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[PHYTOCHEMISTRY 2 – LECTURE 9] Prof. Talal AbuRjai November 24, 2016 Alkaloids The Alkaloids are derived from amino acids pathway, during glycolysis process all the essential amino acids are produced and during shikimate pathway the three aromatic amino acid was produced, all these amino acids are considered as starting material for the production of Alkaloids -which are the most important source of the drugs- , the Alkaloids have nitrogenous compound came from the amino acid. The nitrogen has two free electrons which give the Alkaloids its characteristics. Mainly the compounds which have Nitrogen are considered as a base (Alkaloids word came from Alkali which are bases). Usually in Alkaloids the nitrogen is found in the heterocycle (not as free form), as they are considered one of the most important secondary metabolites, so we distinguish most of them by the suffix “-ine” at the end, e.g.: Caffeine, Morphine, Cocaine, Atropine, and Vincristine. Notice that the Oleandrin, Kampherol, Quercetin… doesn’t end with “-ine” so it’s not an Alkaloids. Be careful, even though the starting material of the Alkaloids biosynthesis is amino acids, but they are not proteins nor nucleic acid nor polypeptides. The naming of the Alkaloids is derived mainly from: 1- The genus part like: Atropa belladonna- Atropine. 2- The species like: Erythroxylum coca- Cocaine. 3- According to their mechanism of action like: Emetine which induces emesis. 4- Or according to the inventor name like: Pelletierine. Why does the plant produce the Alkaloids or any secondary metabolite? Due to defence mechanism, or as a waste, or as a reserve for them (the plant’s nitrogen before pollination is higher than during pollination, which means that the plant reutilize the nitrogen in the Alkaloids to obtain the necessary amount for the growth of the nitrogenous compounds). Another reason that these Alkaloids have been created by “Allah” as DRUGS and we have to search for them and isolate them, we know nothing about the sympathomimetic drugs without the discovery of them. 1|Page [PHYTOCHEMISTRY 2 – LECTURE 9] Prof. Talal AbuRjai November 24, 2016 Methods of identification and extraction of Alkaloids: 1- Precipitate when treated with heavy iodide metals by many agents such as Dragendorff’s reagent (its bisthmus iodide salt) when it’s reacted with the Alkaloids it will give an orange colour or with TLC technique to give orange colour too. 2- Mayer’s reaction which will give white ppt. How do the cocaine abusers take the cocaine- the method of administration? Snorting, smoking, I.V . To be administered by IV, it must be water soluble-in a salt form, and to be snorted or smoked it must be free base (able to burn)-not a salt. So I used both the salt and the non salt forms of cocaine, which is something very easy! Focus here please, My Alkaloids which have the Nitrogen, when we add to it HCl, and make distribution for this (in a separatory funnel), once in aqueous(water) and other in organic(chloroform), the Alkaloids will distribute and separate depending on the media we add; When we add an acid HCl to the Alkaloids (base); a salt will be formed, so I’ll find my Alkaloids in the aqueous phase. If we added a base NaOH to the aqueous phase, the salt will be expelled from it’s salt form and will become a free base dissolved mainly in the organic phase(Again, if we added an acid HCl to the organic phase (which is basic), a salt will be formed, so I’ll find my Alkaloids in the aqueous phase…) and so on. All these process are controlled by the pair of electrons in the Nitrogen. The method of extraction of any plant which contains Alkaloids is dependent on pH manipulation; in which we can move easily from salt to free base by changing the pH, low pH will go to salt, and high pH will go to base. Note that when we add the HCl to the Alkaloids, not only the Alkaloids will go to the aqueous phase but either any water soluble materials will also be moved and stay there. 2|Page [PHYTOCHEMISTRY 2 – LECTURE 9] Prof. Talal AbuRjai November 24, 2016 Then, with the addition of NaOH, the Alkaloids will go to the organic phase, and the dissolved water soluble materials are still in the aqueous. So this process is not only an Extraction method, rather than it’s for Purification of the compound. [Only in Alkaloids] Also when we add NaOH to the Alkaloids, not only the Alkaloids will go to the organic phase but either any organic soluble materials(wax, fats…) will also be moved and stay there. Then, with the addition of HCl, the Alkaloids will go alone to the aqueous phase, and the dissolved organic soluble materials are still in the organic. When we do extraction, first we start with a De fatting step: in order to get rid of any fatty material, it’s done by washing the powdered plant material with petroleum ether; which extracts non-polar fats and waxes, so the residue is polar material. Then we add to the residue an acid solution and it will go to the aqueous solution, if we then added a base (Ammonia) it will become free base. ****************************************************** Example of typical Alkaloids is the morphine; it has heterocycle which have Nitrogen. There are three main types of Alkaloids: 1-Mainly, True Alkaloids: it’s originally derived from Amino Acid and the nitrogen is in the heterocycle. 2- Proto Alkaloids: are derived from Amino Acid ,but don't have any heterocycle, like: colchicines. 3|Page [PHYTOCHEMISTRY 2 – LECTURE 9] Prof. Talal AbuRjai November 24, 2016 3-Psedo Alkaloids: have heterocycle but is not derived from Amino Acid, like the Terpenoids and Purines. We have many ways for the Classification of Alkaloids: Depending on the heterocycle (indole, pyrolidine,pyridine…). Or according to the Amino Acid(ornithine ,tyrosine, tryptophan) each type of this Amino Acid will give me different type of heterocycle . E.g.: tryptophan gives me indole (no way to get the indole heterocycle from any other Amino Acid rather than the tryptophan) . HETEROCYCLIC RING SYSTEMS: (Please memorize all of their structures) H N N H H H pyrrole piperidine pyrrolidine N N N N N tropane pyrrolizidine quinolizidine pyridine N N N C C N N N N N H quinoline isoquinoline indole N H dihydroindole N H benzylisoquinoline purine -phenylethylamine Another table showing the Amino Acid precursors which is found in all of these plants: 4|Page [PHYTOCHEMISTRY 2 – LECTURE 9] Prof. Talal AbuRjai November 24, 2016 We will study the Alkaloids according to the Amino Acid; these structures are for other types of Alkaloids: 1-Nicotine; the C5 comes usually from the ornithine Amino Acid. 2-Phenelethyl amine comes from tyrosine. 3-Indole comes from tryptophan (C6). 4-Lycopodine; the C5-N comes from Lysine. [We will study each of them in details one by one later on] In some cases, the Alkaloids start from Amino Acid as aliphatic but in most cases they cyclise, e.g.: ****The steps and the structures of the “biosynthesis” are not for memorizing, it’s just a demonstration for you to understand 1- Cocaine biosynthesis: Started from Ornithine Amino Acid, then cyclisation, then methylation by SAM (s-adenosylmethionine),… until reaching to the cocaine. Note that whenever you see SAM; so methylation happens [note the structure in the slides became CH3-NH]. 2- Morphine biosynthesis; came from tyrosine. 5|Page [PHYTOCHEMISTRY 2 – LECTURE 9] Prof. Talal AbuRjai November 24, 2016 Decarboxylation of tyrosine gives tyramine , hydroxylation of tyramine gives Dopamine. Then the tyrosine gives an intermediate, which work with dopamine to give us a compound named as “Norcoclaurine” with two SAM molecules , a methyl group displaces two of the H atoms of the OH group… with multi steps we reach Codeine compound, then finally the Morphine. *Notes: -All of these steps came from only one Amino Acid !! -the tyrosine resembles the phenylalanine structure but with an extra OH. 3- Physostigmine; it’s structure have iodole, so definitely it came from tryptophan. Tryptophan decarboxylatongives Tryptamine, then with multi steps it gives Physostigmine [which is a cholinergic drug used for glaucoma]. We have many Classification of Alkaloids Based on Amino Acid from which they were derived: (Biosynthetic Origin) 1. Ornithine Derived Alkaloids 2. Lysine Derived Alkaloids 3. Nicotinic Acid Derived Alkaloids 4. Tyrosine Derived Alkaloids 5. Tryptophan Derived Alkaloids 6. Anthranilic Acid Derived Alkaloids 7. Histidine Derived Alkaloids 8. Amination Reaction Derived Alkaloids 9. Purine Alkaloids 6|Page [PHYTOCHEMISTRY 2 – LECTURE 9] Prof. Talal AbuRjai November 24, 2016 Let’s start with the first group, and we will talk about part of it in this lecture: *** Ornithine Derived Alkaloids : 4 carbons: C4-N, by its decarboxylation it gives two major KEY Alkaloids:1- Solanaceae الفصيلة الباذنجية, e.g.; Hyoscyamine, Hyoscine, Atropine. 2- Coca: e.g.; Cocaine . * In other words, Atropine and Cocaine came from the same precursor, but from pharmacological point of view they are totally different; Atropine is an anticholinergic drug, while Cocaine is a CNS stimulant. * Both Solanaceae and Coca have Tropane nucleus; The Solanaceae Alkaloids: They are the key drugs for us, before them we weren’t able to know any of the sympathomimetic drugs ,parasympathomimetic drugs…. and so on. 1- Atropine/ Hyoscyamine Be careful that the plant itself doesn’t have Atropine, but the Atropine (which is optically inactive) is extracted from Hyoscyamine, so it’s the racemic mixture of hyoscyamine (both have the same exact structure). Tropic Acid Me NCH3 N H O Me O * Tropine base CH 2OH O N CH 2OH O O O OH (-)-Hyoscyamine Atropine The atropine is the ester of tropine base and tropic acid. Tropic Acid [Tropane+OH tropine] O NCH3 O 2- Hyoscin ; 6,7-Epoxy Atropine. Scopoline base O OH 7|Page [PHYTOCHEMISTRY 2 – LECTURE 9] Prof. Talal AbuRjai November 24, 2016 Separation of the Alkaloid mixtures: Alkaloids in the form of HCl salts 1- Alkalinize by NaHCO3 pH 7.5 2- Extract with Ether Ether Hyoscine free base (pKa = 6.2) Aqueous layer Atropine & Hyoscyamine HCl (pKa = 9.3) Convert to oxalate salts, Fractional Crystallization (Acetone/ Ether) Atropine Oxalate Crystals Hyoscyamine Oxalate Solution In order to separate the hyoscine from atropine, we use weak base NaHCO3 pH=7.5 , so in the aqueous layer we will find the strong hyoscyamine because its pKa is 9.3 , but hyoscine went out as a free base because its weaker than the hyoscyamine This is the meaning of pH Manipulation . *** Chemical tests: specific tests which give specific colours with the Solanaceae Alkaloids, to distinguish Atropine from hyoscine • Vitali-Morin’s test: Solid Alkaloids + fuming HNO3 → Evaporate to dryness, dissolve residue in acetone, add methanolic solution of KOH → Violet colour. • P-dimethylaminobenzaldehyde: Alkaloids + reagent in porcelain dish and heat on boiling water path → Intense Red Colour → Cherry Red after cooling. • Gerrard’s test: Alkaloids + 2% HgCl2 in 50% Ethanol → Red colour - Atropine Red after warming - Hyoscyamine White ppt - Hyoscine Structure Activity Relationship 8|Page [PHYTOCHEMISTRY 2 – LECTURE 9] Prof. Talal AbuRjai November 24, 2016 Cationic Head: Positively charged Quaternary ammonium compounds (the Alkaloids will not work with any modification of the nitrogen). Cyclic substitution: at least one cyclic substituent, aromatic is the most used, came from tropic acid. Esteratic Group: Necessary for effective binding. Pharmacological Activity: Anticholinergics: Inhibit the neurological signals transmitted by the endogenous neurotransmitter, acetylcholine. All the activity of Atropine depends on its mechanism of action and its similarity of Ach. Symptoms of poisoning includes: mouth dryness (first sign), dilated pupils, ataxia, urinary retention, hallucinations, convulsions, coma, and death. *Solanaceae Alkaloids compete with acetylcholine for the muscarinic site of the parasympathetic nervous systemthus preventing the passage of nerve impulses, and are classified as anticholinergics. *Acetylcholine binds to two types of receptor site, described as muscarinic or nicotinic, from the specific triggering of a response by the Amanita muscaria Alkaloids muscarine or the tobacco Alkaloids nicotine respectively. *From this picture: Look at the muscarine’s quaternary ammonium (which have N+) and the Ach’s quaternary ammonium,,, they are similar, so this is why the Muscarine is an agonist for Ach. The Atropine structure have quaternary ammonium (this charged structure is the one we find in our body), but because of the similarity and distance between the 9|Page [PHYTOCHEMISTRY 2 – LECTURE 9] Prof. Talal AbuRjai November 24, 2016 nitrogen , oxygen and bulky phenolic group, it will compete with Ach at the muscaranic receptors. [Not any quaternary ammonium can compete!] • The structural similarity between acetylcholine and muscarine can readily be appreciated, and hyoscyamine is able to occupy the same receptor at the active site. • As you know, the side-chain also plays a role in the strength between head and drugs, also in the binding, explaining the difference in activities between the two enantiomeric forms. • The agonist properties of hyoscyamine and hyoscine give rise to a number of useful effects, Including: 1. Anti spasmodic action on the gastrointestinal tract (Spasmopan)- mainly we use scopolamine (hyoscine) . 2. Anti secretory effect controlling salivary secretions during surgical operations. 3. Mydriasis to dilate the pupil of the eye for examination. The mydriatic use also has a very long history. Indeed, the specific name belladonna for deadly nightshade means ‘beautiful lady’ and refers to the practice of ladies at court who applied the juice of the fruit to the eyes, giving widely dilated pupils and a striking appearance, though at the expense of blurred vision through an inability to focus. • Agonist effect of Ach: Hyoscine has a depressant action on the central nervous system and finds particular use as a sedative to control motion sickness. • One of the side-effects from oral administration of tropane Alkaloids is dry mouth (the antisecretory effect) but this can be much reduced by transdermal administration. • In motion sickness treatment, hyoscine can be supplied via an impregnated patch worn behind the ear. • Hyoscine under its synonym scopolamine is also well known, especially in fiction, as a ‘truth drug’ used with criminals. 10 | P a g e [PHYTOCHEMISTRY 2 – LECTURE 9] Prof. Talal AbuRjai November 24, 2016 • This combination of sedation, lack of will, and amnesia was first employed in child-birth, giving what was termed ‘twilight sleep’, and may be compared with the mediaeval use of stramonium. • Atropine also has useful antidote action in cases of poisoning caused by cholinesterase inhibitors, e.g. physostigmine and neostigmine and organophosphate insecticides. *We have two types of poisoning: 1- Systemic method 2- Antidote method If I know that the person swallowed a specific known material, so I will give him an antidote for the known material. But unfortunately, mainly we don’t know what did the patient swallow, so we: a. Delay the absorption; by induce vomiting, by Charcoal, or by gastric lavage. b. Then we should give a systemic Atropine. (it’s the DOC) *In any war threats we give Atropine; because any chemical weapon will collapse the heart, so giving anticholinergic drug will prevent this collapsing. But excess giving of Atropine can kill the patient! *Last Note: Atropine intoxication causes hypertension and increased heart rate. < The End of the sheet > Be kind.. for everyone you meet is fighting a battle, you Know nothing about… Best of success… :) Written by: Qamar AbuHassan 11 | P a g e