9.0 Alkaloids RA Macahig FM Dayrit Introduction Among all the groups of natural products, alkaloids havethe most colorful history, having achieved the most fameand notoriety as drugs. Where alkaloids occur, they tend todominate the biological activity. Despite their relativelylimited distribution, the alkaloids probably have the mostsignificant impact in human history particularly inmedicine, social issues, economics and politics. In 1819, Carl Friedrich Meissner, a pioneering Germanpharmacist, coined the term alkaloid which referred toany natural product with the characteristic presence of thebasic nitrogen atom, excluding peptides. (Amides, however, are generally included.) 9.0 Alkaloids (Dayrit) Introduction Because many alkaloids can bepurified from crude extracts byacid-base extraction andrecrystallization, these were the firstnatural products to be purified,characterized and commercialized. The powerful and immediate effects ofalkaloids are thought to be due to thepresence of the cationizable N-atomwhich gives it lipid- and water-solublecharacteristics, and enables it to crossmembrane barriers more readily. 9.0 Alkaloids (Dayrit) A number of fungi produce toxic alkaloids, notably Claviceps purpurea.
Introduction Many of the earliest pure compounds to be used as drugsdeveloped were alkaloids: Cocaine: anaesthetic, from South American Erythroxylum coca Quinine: antimalarial, from the bark of the Cinchona tree Morphine: anaesthetic, from opium (Papaver somniferum) Emetine: for amoebiasis, from ipecac, the powdered roots (Cephaelis species) Strychnine: poison, from the seeds of Strychnos nux-vomica The alkaloids have a relatively limited distribution in naturecompared with the other natural product groups. Alkaloids wereoriginally thought to be uniquely plant products until the 1950swhen several alkaloids were isolated from bacteria, fungi andalgae, insects, and amphibians. A number of fungi produce toxic alkaloids, notably Clavicepspurpurea. 9.0 Alkaloids (Dayrit) Introduction In the plant kingdom, the angiosperms produce alkaloids:Apocynaceae, Papaveraceae, Rubiaceae, Ranunculaceae,Solanaceae, and Berberidaceae. Among the monocots, only theAmaryllidaeae and Liliaceae produce alkaloids. The discovery of many alkaloids areassociated with anthropologicalexplorations. Here, a Kams youth from aBrazilian tribe holds a blossom of Culebraborrachera which is a toxic psychoactiveplant. It contains tropane alkaloids thatcan induce a frightening state of psychoticdelirium, and ultimately stupor and death. (cms.herbalgram.org) 9.0 Alkaloids (Dayrit) Introduction Some animals, notably some soft corals and frogs producehighly bioactive alkaloids. In some cases, however, the alkaloidswere found to have been ingested in the diet by the organism andthen modified for use. Well-known examples are thepyrrolizidine alkaloids in caterpillars and moths. Alkaloids aremuch less common in mammals. Intermedine (I) and lycopsamine (II) ingested from the leaves of Mikania scandens monocrotaline (III) 9.0 Alkaloids (Dayrit) Introduction There are four major groups of nitrogen-containing organiccompounds in biological systems: the amino acids (peptidesand proteins), the nucleoside bases (DNA and RNA), theporphyrins; and the alkaloids. The first 3 groups are primarymetabolites; the alkaloids are secondary metabolites. Alkaloids are defined simply as nitrogen-containing naturalproducts. In terms of chemical structure, alkaloids can beclassified into the following: 2, 3, and 4 alkyl amines; andheterocyclic amines (e.g., pyrrolidine, pyridine, indole,quinoline, and isoquinoline). 9.0 Alkaloids (Dayrit) Caffeine, widely used central nervous system stimulant
Ajmaline, antiarrythmic thatfunctions by inhibition of glucoseuptake by heart tissuemitochondria Atropine (hyoscyamine),anticholinergic, antidote to nervegas poisoning Caffeine, widely used centralnervous system stimulant Camptothecin, potent anticanceragent Cocaine, topical anesthetic,potent central nervous systemstimulant, and adrenergic blockingagent, drug of abuse (Kutchan, The Plant Cell, 7, , July 1995) Codeine, relatively nonaddictiveanalgesic and antitussive; Coniine,first alkaloid to be synthesized,extremely toxic, causes paralysisof motor nerve endings, used inhomeopathy Emetine, orally active emetic,amoebicide; morphine, powerfulnarcotic analgesic, addictive drugof abuse; Nicotine, highly toxic,causes respiratory paralysis,horticultural insecticide Pilocarpine, peripheral stimulantof the parasympathetic system,used to treat glaucoma Quinine, traditional antimalarial,important in treating Plasmodiumfalcipafum strains that are resistantto other antimalarials Sanguinarine, antibacterialshowing antiplaque activity, usedin toothpastes and oral rinses
Scopolamine, powerful narcotic,used as a sedative for motionsickness Strychnine, violent tetanicpoison, rat poison, used inhomeopathy; Taxol, antitumoragent (+)-Tubocurarine,nondepolarizing muscle relaxantproducing paralysis, adjuvant toanesthesia Vinblastine, antineoplastic that isused to treat Hodgkins diseaseand other lymphomas. Survey of some well-known alkaloids.
9.0 Alkaloids (Dayrit) 9.0 Alkaloids (Dayrit) Merck, one of the worlds largest pharmaceutical companies, made its initial fortune from cocaine, morphine, and codeine. 9.0 Alkaloids (Dayrit) 9.0 Alkaloids (Dayrit) Introduction Many alkaloids are toxic in thecytoplasm, even in the plants that producethem.Their accumulation, therefore,requires a well-regulated andcompartmentalized system. The mostcommon storage organ is the vacuole. In some plants, alkaloids are synthesizedin one part of the plant and then aretransported to another part for storage. Intobacco, for example, alkaloids (e.g.,nicotine) are synthesized in the roots andare then transported via the xylem to theleaves where they are accumulated. 9.0 Alkaloids (Dayrit) Many alkaloids are mixed metabolites.
Introduction Among the natural products groups, the biochemistry of alkaloids is the most complex. Many alkaloids are mixed metabolites. Enzymes involved in alkaloid biosynthesis are associated with diverse subcellular compartments including the cytosol, vacuole, tonoplast membrane, endoplasmic reticulum, chloroplast stroma, thylakoid membranes, and perhaps unique biosynthetic or transport vesicles. Localization studies have shown that sequential alkaloid biosynthetic enzymes can also occur in distinct cell types, suggesting the intercellular transport of pathway intermediates. (PJ Facchini, Ann. Rev. of Plant Physiol. and Plant Mol. Bio., Vol. 52: 29-66) 9.0 Alkaloids (Dayrit) Overview Despite the wide variety and complex structures observedamong the alkaloids, most of the compounds from this groupare formed from only a handful of starting materials.Thenitrogen and the initial carbon skeleton are derived from thefollowing: A. aliphatic amino acids: lysine, glutamic acid, and ornithine; B. aromatic amino acids: phenylalanine, tyrosine, andtryptophan; and C. others: secologanin: terpene-derived C10 unit. 9.0 Alkaloids (Dayrit) 9.0 Alkaloids (Dayrit) Overview The major reactions in alkaloid biosynthesis are common biosynthetic mechanisms: Oxidation: epoxidation, aromatic hydroxylation, etc. Oxidation: dehydrogenation (-2[H]); in the case of thealkaloids, this includes the conversion of amine imine. Reduction: hydrogenation (+2[H]); in the case of thealkaloids, this includes the conversion of imine amine. Phenolic dimerization by radical coupling. Decarboxylation, in particular in the conversion of aminoacid to amine. 9.0 Alkaloids (Dayrit) Reactions which are particular to alkaloid biosynthesis.
9.0 Alkaloids (Dayrit) Reactions which are particular to alkaloid biosynthesis.
tryptophan 9.0 Alkaloids (Dayrit) Aliphatic alkaloids The aliphatic alkaloids can be classified into three main types, depending on its biogenesis: the amino acid ornithine the amino acid lysine the polyketide pathway with the nitrogen atom beingintroduced in a late step. 9.0 Alkaloids (Dayrit) Aliphatic alkaloids from ornithine
Glutamic is transformed into ornithine by addition of another CH2 unit. Therefore, in a way, glutamic acid is the original precursor and ornithine is the immediate precursor. Decarboxylation and loss of one nitrogen leads to formation of the pyrrolidine ring. There are three main types: pyrrolidine (monocyclic), tropane (bicyclic) and pyrrolizidine (fused). 9.0 Alkaloids (Dayrit) Ornithine comes from glutamic acid.
9.0 Alkaloids (Dayrit) Pyrrolidine alkaloids from ornithine
Pyrrolidine alkaloids from ornithine. Labeling studies show that although pyrrolidine itself is symmetric, the biosynthesis is regiospecific.This suggests that once ornithine is held by the enzyme, biosynthesis proceeds without release of any of the intermediates. 9.0 Alkaloids (Dayrit) Tropane alkaloids from ornithine
Tropane alkaloids from ornithine. Consistent with what has been observed, labeling shows that the biosynthesis is regiospecific. 9.0 Alkaloids (Dayrit) Pyrrolizidine alkaloids from ornithine
Pyrrolizidine alkaloids from ornithine. Pyrrolizidine alkaloids are common in the butterflies Senecio and Crotolaria species. 9.0 Alkaloids (Dayrit) Pyrrolizidine alkaloids are converted into aphrodisiac substances which the male butterflies store in its wing hair pencils. These compounds also protect the plants against feeding by mammals because these compounds are converted in the liver into toxic and carcinogenic compounds. 9.0 Alkaloids (Dayrit) Polyhydroxylated cycloalkyl alkaloids found in the leaves, flowers and seeds of Ipomoea carnea (Convolvulaceae) cause natural intoxication of livestock by inhibiting key digestive enzymes. Alkaloids 1 and 2 are powerful inhibitors of lysosomal a-mannosidase; 3, 4, and 6 showed potent inhibitory activity toward rat lysosomal b-glucosidase; and alkaloid 5 was a moderate inhibitor of a- and b-mannosidases. (Haraguchi, et al., J. Agric. Food Chem. 2003, 51, ) 9.0 Alkaloids (Dayrit) Aliphatic alkaloids from lysine
Lysine is modified following an analogous pathway to ornithine. There are many similarities between the ornithine-derived and lysine-derived alkaloids. The alkaloids produced are the 6-membered piperidine, homotropane and quinolizidine structures. 9.0 Alkaloids (Dayrit) Alkaloids from lysine. 1-Piperidine and pellieterine are key intermediates to this group of alkaloids. Quinolizidine alkaloids have the characteristic fused 6,6-bicyclic group and are derived from lysine.Lupinine is a dimeric metabolite while sparteine is trimeric. 9.0 Alkaloids (Dayrit) Aliphatic alkaloids from polyketides
Some aliphatic alkaloids are derived from the polyketide pathway.The biogenesis of these alkaloids can be determined by studies using labeled acetyl CoA. 9.0 Alkaloids (Dayrit) Polyketide-derived piperidine alkaloids
Polyketide-derived piperidine alkaloids. Some alkaloids having the piperidine-type structure are not derived from lysine. 9.0 Alkaloids (Dayrit) Alkaloids from phenylalanine and tyrosine
The aromatic alkaloids derived from phenylalanine and tyrosine form a diverse and often structurally complex group of metabolites. By tradition, these alkaloids are identified according to plant family, of which the best known are: Papaveraceae, Morphinan, Erythria, Berberidaceae, Amaryllidaceae. Structurally and biosynthetically, there are six main groupings: 1. Phenylethylamines 2. Phenylethylamine + alkyl aldehyde or ketone 3. Phenylethylamine + benzaldehyde (C6-C1) 4. Phenylethylamine + C6-C2 5. Phenylethylamine + C6-C3 6. Phenylethylamine + secologanin 9.0 Alkaloids (Dayrit) Alkaloids from phenylalanine/tyrosine
Alkaloids from phenylalanine/tyrosine. Structurally, there are six main types. 9.0 Alkaloids (Dayrit) Alkaloids from phenylalanine/tyrosine
Alkaloids from phenylalanine/tyrosine. Structurally, there are six main types. 9.0 Alkaloids (Dayrit) Alkaloids from phenylalanine/ tyrosine: Simple phenylethylamines
Alkaloids fromphenylalanine/tyrosine: Simplephenylethylamines.Biosynthesis of thisgroup involvessimply loss of thecarboxylic acidcarbon. Someimportant membersof this group are thehallucinogeniccompound mescalineand the drugepinephrine. 9.0 Alkaloids (Dayrit) Alkaloids from phenylalanine/ tyrosine: Condensation of phenylethylamine with alkyl aldehydes or ketones.This group of alkaloids is formed via a Pictet-Springler or Bischler-Napieralski condensation. The alkaloids shown here are found in the hallucinogenic peyote cactus plant. 9.0 Alkaloids (Dayrit) Alkaloids from phenylalanine / tyrosine + Ar-C1
Alkaloids from phenylalanine / tyrosine + Ar-C1. Phenylethylaminecouples with Ar-C1 (benzaldehyde) via a Pictet-Springler condensation.This is followed by oxidation of the phenol. 9.0 Alkaloids (Dayrit) Alkaloids from phenylalanine / tyrosine + Ar-C1
Alkaloids fromphenylalanine /tyrosine + Ar-C1.The two oxidizedrings can couplevia differentfoldingconformationsleading topara- para, para-orthoor ortho-paracoupling. 9.0 Alkaloids (Dayrit) Alkaloids from phenylalanine / tyrosine + Ar-C1
Alkaloids fromphenylalanine / tyrosine +Ar-C1. (overview) Couplingof the radical intermediatesin different foldingconformations leads topara- para, para-ortho and ortho- para couplings. This is atheme that is repeated forother alkaloids with similarstructural characteristics. The alkaloid families thatcomprise this group includethe Amaryllidaceae andMesembrine species. 9.0 Alkaloids (Dayrit) Alkaloids from phenylalanine / tyrosine + Ar-C2
Alkaloids from phenylalanine / tyrosine + Ar-C2. Condensation of phenylethylamine with an Ar-C2 group, such as phenylpyruvic acid, yields the benzyltetrahydro isoquinoline structure. These alkaloids are characteristic of the Papaveraceae. Reticuline is a key intermediate of this group. 9.0 Alkaloids (Dayrit) Alkaloids from phenylalanine / tyrosine + Ar-C2
Alkaloids from phenylalanine / tyrosine + Ar-C2. The Aprophine alkaloids are produced by oxidation of reticuline. Various isomeric radical intermediates are formed. Alkaloids from phenylalanine / tyrosine + Ar-C2
Alkaloids from phenylalanine / tyrosine + Ar-C2. Four regiochemical couplings are observed: ortho-ortho, ortho-para, para-ortho, and para-para. Alkaloids from phenylalanine / tyrosine + Ar-C2
Alkaloids from phenylalanine / tyrosine + Ar-C2. The Aprophine alkaloids are produced by radical coupling of the benzylisoquinoline system of reticuline. Schematic presentation of the biosynthesis of codeine, laudanine, and (S)-scoulerine from (S)-norcoclaurine in the opium poppy. The cellular localizations of the enzymes indicated have been determined experimentally. (Jorgensen et al., Curr Opinion in Plant Biol 2005, 8:280291) 9.0 Alkaloids (Dayrit) Alkaloids from phenylalanine/tyrosine + Ar-C2
Alkaloids from phenylalanine/tyrosine + Ar-C2. The morphine alkaloids are produced from thebaine. Note that the level of methylation decreases towards the end of the biosynthetic sequence from thebaine codeine morphine. 9.0 Alkaloids (Dayrit) Alkaloids from phenylalanine / tyrosine + Ar-C2
Alkaloids fromphenylalanine /tyrosine + Ar-C2. Coupling using theN-methyl group. 9.0 Alkaloids (Dayrit) Alkaloids from phenylalanine / tyrosine + Ar-C3
Alkaloids fromphenylalanine /tyrosine + Ar-C3. This group ishomologous to thebenzyltetrahydro- isoquinolines(dopamine + C2).The biosyntheticsteps are assumed tobe similar. 9.0 Alkaloids (Dayrit) Alkaloids from phenylalanine / tyrosine + secologanin
Alkaloids from phenylalanine / tyrosine + secologanin. Secologanin is an iridoid belonging to the monoterpene group. Condensation of phenylethylamine with secologanin leads to a group of mixed metabolites. 9.0 Alkaloids (Dayrit) Alkaloids from phenylalanine / tyrosine + secologanin.
9.0 Alkaloids (Dayrit) Alkaloids from tryptophan: the indole alkaloids
The indole alkaloids are derived from tryptophan and arefound in both plants and microorganisms.They comprise thesingle largest group of alkaloids, accounting for almost one- fourth of all alkaloids isolated.Many of the members of thisgroup are biologically active and some possess very importantmedicinal properties. Among the best known sources are:Catharanthus, Curare, Rauwolfia, and Vinca plant species andthe ergot fungi. The indole alkaloids can be classified as follows: 1. Simple indole alkylamines 2. Simple -carbolines 3. Tryptophan + C5 4. Tryptamine + secologanin 9.0 Alkaloids (Dayrit) Indole alkaloids. Structural groups..
9.0 Alkaloids (Dayrit) Indole alkaloids. Structural groups..
9.0 Alkaloids (Dayrit) Simple indole alkaloids
Simple indole alkaloids. Decarboxylation of tryptophan yieldsserotonin, a neurotransmitter; methylation yields bufotenin, ahallucinogenic compound isolated from toadstools. 9.0 Alkaloids (Dayrit) Simple indole alkaloids
Simple indole alkaloids. Bishler-Napieralski condensation oftryptamine with simple alkyl groups yields the b-carbolines. Theharmanes are CNS stimulants. 9.0 Alkaloids (Dayrit) Ergot alkaloids. Condensation with C5 DMAPP
Ergot alkaloids. Condensation with C5 DMAPP. This group ofmetabolites is produced by the fungus Claviceps purpurea and includesthe hallucinogen lysergic acid. 9.0 Alkaloids (Dayrit) Indole alkaloids: tryptophan + secologanin
Indolealkaloids:tryptophan +secologanin.More than 1,100compoundsfrom this groupof mixedmetaboliteshave beenidentified.Theyoccurpredominantlyin Loganiaciae,Apocynaceae,and Rubiaceae.This figuregives the majorskeletal types. Indole alkaloids: tryptophan + secologanin
Indole alkaloids:tryptophan +secologanin. TheVincosan alkaloidsyield straight- forwardincorporation ofsecologanin. Loss of glucoseenables moreextensivestructuralchanges to occur.The glycoside ishypothesized toact as aprotecting group. Many alkaloidsare formed fromstrictosidine. Indole alkaloids: tryptophan + secologanin
Indolealkaloids:tryptophan +secologanin.Loss of glucoseinitiates thechemicaltransformation.Reserpine is atranquilizer andsedative isolatedfrom the roots ofRauwolfiaserpentina. 9.0 Alkaloids (Dayrit) Indole alkaloids: tryptophan + secologanin
Indolealkaloids:tryptophan +secologanin.Strychnine(from theseeds ofStrychnosnux-vomica)was used inmedicine as aCNSstimulant. Athigher doses,it was used aspoison forhumans and rodents. 9.0 Alkaloids (Dayrit) Indole alkaloids: tryptophan + secologanin
Indole alkaloids:tryptophan +secologanin. Thecinchona alkaloids(from the bark ofCinchona spp.)involve extensiverearrangement.Quin ine was used as anantimalarial drug. 9.0 Alkaloids (Dayrit) Alkaloids from other pathways
Other groups of alkaloids arise from various pathways. A number of them are metabolites from other biogenetic groups, but are classified as alkaloids simply because they have an amine functionality. This mixed group of alkaloids includes: the quinoline alkaloids (from anthranilic acid, shikimates) terpene alkaloids nicotine alkaloids xanthine alkaloids. 9.0 Alkaloids (Dayrit) Quinolinealkaloids.Except for thecinchonaalkaloids, thequinolinealkaloids aremixedmetabolitesbeing derivedfrom anthranilicacid, whichbelongs to theshikimategroup, andpolyketides. 9.0 Alkaloids (Dayrit) The terpene alkaloids. The sequence of addition of nitrogen into theterpene is suggested to be: R-CH2-OH R-CHO R-CH2-NH2 (whereR is a terpene metabolite). 9.0 Alkaloids (Dayrit) The terpene alkaloids. Steroidal alkaloids are formed from completedsteroids. Solasidine and tomatidine occur in potatoes and tomatoes,respectively. 9.0 Alkaloids (Dayrit) Nicotine alkaloids Tobacco (Nicotiana tabacum) is another plant from which a large commercial sector has formed. It is a practice that originated from the American Indians. Nicotiana comes from the name of Jean Nicot, a French diplomat who probably introduced the habit to Europe; tabacum comes from the Indian name for the pipe that was used to smoke it. Nicotine, the chief constituent of N. tabacum, is formed from nicotinic acid. 9.0 Alkaloids (Dayrit) Nicotinic acid.In plants, nicotinic acid is biosynthesized fromtryptophan.
9.0 Alkaloids (Dayrit) Nicotinic acid. In bacteria, nicotinic acid is biosynthesized fromglyceraldehyde + aspartic acid.
9.0 Alkaloids (Dayrit) Nicotinic acid. Mimosine, which resembles phenylalanine, is a toxinfound in grass which is used as animal feed. 9.0 Alkaloids (Dayrit) Nicotinic acid. Biosynthesis of nicotine
Nicotinic acid. Biosynthesis of nicotine. Nicotine is a ganglioniccholinergic-receptor agonist. Chronic ingestion of nicotine often results inpsychological addiction and physical dependence. 9.0 Alkaloids (Dayrit) Xanthine alkaloids are important components of a number of culturally, historically and commercially important plants, in particular coffee, cola (kolanut), tea and cacao (chocolate). The active constituents are methyl xanthines, the best known of which are: caffeine, which occurs in coffee (Coffea arabica); theophylline, which is found in tea (Camellia sinensis); and theobromine, which is found in cacao (Theobroma cacao). Note that theophylline and theobromine are isomers. 9.0 Alkaloids (Dayrit) The methylxanthines (caffeine, theophylline and theobromine) are CNS stimulants and smooth muscle relaxants. Research into their physiological mechanisms are continuing research topics. The biogenetic origin of xanthine is complex and arises from various primary metabolites. Carbons 2 and 8 come from an active 1-carbon fragment (e.g, formate, methyl methionine, etc.); carbon 6 comes form CO2; and carbon atoms 4 and 5 and nitrogen 7 come from glycine. The nitrogen atom at 1 comes from aspartic acid, while those at 3 and 9 come from the amide nitrogen of glutamine. 9.0 Alkaloids (Dayrit) Summary Structurally, the alkaloids are a very diverse group; the onlyunifying characteristic is the presence of an amine. The origin of the carbons in alkaloids include the aliphaticamino acids (ornithine and lysine), aromatic amino acids(phenylalanine, tyrosine and tryptophan, which arises fromshikimic acid via phenylpropanoids), anthranilic acid (fromshikimic acid), polyketides, and terpenes. 9.0 Alkaloids (Dayrit) Tropane alkaloids (e.g., Atropa) Pyrrolizidine alkaloids
Summary The alkaloids are divided into characteristic structures, which are also usually associated with specific plants or organisms. Among the best known groups of alkaloids are: Tropane alkaloids (e.g., Atropa) Pyrrolizidine alkaloids Phenylethylamines: (e.g., Ephedra) Phenylalanine + C6-C2: (e.g., Aprophine, Papaver andErythrina) Tryptophan + DMAPP: (e.g., ergot alkaloids) Tryptophan + secologanin: (Vinca, Catharanthus, Strychnos,Cinchona) Steroidal alkaloids Nicotinic acid: (Nicotiana) Xanthine alkaloids: (Coffea, Camelia, Theobroma) 9.0 Alkaloids (Dayrit) Overview of alkaloid biosynthesis
Overview of alkaloid biosynthesis. The biogenetic location of thexanthines is diverse and not included here. 9.0 Alkaloids (Dayrit)