1 ALKALOIDS One of the most important secondary metabolites from the pharmacological point view • structural diversity • therapeutic usage • number of structures Alkaloids are prevalently products of higher plants secondary metabolism. Lower number of alkaloids is produced by cyanobacteria, fungi and some amphibians. Designation „alkaloid“ was added to pharmacist W. Meissner (1819) and was used because of expression of their alkalic nature, although some of them are of neutral character (colchicine). ALKALOIDS Significant physiological effect of alkaloids was a stimulus for their early research and discoveries, in which lots of pharmacists have been involved. This research was leading to isolation and characterization of typical examples • morphine (Sertürner, 1806) • strychnine (Pelletier and Caventou, 1818) • quinine (Pelletier a Caventou 1820) • coniine (Giesecke, 1872) • nicotine (Posselt a Reimann, 1828) • atropine (Hesse, 1831) • codeine (Robiquet, 1832) • papaverine (Merck, 1848) Physiologic effect of alkaloids is often observed in their extreme toxicity. But, in many sublethal doses, alkaloids posses therapeutically advantageous pharmacological properties and are used as valuable therapeutics. 2 ALKALOIDS The plant usually produces more alkaloids (major and minor) • often the same basic structure (skeleton), different in various substituents • in such as group we can presume common precursors • Exceptions: for example Chinae cortex – bark of cinchona, here can be found two different types of alkaloids: with quinoline and indol core • alkaloids are mostly stored in tissues showing active growth, and then in sheaths of vascular bundles and in lactifers • alkaloids are often stored in form of hydrophilic salts with organic acids in vacuoles (for example tartric acid, citric acid, oxalate, malate, aconitic acid, chelidonic acid, meconic acid) • alkaloids can be also found as insoluble substances bound with tannins • The place of alkaloid storage is not always the same as place of biosynthesis. • For example: Nicotine is produced in roots and it is transported to leaves when it is accumulated. ALKALOIDS • The natural function of alkaloid production has not been recognized until present. • In toxicity or bitter taste of majority of alkaloids was observed the calculated defense of alkaloid plants against „predators“. • But this is contradictory to that fact that there is much bigger majority of plants which do not use protection from alkaloid content. • Some insect species are specialized on certain plant with alkaloid content (Atropa, Cinchona) and cause several damage to their cultures. • Selective toxicity of quinine is principle of its therapeutic usage. For human relatively not poisonous, for Protozoans toxic in very low dosage • In opposite: for human are toxic berries and leaves of Atropa, and are without problem consumed by pheasants and rabbits (which are to hyosciamine practically insusceptible • Hypothesis: alkaloids could mediate interspecies competition (allelopathy) or blastokolin effect similarly to coumarins • Biosynthesis of alkaloids is energy-demanding, needs highly specific enzymes. This gives evidence of certain role of these compounds, which is not clear until now. In respect to their structural diversity, also the functional diversity could be large. 3 ALKALOIDS • Bases of alkaloids are lipophilic, poorly soluble in water, mostly crystalline colorless compounds. • With acid form colorless crystalline salts (exceptions: yellow berberine, chelidonine and cotarnine) of bitter taste. • If optically active, than prevalently levorotary • Precipitation reactions important for their proof: • with solution of potassium bismuth iodide (Dragendorff) and solution of potassium mercury iodide (Mayer) produce precipitate, formation of poorly soluble salts with dihydrotetrachloroplatinic acid , picric acid and ammonium reineckate solution • Colored reactions • with concentrated mineral acids or their mixtures • Several alkaloids can be found in liquid form of base (nicotine, coniine, sparteine), easily can be isolated from raw plant material by using hydrodistillation. • Different solubility of alkaloid bases and their corresponding salts allows their relatively easy purification. ALKALOIDS Occurrence • alkaloids are present in 10-15 % of vascular plants • rarely found in lower plants (Claviceps – ergot alkaloids), gymnosperms (Coniferae – conifers), or monocotyledonous (Liliaceae) • occurre especially in some dicotyledonous plants, prevalently in families • Apocynaceae Papaveraceae • Solanaceae Ranunculaceae • Fabaceae Rubiaceae • Rutaceae Loganiaceae • rarely distributed in big or bigger group of plants. 4 ALKALOIDS • number of alkaloids isolated till present is around 8000 and constantly grows • in last tens of years increases the importance of partial and total synthesis, especially when there is need to obtain from practical reasons (biological assays, therapeutic usage) BASIC BUILDING BLOCKS OF ALKALOIDS Based on current knowledge it is possible to declare, that basic building blocks of alkaloids produced by plants are • aliphatic aminoacids • ornithine and lysine • aromatic aminoacids • phenylalanine, tyrosine, tryptophan and histidine • several alkaloids are produced • nicotinic acid and anthranilic acid, which are products of secondary metabolic processes • Several other aminoacids can be used for biosynthesis of alkaloids • glycine, cysteine, methionine, asparagic acid and proline. 5 BASIC BUILDING BLOCKS OF ALKALOIDS CH2 NH2 CH2 CH2 CHNH2 COOH CH2 CH2 CH2 CHNH2 COOH CH2 NH2 R CH2 CH NH2 COOH N COOH N H CH2 CH NH2 COOH N N H CH2 CH NH2 COOH NH2 COOH ornithine lysine R=H, phenylalanine R=OH, tyrosine nicotinic acid tryptophan histidine anthranilic acid Other compounds joining alkaloid biosynthesis CH2 NH2 COOH CH2 SH CH NH2 COOH CH NH2 COOH CH2 CH2 S CH3 CH NH2 COOH CH2 COOH N H COOH glycine cysteine methionine aspartic acid proline 6 ALKALOIDS • basic structure or part of structure of some alkaloids is terpenoid skeleton (hemi-, mono-, di- a triterpenes, such as steroids). • other group of alkaloids is produced via incorporation of nitrogen into polyketide skeleton, for example coniine. • many other widely distributed bases of plant origin, for example methyl-, trimethyl-, and further simple alkylamines with open chain, and also cholines and betaines are not classified as alkaloids, but as „biogenic amines“ • other heterocyclic nitrogenous bases, which do not belong to alkaloids are for example thiamine (regarding to its general spread in living organisms and also purine bases, for example caffeine, theobromine and theophyline and group of betalaines. ALKALOIDS CLASSIFICATION • true, derived from aminoacids, atom of nitrogen pasted in form of heterocycle (morphine, quinine, hyoscyamine, strychnine and others) • protoalkaloids, derived from aminoacids, atom of nitrogen is not part of heterocycle, can be simple basic amines (ephedrine, meskaline, cathinone, psilocybine) • pseudoalkaloids, posses the character of true alkaloids but are not derived from aminoacids • mostly of isoprenoid origin and are classified also as terpenoid alkaloids, for example diterpenoid alkaloid aconitine • or can be of acetate origin, for example coniine 7 BIOSYNTHESIS OF ALKALOIDS Most important reactions involved in alkaloid biosynthesis are: • formation of Schiff bases, when primary amino group condens with carbonyl group of aldehyde to produce substance with azomethine residue (–CH=N–) to form aldimine. • Mannich condensation, when compounds with active hydrogen condense with formaldehyde in presence of NH3, aliphatic primary or secondary amine and system C-C-N is produced • aldol type condensations between compounds containing imino groups A panel of other reaction is involved in alkaloid biosynthesis, such as oxidation, reduction, metathesis and others. For example in group of benzylisoquinoline alkaloids it is oxidative phenolic coupling, biosynthesis of big group of indole alkaloids involves connection of tryptophan skeleton with C9-10 fragment of terpenoid origin. BIOSYNTHESIS OF ALKALOIDS C O NH2 R N RC C OCH NH2 R NHRCC N + H CH CH2 NCHCH2 NCHCH NH CH CH2 + - H2O a) Formation of Schiff bases b) Mannich condenzation (after formation of Schiff base) + + - H2O c) Condenzation of aldol type compounds between substances with iminogroups 8 BIOSYNTHESIS OF ALKALOIDS C NCH NH C N CH NH N H N N N N C CH NH C C N CH2 N CH O N C O - 2H+ - 2e + 2H+ +2e Hydrogenation of imino group Formation of imino group via satturated amines dehydrogenation Dehydrogenation leading to formation of aromatic ring - 2H+ - 2e - 2H+ - 2e - 2H+ - 2e Isomerization of double bond of imino group to -unsaturated amino group carbinolamine amide O O Oxidation of C adjoining with N to produce carbinolamines or amides METABOLISM OF AMINOACIDS IN RELATION TO ALKALOID BIOSYNTHESIS N H + OPOCH2 CH3 CHO N H + OPOCH2 CH3 CH2 NH2 pyridoxal-5'-phosphate pyridoxamine-5'-phosphate CH2CH2 COHOOC COOH CH2 CH2 CHHOOC COOH NH2 CH2 CH2 COHOOC COOH CH2CH2CHHOOC COOH NH2 R CH NH2 COOH R COCOOH R CH NH2 COOH R COCOOH pyridoxalpyridoxamine -ketoglutaric acid glutamic acid   pyridoxal pyridoxamine 9 AMINES AND CORRESPONDING AMINOACIDS CH3NH2 CH2 NH2 COOH CH3CH2NH2 CH2CH2NH2 CH2CH2NH2 OH NNH CH2CH2NH2 N H CH2CH2NH2 CH NH2 COOHCH3 CH2 CH NH2 COOH CH2CH NH2 COOH OH NNH CH2CH NH2 NH2 N H CH2CH NH2 NH2 methylamine glycine ethylamine phenylethylamine tyramine alanine phenylalanine tyrosine histidine tryptophantryptamine histamine OXIDATIVE AND NON-OXIDATIVE TRANSFORMATION OF AMINOACID R CH NH2 COOH R C NH COOH RCO COOH NH3 CH2 R CH NH2 COOH CH R CH COOH NH3 FAD FAD-H2 H2O + Oxidative transformation of aminoacidi to -ketoacid depending on FAD Non-oxidative deamination of aromatic aminoacids deaminase + R = H, OH "ammonialyase" 10 OXIDATION OF AMINES RCH2 NH2 RCHO CH2 (CH2 ) CH2 NH2 NH2 (CH2 ) CH2 NH2 CHO monoaminooxidase n n diaminooxidase n = 2, putrescine n = 3, cadaverine ALKALOIDS DERIVED FROM ORNITHINE NH2 NH2 COOH NH NH2 COOH CH3 NH NH2 CH3 NH H CH3 O CH3 N + CH3 N + C1 -CO2 O OH +H ornithine N-methylputrescine 4-methylaminobutanal N-methyl-1-pyrroline N-methylpyrrolidine +2e 11 ALKALOIDS DERIVED FROM ORNITHINE CH3 N + CH3 CO CH COOH CH3 COCH COOHCH3 N CH3 COCH2 CH3 N CH2 COCH2 CH3 N CH3 N + CH3 NCH2 COCH2 CH3 N hygrine cuscohygrine TROPANE ALKALOIDS CH3 N + CH3 CO CH COOH N C C C O COOH CH3 CH3 N O -CO2 ketone of ekgonine tropinone 12 TROPANE ALKALOIDS CH3 N O CH3 COCH2 CH3 N CH3 N + CH2 O 1 76 5 CH3 N 4 2 3 OHH CH3 N H OH N 1 2 3 4 5 7 6 CH3 OH H N CH3 H OH -2H+ +2H+ +2e tropine (tropin-3-ol) pseudotropine (tropin-3-ol) = =   -2e hygrine tropinone REACTIONS OF TROPANE CORE N CH3 O H C O CH CH2 OH N CH3 O H C CH CH2OH O T O C O C CH2 N CH3 O T O C O C C H2 C O O T L-hyoscyamine D-hyoscyamine atropine (D, L-hyoscyamine) 6, 7-epoxidation dimerization scopolamine apoatropine belladonineT = tropyl residue 1 2 3 4 5 6 1 2 5 7 6 7 13 ACIDS ESTERIFIING TROPANOL C CH2 H OH COOH COOH OCH3 OCH3 CH CH COOH CH3 CH CH3 COOH CH3 CH CH3 CH2 COOH C C CH3 H CH3 COOH (-)-tropic acid veratric acid cinnamic acid isobutyric acid isovaleric acid tiglic acid EPOXIDATION OF TROPANE CORE CH3 N OH COCH CH2 OH C6 H5 CH3 N CH3 N OH CH3 N O 6,7 - dehydro- hyoscyamine 6 - hydroxy- hyoscyamine scopolamine hyoscyamine - 2H HOH - 2H 6 7 14 DERIVATIVES OF PSEUDOTROPINE N CH3 H O COC6 H5 COOCH3 cocaine derivative of 2-carboxy-tropan-3--ol 2 3- PYRROLIZIDINE ALKALOIDS CC CH2 O CO H CH3 CH2 HO CO CC H CH3 CH3 OH senecionine (retronecine + senecic acid, Asteraceae) 15 PYRROLIZIDINE ALKALOIDS NH2 NH2 COOH NH2 NH2 NH2 CHO CH2 N NH2CHO C CH2 NH2 O H NH CHO CHO N + C CHO N CHO N H CH2OH N 7 H CH2OHOH +-CO2 [O] -H2O [O] -NH3 -OH +2H ornithine putrescine 4-amino- butanal 4-amino- butanal dihydrosupinidine 7OH, heliotridine 7OH, retronecine +2H +2e +2e ALKALOIDS DERIVED FROM LYSINE SIMPLE PIPERIDINE DERIVATIVES NH2 NH2 HOOC NH2 NH2 NH CH3 CHO N + CH3 CO CH3 CH COOH N O CH3 N + CH3 CH2 O N CH3 O -CO2 +C1 [O] -OHlysine cadaverine N-methylaminopentanal N-methyl- -1-piperideine N-methylisopelletierine pseudopelletierine _ 16 ALKALOIDS DERIVED FROM LYSINE QUINOLIZIDINE ALKALOIDS NH2 NH2 COOH NH2 NH2 NH2 CHO NH2 CHO CHO NH CHO N + CHO CHO N CH2 N H OH N N H CH N N + CH2 N N N + N N N + N + N N N H H N NH O - -CO2 lysine cadaverine [O] + -NH3 -OH- aminoaldehyde dialdehyde quinolizidin-5-aldehyde lupinine lysine +2H+, +2e -OH+2H+, +2e - H+ - 2e 1. double bond migration 2. - H+, - 2e + H+, +2e A B C D Lupinus luteus +2H+, +2e sparteine cytisine COMPOSED PIPERIDINE ALKALOIDS NH2 NH2 CO2H NH2 O CO2H N CO2H O CH3 N OHH HH O CH3 N OHH HH lysine -H2O-NH3 -keto--aminokapronic acid 1-piperidin-2-karboxylic acid lobeline isolobinine phenylalanine C4 residue 17 ALKALOIDY DERIVED FROM PHENYLALANINE AND TYROSINE ALKALOIDS OF PHENYLETHYLAMINE TYPE CH2 CH NH2 COOH CH2 CH2NH2 CO CH2 NH2 CO CH NH2 H C H O CO CH NH2 CH2 OH CO CH NH2 CH3 CH CH NH2 CH3 OH C C NH CH3 CH3 H OH H CH C NH CH3 OH CH3 H phenylalanine [O]-CO2 phenylethylamine -aminoacetophenone HCOOH + 2H+ + 2e reduction +2H+ + (-)-ephedrine (+)-pseudoephedrine - H2O (formiate) +C1 +2e (methionine) +C1 ALKALOIDS DERIVED FROM TYROSINE OH CH2CH NH2 COOH OH CH2CH2NH2 OH CH2CH2NH2OH OH CH2CH2NH2OH OH O CH2CH2NH2OCH3 CH3O CH2CH2NH2O OH CH3 CH3 CH3O tyrosine [O]-CO2 +C1 tyramine a b c dopamine a [O] 3,4,5-trihydroxyphenylethylamine b mescaline c 3,4-dimethoxy-5-hydroxy- phenylethylamine 18 TETRAHYDROISOQUINOLINE ALKALOIDS N OH CH3 O CH2 O O O OHC CO2H CH3 CH3O O CO CH3 CH3 N CH3 O CH2 O O hydrastinine + opianic acid hydrastine [O] BENZYLISOQUINOLINE ALKALOIDS N1 N1 1-benzyltetrahydroisoquinoline 19 BIOSYNTHESIS OF PAPAVERINE NH2 OH CO2H NH2 OH CO2 HOH NH2 OH OH O OH CO2 HOH H C OH OH O NH OH OH OH OH NH O O O O CH3 CH3 CH3 CH3 N O O O O CH3 CH3 CH3 CH3 tyrosine [O] DOPA DOPAMINE -CO2 -CO2 transamination - H2O norlaudanosoline methylation norlaudanosine - 4H, - 4e papaverine 3,4-dihydroxyphenylpyruvate 3,4-dihydroxyphenylacetaldehyde BIOSYNTHESIS OF MORPHINAN ALKALOIDS NH OH OH OH OH NH2 OH COOH NH OH OH OH OH N O OH O OH CH3 H CH3 CH3 N O O O O CH3 H CH3 CH3 H N O O O O CH3 H CH3 CH3 N O O O CH3 H CH3 CH3 N OH O O CH3 H CH3 H N OH O OH CH3 H H a b c d e a b c d e + 3C1 (-)-reticuline -2H+ salutaridine -2H+ - H2O thebaine codeine morphine demethylation norlaudanosoline -2e -2e 20 BIOSYNTHESIS OF APORPHINE ALKALOIDS NH OH OH OH OH NH OH OH OH OH NH OH OH OH OH NH OH OH OH OH N CH3 norlaudanosoline bulbocapnine type glaucine type aporphine PROTOPINE AND BENZOPHENANTHRIDINE ALKALOIDS N O OH CH3 OH OCH3 CH3 N O OH OH OCH3 CH3 N 6 O O O O N O O O O O CH3 NH O O O O CHO NH O OCHO O O N O O O O OH CH3 reticuline a b -2H+ -2e sculerine a b stylopine a c A B C D +C1 [O] protopine a c b chelidonine b opening of B ring c c 21 PHTALIDTETRAISOQUINOLINE ALKALOIDS N O OH OH OCH3 CH3 NH O OH OH OCH3 CH3 COOH OH NH O OH OH OCH3 CH3 COOH OH OH NH O OH OCH3 CH3 OH OH OH HOOC N OCH3 OH CH3 O O OMe O O N O OCH3 COO O O CH3 CH3 sculerine a b [O] [O] a b a b [O] a -H2O methylation narcotine hydrastine + 2C1 - H2O FORMATION OF METHYLENDIOXY GROUP O OH CH3 O + O CH2 H O CH2 O -2H+ -2e 22 BISBENZYLIQUINOLINE ALKALOIDS N OCH3 CH3 H O N + O OH CH3 (CH3)2 H OHO tubocurarine ALKALOIDS OF AMARYLLIDACEAE FAMILY CH2 CH NH2 COOHOH CH2 CH NH2 HOOC CH2 CH2 NHCH2 CH2 OH OH OH N H OH OH OH NH OH OH OH NH OH OH OH O OH N OH CH3 OCH3 N OH OH OCH3 NH OH OH N OH OH O O OCH3 N OHO CH3O O O N OH CH3 OCH3 H tyrosine phenylalanine norbelladine lycorine pretazettine galanthamine 23 COLCHICINE ALKALOIDS CH2 CH NH2 HOOC OHCH2 CH NH2 COOH OCH3 OCH3 H NCH3 O O CH3 CH3 OH OCH3 OCH3 H NH CO O O CH3 CH3 CH3 O tyrosine a a aa a a c phenylalanine O-methylandrocymbine colchicine b b b b b b a aa a a a c A B C b b b b b b b b b b b b b b b COMPOSITE BENZYLISOQUINOLINE ALKALOIDS NH2 OH OH O O CH3OOC CHO Gl O O CH3 OOC Gl NH OH OH NH OH OH CHO CHOHOOC NH OH OH CHO CHO N OH OH CHO NH2 OH OH NH O O N O OCH3 CH3 CH3 R dopamine secologanine - H2O hydrolysis oxidation -CO2 acid dialdehyde -OH- reduction dopamine - H2O methylation R = CH3, emetine R = H, cephaeline 24 OTHER NITRIGENOUS COMPOUNDS DERIVED FROM PHENYLALANINE CH2 CH NH2 COOH CH CH2 COOH NH2 CH2 NH CO (CH2)4 CH CH CH (CH3)2OH OCH3 phenylalanine  -phenyl--aminopropionic acid  capsaicine 4-hydroxy-3-methoxybenzylamide of trans-8-methyl-6-nonenic acid ALKALOIDS DERIVED FROM TRYPTOPHAN „INDOL ALKALOIDS“ RICH AND PHARMACEUTICALLY IMPORTANT SOURCE OF THESE ALKALOIDS ARE MEMBERS OF FAMILIES: • APOCYNACEAE (Rauwolfia, Catharanthus, Aspidosperma) • RUBIACEAE (Cinchona) • LOGANIACEAEA (Strychnos) • CLAVICIPITACEAE (Claviceps) • EUPHORBIACEAE PARTNERSHIP OF HEMITERPENIC OR MONOTERPENIC UNIT 25 TRYPTOPHAN FORMATION O C CH2 OH COOH COOH NH2 COOH O CH2 OP OHOH NH COOH N H COOH CH C C H C H OH OH OH CH2 OP N H C H C H OH OH CH2 OP N H N H NH2 COOH CH2 CH NH2 OH COOH shikimic acid glutamine chorismic acid anthranilic acid 5-phosphoribosyl- -1-diphosphate N-(5'-phosphoribosyl)anthranilic acid carboxyphenylamino-deoxy- ribuloso-5-phosphate -CO2, - H2O L-serineL-serine indolyl-3-glycerolphosphate indol tryptophan SIMPLE INDOL ALKALOIDS INDOLYLALKYLAMINES NH2N H COOH H NN H (O) S + CH3 N H N H (O) CH3 NN CH3 NHCOO CH3 CH3 CH3 tryptophan [O] tryptamine N-methylation physostigmine methylcarbamination -CO2 26 SIMPLE INDOL ALKALOIDS INDOLYLALKYLAMINES CHCH2 NH2 N H COOH CH2 CH2 N(CH3 )2 N H CH2 CH2 N(CH3 )2 N H OH CH2 CH2 N(CH3 )2 N H O P O O OH tryptophan - CO2 N-dimethyltryptamine [O] psilocine psilocybine phosphorylation methylace COMPOSITE INDOL ALKALOIDS N H NH O OGl H H H H H3 COOC strictosidine 27 MONOTERPENIC PRECURSORS CH2 OH CH2OH OC CH3 O H H OH O Gl O H H O Gl CHO OC O O Gl O O CH3 CO - CH3 CO - geraniol iridoid skelet loganine secologanine gentiopicroside CLASSIFICATION ACCORDING TO MONOTERPENIC UNIT 1 2 3 4 7 5 6 1 2 3 4 7 5 6 1 2 3 4 7 5 6 1 2 3 4 7 5 6 1 2 3 4 7 5 6 Types of monoterpenic precursors yohimbane type (= corynantheine, = gentiopikrine, = loganine) x x x x x x x x x ibogaine type aspidospermine type a b x x a b x 28 EXAMPLES N N H H COOCH3 N N H COOCH3 H OAc OH CH3 OCH3 N N H O H3COOC H CH3 N N H H3 COOC H N H O N3 2015 CH3 H H CH3OOC H OOC O O O O CH3 CH3 CH3 CH3 N H N3 2015 18 19 H H CH3OOC H OH yohimbane monoterpenic unit tabersonine vindoline aspidospermine monoterpenic unit voacangine catharanthine ibogaine monoterpenic unit E reserpineyohimbine ALKALOIDS OF STRYCHNOS NUX VOMICA N N O H H HCO CH3 O H H H N O R R H N R = H, strychnine R = OCH3, brucine spermostrychnine 29 ALKALOIDS OF VINCA MINOR N CH3 OOC N OH H N C2H5OOC N H vincamine ethyl-apovincaminate BISINDOL ALKALOIDS CATHARANTHUS ROSEUS N H N CH2 OH CH3 COOCH3 N N COOCH3 H CH2 H OCOCH3 OH H R CH3 OCH3 catharanthine (velbanamine) (ibogaine type) vindoline (aspidospermine type) R = CH3, vincaleucoblastine R = CHO, leucocristine 30 BISINDOL ALKALOIDS STRYCHNOS TOXIFERA N N H CH2 H CHO H OH N + N CH2 H HOH CH3 CH N + N CH2 H H OH CH3 CH H H Cl Cl Wieland Gumlich aldehyde (caracurine VII) C-toxiferine MONOTERPENIC ALKALOIDS OF QUININE TYPE N H NH2 N H 5 N HOOC CHO N H 3 2 4 5 6 7 N OH O NH CHO CHO NH2 OH OCH3 OCH3 NH2 NH O CHO OH CHO 5 6 7 8 OCH3 N 1 4 3 C9 N H 2 OH HH H A B C [O] alkaloid of yohimbane type [O] [O] hydroxylation methylation -CO2 monoterpenic unit (yohimbane type) 1' 2' 3' 4' 5' 6' 7' 8' cinchonamine 1' 2' 3' 4' 5' 6' 7' 8' quinine tryptamine 31 HEMITERPENIC ALKALOIDS – ERGOT N H 4 NH2 COOH CH2 OPP N H NH2 COOH N H NH2 COOH NH NH CH2 H H CH3 OH N NH CH3 H H CH3 N NH CH2 H H CH3 OH N NH CH2 H H CH3 N NH CH2 H CH3 OH H 4 10 N 8 9 3 NH 2 H CH3 15 11 12 13 14 7 H HOOC N NH H CH3 H HOOC DMAPP tryptophan 4-dimethylallyltryptophan 4-isopenthenyltryptophan isolysergic acidlysergic acid lysergol lysergeneelymoclavine agroclavinechanoclavine -CO2 [O] methylation cyclisation ERGOT ALKALOIDS N NH H CH3 H OC NH CH CH3 CH3 N N NH H CH3 H OC NH CH3 C O O N O CH2 H H OH ergometrine ergotamine 32 ALKALOIDS DERIVED FROM HISTIDINE N H N NH2 COOH OO H H H5C2 CH2 NN CH3 histidine pilocarpine ALKALOIDS DERIVED FROM NICOTINIC ACID CH CH2 OH OH CH2OH CH NH2 COOH CH2 COOH N COOH COOH N COOH NH2 NH2 COOH NH2 NH2 NHNH2 CH3 C NH H CH3 O N + CH3 N COOH N + CH3 N CH3N COOH N CH3 N glycerol + asparagic acid quinolinic acid nicotinic acid a) b) - CO2 - CO2 + C1 [O] - OHornithine putrescine N-methylputrescine N-methylamino- butanal N-methyl-1- -pyrroline c) + - CO2 nicotine -2H+, -2e 33 ALKALOIDS OF RICINUS SPECIES N CONH2 N COOH N H O C N O CH3 nikotinic acid nicotinamide ricinine - H2O ARECA ALKALOIDS N C CH3 O OR N H C O OR R = CH3, arecoline R = H, arecaidine R = CH3, guvacoline R = H, guvacine 34 ALKALOIDS DERIVED FROM ANTHRANILIC ACID NH2 CO SCoA CH CO SCoA COOH N CO O SCoA H H 6 7 8 5 N 1 2 3 4 OH OH N OH OH 2 3 O1 6 7 8 5 N 4 O R R CH3 anthranilic acid malonyl-CoA ketoacid 2,4-dihydroxyquinoline 3-dimethylallyl-2,4-dihydroxyquinoline DMAPP cyclisation hydroxylation methylation R = H, dictamine R = OCH3, skimainine TERPENIC ALKALOIDS N O CH2 H O O CH3 O CH3 CH3 O C CH3 OH O OH O H N H OH OH OH COCH3 aconitine napeline 35 STEROIDAL ALKALOIDS 22 18 19 H H H H H 5-pregnane 5-cholestane C-nor-D-homo-5-cholestane STEROIDAL ALKALOIDS N OH NH O OH H CH3 H CO CCH3 OH CR H CH3 O N OH OH OHO OH OCOCH3 OCOCH3 O CO CH CH3 CH2CH3 solanidine tomatidine R = H, protoveratrine A R = OH, protoveratrine B 36 ALKALOIDS OF CONIUM MACULATUM CH3 COOH C O O O OH O C O OH O C O O H O NH2 N N H H 4 red. +2H+ L-alanine cyclisation 5-oxooctanic acid 5-oxooctanal 5-oxooctylamine -coniceine coniine enzyme +2e DERIVATIVES OF PURINE O CH2 OP OH OH OPP O CH2 OP OH OH NH2 CH2 C N H C H O O NH Rib O P N N NH2 Rib O P N N NH2 Rib O P O NH2 N N Rib O P N N OH N N Rib O P N N OH OH N N H NH N H O O N NN N O O CH3 CH3 CH3 asparagine asparagic acid PPOH glycine formiate glutamine CO2 aspartate formiate P-ribosylamin P-ribosyl-formyl- glycylamide P-ribosyl- aminoimidazol P-ribosyl-carboxyamido- aminoimidazol inosinmonophosphate (IMP) xanthinmonophosphate xanthine caffeine 1 2 3 4 5 6 7 8 9