S CoA CH2 2+ Mn COOH COOH oxalacetic acid malonic acid malonyl-coensyme A Figure 11.12 Synthesis of malonyl-CoA from oxalacetic acid  the most commonly occurring saturated fatty acids in plants are listed in Figure 11.13. CH3 – (CH2)10 – COOH – laurinic acid = dodecane acid CH3 – (CH2)12 – COOH – myrystinic acid = tetradecane acid CH3 – (CH2)14 – COOH – palmitinic acid = hexadecane acid CH3 – (CH2)16 – COOH – stearinic acid = octadecane acid CH3 – (CH2)18 – COOH – arachinic acid = eicosane acid Figure 11.13 Saturated fatty acids in plants  the most commonly occurring unsaturated fatty acids in plants are shown in Figure 11.14-17. H 10 9 H C C 18 1 H3C (H2C)7 (CH2)7 COOH Figure 11.14 Oleic acid (9-cis-octadecen acid) 18 13 12 11 10 9 1 H3C (CH2)4 CH CH CH2 CH CH (CH2)7 COOH Figure 11.15 Linolic acid (9,12-di-cis-octadeca-dien acid) 18 17 16 15 14 13 12 11 10 9 1 H3C CH2 CH CH CH2 CH CH CH2 CH CH (CH2)7 COOH Figure 11.16 α-linoleic acid (9,12,15-tri-cis-octadeca-trien acid) 206  Synthesis, role and usage of lipids. Oils and waxes 18 13 12 11 10 9 8 7 6 1 H3C (CH2)4 CH CH CH2 CH CH CH2 CH CH (CH2)4 COOH Figure 11.17 γ-linoleic acid (6,9,12-tri-cis-octadeca-trien acid)  Omega-3 fatty acids (ω-3 fatty acids or n-3 fatty acids) are polyunsaturated fatty acids with a double (C=C) bond at the third carbon atom (in n-3 position) from the end of the carbon chain. In ω-6 fatty acids this double bond can be found at the sixth carbon atom from the methyl group at the end of the carbon chain. Each double bond is in cis position both in ω-3 and ω-6 fatty acids.  Omega-3 fatty acids include α-linoleic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA); while omega-6 fatty acids contain linolic acid and arachidonic acid.  The human body is not able to synthesize the above compounds, therefore they are considered essential fatty acids and vitamin-like materials (vitamin F), and they should be taken with food.  Sources of ω-3 and ω-6 fatty acids include milk, fish, meat, eggs; various plant oils such as linseed oil, soy oil, rapeseed oil, olive oil, sunflower oil, corn (maize) oil, poppyseed oil; as well as oily seeds like nuts and peanuts. The optimal intake of ω-3 : ω-6 fatty acids would be 1:3 – 1:5.  The omega-3 and omega-6 fatty acids enhance quality of life and lower the risk of premature death. They function via cell membranes, in which they are anchored by phospholipid molecules. They have a beneficial effect on the cardiovascular system, lowering the level of triglycerides, as well as pulse rate, blood pressure and the risk of atherosclerosis. They are needed for the proper functioning of the immune system, and are valued also for their anti-inflammatory character.  DHA was proven essential to pre- and postnatal brain development, whereas EPA seems to be more influential on behaviour and mood. Both DHA and EPA generate neuroprotective metabolites (Kidd 2007).  Arachidonic acid is a polyunsaturated omega-6 fatty acid (Figure 11.18-19), which is the starting material of the biosynthesis of prostaglandins 20 15 14 13 12 11 10 9 8 7 6 5 1 H3C (CH2)4 CH CH CH2 CH CH CH2 CH CH CH2 CH CH (CH2)3 COOH Figure 11.18 Arachidonic acid (5,8,11,14-tetracis-eikosa-tetraen acid) 207 Pharmacognosy 1  its correct structure: 9 8 5 3 1 6 7 4 2 COOH 10 13 CH3 16 18 20 11 12 14 15 17 19 Figure 11.19 Arachidonic acid  one of the special and rarely occurring representatives of unsaturated fatty acids is ricinolic acid (Figure 11.20), which can be found in castor-oil bean (Ricini semen, source plant: Ricinus communis) 18 12 11 10 9 1 H3C (CH2)5 CH CH2 CH CH (CH2)7 COOH OH Figure 11.20 Ricinolic acid  80-90% of castor oil (Ricini oleum) is the glycerol-ester of ricinolic acid; the oil is known for its purgative action; it cannot contain ricinine (toxic pyridine-derivate, acid nitrile, Figure 11.21) and ricine (toxic protein) CH3 O C N N O CH3 Figure 11.21 Ricinine  fats can be stored as reserve nutrients mainly in seeds, from which the fats and fatty oils are recoverable by pressing for food and pharmaceutical purposes  fats and fatty oils are insoluble in water and in alcohols, but they are well-soluble in nonpolar solvents (hexane, benzene, ether, chloroform, ethylacetate)  under the influence of air and light they can be quickly oxydized, and become rancid → during this process organic peroxy-derivatives and free radicals are formed  storage: in a cool place, in tightly closed dark (brown) flask → protection from light 208 Chapter 14 General features of alkaloids 14.1 Definition of alkaloids According to the old definition, alkaloids are end products of plant metabolism, organic heterocyclic bases containing a N-atom, and characterised by marked physiological action. According to the new definition, alkaloids are cyclic organic compounds, which contain the N-atom in the state of negative oxydation grade; occurring in various living organisms in limited quantities. 14.2 Distribution of alkaloids in plants Alkaloids can be found predominantly in plants, but they occur also in animals (salamanders, frogs, insects, sea animals etc.), as well as in fungi and bacteria. Alkaloids are more typical in dicotyledonous plants, where a huge variety of alkaloids can be detected in substantial amounts; whereas only a few monocotyledonous families are characterised by the presence of alkaloids. Alkaloids frequently occur in the dicot plant families Annonaceae, Apocynaceae, Fumariaceae, Lauraceae, Loganiaceae, Magnoliaceae, Menispermaceae, Papaveraceae, Ranunculaceae, Rubiaceae, Rutaceae and Solanaceae; as well as in the monocot families Amaryllidaceae and Liliaceae. Several alkaloid-containing plants keep off certain herbivorous animals, which in turn accumulate these alkaloids in their bodies, frightening away predators. Alkaloids exert a strong physiological effect, being mostly toxic to animals and humans, already in low concentrations. Alkaloid-containing drugs typically have narrow therapeutic range, which means that there is little difference between therapeutic and toxic doses. The highest quantities of alkaloids are present in the organs of fully developed plants (root, leaf, flower, seed) or in their tissues (e.g. bark). In plants alkaloids occur in the form of their water soluble salts, or bind to phenolic acids in the vacuole of the cells. Alkaloids form salts mainly with organic acids, such as citric acid, malic acid, tartaric acid and benzoic acid. 14.3 Alkaloid biosynthesis Alkaloids are typically synthetized from amino acids. The most important starting materials of biosynthesis include ornithine, lysine, phenylalanine, tyrosine, tryptophan and hystidine. The biosynthesis of alkaloids is a genotypic property; precursors and end products can already be detected in cell- and tissue cultures. The most characteristic N-containing heterocycles of alkaloids include pyrrol, pyrrolidine, pyridine, piperidine, indole, quinolone and isoquinoline. Alkaloids can be classified according to their origin (derived from amino acids or other substances); whether they possess a heterocyclic ring with nitrogen, or contain the N- atom outside the ring; and according to the type of the N-containing heterocycle. 265 Pharmacognosy 1 14.4 Classification of alkaloids (1) Protoalkaloids (Nonheterocyclic alkaloids) Protoalkaloids (e.g. mescaline and ephedrine) do not have a heterocyclic ring with nitrogen, they contain the N-atom in the form of amino group. This group also includes pigments containing quaternary N-atom; e.g.: chromoalkaloids, betalains and their glycosides, betanines are present in Chenopodiaceae (goose-foot sp.). These compounds are pigments with antioxidant activity, not being toxic. Phenyl-ethylamin alkaloids Ephedrine (Figure 14.1) can be found in Ephedra vulgaris (ephedra). Its biological activities include increasing blood-pressure, stimulating the nervous system and dilating the bronchi. H H 1 2 3 C C CH3 OH NH CH3 Figure 14.1 Ephedrine – 1-Phenyl-2-methylamino-propanol-(1) The antibiotic Chloromycetin or chloramphenicol (Figure 14.2) produced by Streptomyces venezuelae has a similar structure to ephedrine, but it is not an alkaloid. H H 1 O2N C 2 C 3CH2OH OH NH C CHCl2 O dichloracetyl-group Figure 14.2 Chloramphenicol Mescaline (Figure 14.3) is a derivative of pyrogallol-trimethyl-ether or of ethylamine. It is not heterocyclic, therefore it can be classified into the group of protoalkaloids. Mescaline can be found in peyote (peyotl) or mescaline-cactus (Lophophora williamsii) and is responsible for causing hallucinations. 266  General features of alkaloids H3C O CH2 CH2 NH2 O H3C O CH3 Figure 14.3 Mescaline Colchicine (Figure 14.4), naturally found in autumn crocus or meadow saffron (Colchicum autumnale), has a tropolone nucleus with nitrogen in side-chain, containing an amid-group. Figure 14.4 Colchicine (2) True alkaloids Alkaloids containing pyridine or piperidine ring Nicotine (Figure 14.5) is one of the best-known examples of alkaloids with a pyridine ring. Nicotine is found in high amounts in various tobacco (Nicotiana) plants, e.g. Nicotiana tabacum. γ β β 2 N1 α α CH3 N Figure 14.5 Nicotine (1-methyl-2(β)-pyridil-pyrrolidine) Coniine (Figure 14.6), one of the few liquid alkaloids, is the main active compound of poison hemlock (Conium maculatum). Coniine is highly toxic, and extracts of poison 267 Pharmacognosy 1 hemlock were once used as a means of execution (e.g. Socrates was sentenced to death by drinking a hemlock-based liquid). 4 5 3 6 2 N1 CH2 CH2 CH3 H propyl-group Figure 14.6 Coniine (2-Propyl-pyperidine) Similar types of alkaloids include lobeline, which can be detected in various Lobelia sp. (lobelias, e.g. Lobelia inflata); and piperine, a pseudoalkaloid in Piper sp. (pepper, e.g. Piper nigrum - black pepper). Tropane alkaloids Tropane alkaloids are alkaloids with pyrrolidine- and piperidine condensated ring systems. Tropane alkaloids are a class of compounds that are derived from the amino acid ornithine, and contain a tropane ring in their chemical structure. Their basic structures include 8-azabicyclo-[3,2,1]-octane (Figure 14.7), nortropane (Figure 14.8) and tropane (Figure 14.9). Tropane alkaloids occur in several members of the nightshade (Solanaceae) family. 7 1 2 CH2 CH CH2 8 NH 3 CH 2 6 CH 5 CH 4 CH 2 2 Figure 14.7 8-azabicyclo-[3,2,1]-octane H 8 N 1 2 7 5 4 6 3 Figure 14.8 Nortropane 268  General features of alkaloids H3C 8 N 1 2 7 5 4 6 3 Figure 14.9 Tropane (N-methyl-8-azabicyclo-[3,2,1]-octane) H 8 N 1 2 7 5 4 H 6 3 OH Figure 14.10 Tropine (3-α-hydroxy-tropane) Atropine (Figure 14.11) is the ester of tropine (Figure 14.10) formed with racemic tropic-acid (α-phenyl-β-hydroxy-propionic acid). Atropine is the characteristic alkaloid of deadly nightshade or belladonna (Atropa belladonna). H 8 N 1 2 7 5 4 H 6 3 α β O C C CH2OH O H Tropic-acid (α-Phenyl-β- hydroxy-propionic acid) Figure 14.11 Atropine Hyosciamine is the ester of tropine with levorotatory (―)-tropic-acid (α-phenyl-β- hydroxy-propionic acid). Scopolamine (Figure 14.12) is the 6,7-epoxyde of atropine, exerting a particularly strong effect on the central nervous system; due to its narcotic action it causes a feeling of exhaustion. However, if overdosed, it will induce strong excitement. Scopolamine can be found in various representatives of the Solanaceae family, including henbane (Hyosciamus niger) (Figure 14.13) and Datura species (Figure 14.14-16). 269 Pharmacognosy 1 H3C 8 N 1 2 7 5 4 H 6 3 α β O C C CH2OH O H Figure 14.12 Scopolamine Figure 14.13 Hyosciamus niger (henbane) 270  General features of alkaloids Figure 14.14 Datura metel (angel’s [devil’s] trumpet) flower Figure 14.15 Datura metel (angel’s [devil’s] trumpet) fruit 271 Pharmacognosy 1 Figure 14.16 Datura stramonium (thorn apple) flower Ecgonine (Figure 14.17) is a tropane alkaloid found naturally in coca leaves. It is the 2- carboxy-derivative of pseudotropine (3-β-hydroxy-tropane). The ester of ecgonine with benzoic acid and methanol is called cocaine, which is the main active compound of the coca shrub (Erythroxylon coca). Cocaine has local anaesthetic effect, which can be attributed to the benzoylester group (Figure 14.18). 272  General features of alkaloids O H3C 8 N C OH + HO CH3 1 2 2 H2O 7 5 4 OH + HO C 6 3 O H Benzoic acid ß-hydroxy group Figure 14.17 Ecgonine O H3C 8 N C O CH3 1 2 7 5 4 O C 6 3 O H group responsible for the localanaesthetic effect Figure 14.18 Cocaine The well-known local anaesthetic drug, Novocain, is the ester of PABA (p-amino- bensoic-acid) with diethylamino-ethanol (Figure 14.19). O CH2 CH3 H2N C O CH2 CH2 N CH2 CH3 Figure 14.19 Novocain Quinoline alkaloids Quinine (Figure 14.20) is isolated from Cinchona bark, collected from various Cinchona species (C. succirubra, C. pubescens). Quinine is valued for its antimalarial and antipyretic property. 273 Pharmacognosy 1 CH CH2 * * quinuclidine HO * * CH N skeleton 5 4 H3CO 6 3 quinoline 7 N 2 skeleton 8 1 Figure 14.20 Quinine Opium alkaloids: alkaloids of poppy (Papaver somniferum) The six opium alkaloids which occur naturally in the largest amounts are morphine, narcotine, codeine, thebaine, papaverine and narceine. Of these, three are phenanthrene alkaloids (morphine, codeine and thebaine), all three used in the drug industry; thebaine usually for conversion into some derivative which is more useful medically. The first major alkaloid formed in the plant is thebaine, this is irreversibly converted to codeine and then to morphine. Morphine (Figure 14.21), the main alkaloid of opium, is the derivative of N-methyl-morphinane. Structurally, the molecule of morphine contains three units: 1. partially hydrogenated phenanthrene skeleton, 2. piperidine ring, 3. dihydrofuran ring. HO O N CH3 HO Figure 14.21 Morphine Opium and morphine are widely used to relive pain and are particularly valuable as hypnotics. Codeine, the monomethyl-ether of morphine, is a milder sedative than morphine and is useful as a cough suppressant. Thebaine, the 3,6-dimethoxy-derivative of 6,7,8,14- tetradehydro-N-methyl-morphinan, is the most poisonous opium alkaloid and is scarcely used medically. The illegal drug heroine is chemically diacetyl-morphine. Papaverine (Figure 14.22) is approved to treat spasms of the gastrointestinal tract, bile ducts and ureter and for use as a cerebral and coronary vasodilator. 274  General features of alkaloids 5 4 H3C O 6 3 isoquinoline N 2 skeleton H3C O 7 8 1 CH2 1’ 6’ 2’ veratrol structural element 5’ 3’ O CH3 (catechol-dimethylether); it is also 4’ present in isoquinoline skeleton O CH3 Figure 14.22 Papaverine (6,7,3’,4’-Tetramethoxy-1-benzyl-isoquinoline) Ergot-alkaloids Ergot alkaloids are produced by ergot, the sclerotium of a fungus, Claviceps purpurea. The pharmacologically active alkaloids of ergot are the derivatives of lysergic acid. Whole ergot preparations were traditionally used in labour to assist delivery and to reduce post-partum haemorrhage, today ergot has been replaced by the isolated alkaloids. Ergometrine produces an oxytocic effect, while ergotamine is employed as specific analgesic for the treatment of migraine. Lysergic acid diethylamide (LSD, Figure 14.23), prepared by partial synthesis from lysergic acid, is a potent psychotomimetic, used illegally as a recreational drug. H5C2 C2H5 N C CH3 O N partially hydrogenated * quinoline skeleton * N indole structure H Figure 14.23 LSD = Liserg-Säure-Diethyl-amide (German) Purine-alkaloids Purine alkaloids are N-methylated derivatives of xanthine (2,6-dihydroxy-purine) (Figure 14.24). 275 Pharmacognosy 1 O δ- OH H H 6 6 H 5 N 5 N 7 N1 7 1N 8 2 4 8 2 4 N HO N N O N 3 9 3 9 δ- H lactame form lactime form Figure 14.24 Xanthine (2,6 – dihydroxy – purine) Xanthine itself does not occur in nature, but the N-methyl-derivatives of the lactame form are naturally occurring compounds. Three well-known examples are caffeine (1,3,7-trimethyl-xanthine), theophylline (1,3-dimethylxanthine) and theobromine (3,7- dimethylxanthine). Beverages such as tea and coffee owe their stimulant properties to these substances. Caffeine (Figure 14.25) stimulates the central nervous system and has a weak diuretic action, whereas theobromine acts in the reverse way. Theophylline exerts a shorter, but more powerful diuretic action than caffeine; it relaxes involuntary muscles more effectively than either caffeine or theobromine. Caffeine occurs naturally in the seeds of various coffee shrubs (Coffea arabica, C. liberica, C. canephora), in cola tree (Cola nut) (Cola acuminata, C. nitida, C. verticillata), and in the leaves of tea shrubs (Camellia or Thea sinensis). O CH3 H3C 6 5 N 7 N1 2 4 8 O N N 3 9 CH3 Figure 14.25 Caffeine (1,3,7-trimethyl-xanthine) Theophylline (Figure 14.26) is the main alkaloid in the leaves of tea (Camellia sinensis). 276  General features of alkaloids O H 6 CH3 5 N N1 7 2 4 8 O N N 3 9 CH3 Figure 14.26 Theophylline (1,3-dimethyl-xanthine) Theobromine (Figure 14.27) is synthesized abundantly in the seeds (beans) of cacao tree (Theobroma cacao). O CH3 H 6 5 N N1 7 2 4 8 O N N 3 9 CH3 Figure 14.27 Theobromine (3,7-dimethyl-xanthine) (3) Pseuodalkaloids Pseudoalkaloids are compounds, whose biosynthesis starts not from amino acids, but other substances. This group includes terpenoid alkaloids such as aconitine, a diterpenoid alkaloid in Aconitum species; steroid-alkaloids of Solanum species; and coniine, having a piperidine skeleton in poison hemlock (Conium maculatum). Steroid-alkaloids Steroid alkaloids arise by the inclusion of basic nitrogen at some point in the steroid molecule. These compounds can be employed in the partial synthesis of steroidal drugs (including several hormones). Species so exploited are Solanum laciniatum and S. aviculare. Solanidine (Figure 14.28), the glycoside of which is solanine, occurs also in the leaves and seeds of potato (Solanum tuberosum). 277 Pharmacognosy 1 H3C 12 17 11 E F 13 N 1 C D 16 CH3 2 9 14 10 8 15 3 A B 7 HO 5 4 6 Figure 14.28 Solanidine Tomatidine (Figure 14.29), the glycoside of which is tomatine, occurs naturally in the leaves of tomato (Lycopersicon esculentum). H CH3 H3C N F 12 17 11 E 13 O 1 C D 16 2 9 14 10 8 15 3 A B 7 HO 4 5 6 Figure 14.29 Tomatidine 278