9.0 alkaloids

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9.0 Alkaloids 9.0 Alkaloids HO O NCH 3 HO H H Morphine N N H CH 3 O HO H Quinine RA Macahig FM Dayrit

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Page 1: 9.0 Alkaloids

9.0 Alkaloids9.0 Alkaloids

HO

O

NCH3

HO

HH

Morphine N

N

H

CH3O

HO

H

Quinine

RA Macahig

FM Dayrit

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9.0 Alkaloids (Dayrit) 2

• Among all the groups of natural products, alkaloids have the most colorful history, having achieved the most fame and notoriety as drugs. Where alkaloids occur, they tend to dominate the biological activity. Despite their relatively limited distribution, the alkaloids probably have the most significant impact in human history particularly in medicine, social issues, economics and politics.

• In 1819, Carl Friedrich Meissner, a pioneering German pharmacist, coined the term “alkaloid” which referred to any natural product with the characteristic presence of the basic nitrogen atom, excluding peptides. (Amides, however, are generally included.)

Introduction

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9.0 Alkaloids (Dayrit) 3

• Because many alkaloids can be purified from crude extracts by acid-base extraction and recrystallization, these were the first natural products to be purified, characterized and commercialized.

Introduction

• The powerful and immediate effects of alkaloids are thought to be due to the presence of the cationizable N-atom which gives it lipid- and water-soluble characteristics, and enables it to cross membrane barriers more readily.

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9.0 Alkaloids (Dayrit) 4

• The alkaloids have a relatively limited distribution in nature compared with the other natural product groups. Alkaloids were originally thought to be uniquely plant products until the 1950s when several alkaloids were isolated from bacteria, fungi and algae, insects, and amphibians.

Introduction

• A number of fungi produce toxic alkaloids, notably Claviceps purpurea.

• Many of the earliest pure compounds to be used as drugs developed 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

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9.0 Alkaloids (Dayrit) 5

Introduction

• In the plant kingdom, the angiosperms produce alkaloids: Apocynaceae, Papaveraceae, Rubiaceae, Ranunculaceae, Solanaceae, and Berberidaceae. Among the monocots, only the Amaryllidaeae and Liliaceae produce alkaloids.

• The discovery of many alkaloids are associated with anthropological explorations. Here, a Kamsá youth from a Brazilian tribe holds a blossom of Culebra borrachera which is a toxic psychoactive plant. It contains tropane alkaloids that can induce a frightening state of psychotic delirium, and ultimately stupor and death.

(cms.herbalgram.org)

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9.0 Alkaloids (Dayrit) 6

Introduction

• Some animals, notably some soft corals and frogs produce highly bioactive alkaloids. In some cases, however, the alkaloids were found to have been ingested in the diet by the organism and then modified for use. Well-known examples are the pyrrolizidine alkaloids in caterpillars and moths. Alkaloids are much less common in mammals.

Intermedine (I) and lycopsamine (II) ingested from the leaves of Mikania scandens

monocrotaline (III)

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9.0 Alkaloids (Dayrit) 7

• There are four major groups of nitrogen-containing organic compounds in biological systems: the amino acids (peptides and proteins), the nucleoside bases (DNA and RNA), the porphyrins; and the alkaloids. The first 3 groups are primary metabolites; the alkaloids are secondary metabolites.

Introduction

• Alkaloids are defined simply as nitrogen-containing natural products. In terms of chemical structure, alkaloids can be classified into the following: 2, 3, and 4 alkyl amines; and heterocyclic amines (e.g., pyrrolidine, pyridine, indole, quinoline, and isoquinoline).

NN N N

N

pyrrolidine pyridine indole quinoline isoquinoline

Page 8: 9.0 Alkaloids

• Ajmaline, antiarrythmic that functions by inhibition of glucose uptake by heart tissue mitochondria

• Atropine (hyoscyamine), anticholinergic, antidote to nerve gas poisoning

• Caffeine, widely used central nervous system stimulant

• Camptothecin, potent anticancer agent

• Cocaine, topical anesthetic, potent central nervous system stimulant, and adrenergic blocking agent, drug of abuse

(Kutchan, The Plant Cell, 7, 1059-1070, July 1995)

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9

• Codeine, relatively nonaddictive analgesic and antitussive; Coniine, first alkaloid to be synthesized, extremely toxic, causes paralysis of motor nerve endings, used in homeopathy

• Emetine, orally active emetic, amoebicide; morphine, powerful narcotic analgesic, addictive drug of abuse; Nicotine, highly toxic, causes respiratory paralysis, horticultural insecticide

• Pilocarpine, peripheral stimulant of the parasympathetic system, used to treat glaucoma

• Quinine, traditional antimalarial, important in treating Plasmodium falcipafum strains that are resistant to other antimalarials

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10

• Sanguinarine, antibacterial showing antiplaque activity, used in toothpastes and oral rinses

• Scopolamine, powerful narcotic, used as a sedative for motion sickness

• Strychnine, violent tetanic poison, rat poison, used in homeopathy; Taxol, antitumor agent

• (+)-Tubocurarine, nondepolarizing muscle relaxant producing paralysis, adjuvant to anesthesia

• Vinblastine, antineoplastic that is used to treat Hodgkin’s disease and other lymphomas.

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9.0 Alkaloids (Dayrit) 11

Survey of some well-known alkaloids.

NH

Coniine from hemlock (Conium maculatum) was used by the ancient Greeks for state executions. Its most famous victim was Socrates.

Lysergic acid is an opiate produced by Claviceps purpurea, a parasitic fungus that grows on some grain crops. The unhygienic practices of medieval Europe caused outbreaks of convulsion which was called “St. Anthony’s Fire”.

NCH3

N

HO2C

N

N

CH3

Nicotine is the principal alkaloid in Nicotiana tabacum. It is addictive and has been recently classified as a drug.

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9.0 Alkaloids (Dayrit) 12

N

H

N

OO

H H

Strychnine was first purified in 1818 by Pelletier and Magendie from the seeds of Strychnos nux-vomica, a plant native to India. It is a deadly poison and was used for many centuries as a rodenticide and vermicide. It is so chemically and biologically stable that it has been found in bodies exhumed after several years (this makes it a bad choice for a poison!) Strychnine was first synthesized in 1954.

Quinine was first purified by Pelletier and

Caventou in 1820. It is the major alkaloid from the bark of the Cinchona tree. Christened the “Jesuit bark,” the bark was traditionally used by Peruvian indians for fever due to malaria.

Quinine was the principal antimalarial drug up to WW II, after which it was supplanted by

chloroquin. N

N H

CH3O

HO

H

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9.0 Alkaloids (Dayrit) 13

Cocaine is the chief alkaloid of the South

American coca bush. It has anaesthetic properties but is very addictive.

CH3N

OCC6H5

CO2CH3

O

• Merck, one of the world’s largest pharmaceutical companies, made its initial fortune from cocaine, morphine, and codeine.

Morphine was first isolated by Sertürner in

1806 from Papaver somniferum. It is still valued up to this day for its pain-killing

properties, although it is highly addictive. It was first synthesized in 1952. Codeine is the

methyl derivative.

O

HO

HO

NCH3

H

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9.0 Alkaloids (Dayrit) 14

Mescaline is a well-known hallucinogenic

compound extracted from the Indian peyote cactus, Laphophora williamsii.

NH2

CH3O

CH3O

CH3O

Caffeine is perhaps one of the most widely consumed alkaloids in the world. It is a member of a group of xanthine alkaloids which is present in coffee. The other famous xanthines, theobromine and theophylline, are found in tea and cocoa, respectively.

N

N

N

N

O

H3C

O

CH3

CH3

Vinblastine is the anticancer drug from Catharanthus roseus (locally known as

chichirica). Because it occurs in very minute amounts in the plant, this plant has been the

subject of intense biotechnology research to try to produce it in vitro using cell culture

techniques.

N

N

CH3OC

N

N

CH3O

HOO

CH3OC OH

O

OCCH3

O

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9.0 Alkaloids (Dayrit) 15

• Many alkaloids are toxic in the cytoplasm, even in the plants that produce them. Their accumulation, therefore, requires a well-regulated and compartmentalized system. The most common storage organ is the vacuole.

Introduction

• In some plants, alkaloids are synthesized in one part of the plant and then are transported to another part for storage. In tobacco, for example, alkaloids (e.g., nicotine) are synthesized in the roots and are then transported via the xylem to the leaves where they are accumulated.

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9.0 Alkaloids (Dayrit) 16

Among the natural products groups, the biochemistry of alkaloids is the most complex.

Introduction

• 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)

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9.0 Alkaloids (Dayrit) 17

Despite the wide variety and complex structures observed among the alkaloids, most of the compounds from this group are formed from only a handful of starting materials. The nitrogen and the initial carbon skeleton are derived from the following:

A. aliphatic amino acids: lysine, glutamic acid, and ornithine;

B. aromatic amino acids: phenylalanine, tyrosine, and tryptophan; and

C. others: secologanin: terpene-derived C10 unit.

Overview

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9.0 Alkaloids (Dayrit) 18

H2NCO2H

NH2

HO2C CO2H

NH2

H2N CO2H

NH2

ornithine

glutamic acid

A. Aliphatic amino acids: lysine

NNH2

CO2H

H

NH2R

CO2H

tyrosine, R = OH

B. Aromatic amino acids: phenlyalanine, R = H;

tryptophan

OH3COC

H

H

O

CHO

C. Others:

secologanin

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9.0 Alkaloids (Dayrit) 19

The major reactions in alkaloid biosynthesis are common biosynthetic mechanisms:

• Oxidation: epoxidation, aromatic hydroxylation, etc.

• Oxidation: dehydrogenation (-2[H]); in the case of the alkaloids, this includes the conversion of amine imine.

• Reduction: hydrogenation (+2[H]); in the case of the alkaloids, this includes the conversion of imine amine.

• Phenolic dimerization by radical coupling.

• Decarboxylation, in particular in the conversion of amino acid to amine.

Overview

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9.0 Alkaloids (Dayrit) 20

A. Mannich reaction : C-C aliphatic bond formation

H

C

H

O + NH2(CH3)H

C

H

NH(CH3)H3C

CCH2

-

O

NH(CH3)

O

B. Aldehyde Amine via pyridoxal / pyridoxamine

R CHO R CH2NH2

pyridoxamine

pyridoxal

Reactions which are particular to alkaloid biosynthesis.

C. Bischler-Napieralski: isoquinoline biosynthesis

NH2

+R C

O

OR' -HOR'

NHO

R

N

R

NNH2

R C

O

OR'

phenylethylaminefrom phenylalanine

tryptamine from tyrosine

+ -HOR'

NN

O

R

NN

R

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9.0 Alkaloids (Dayrit) 21

Reactions which are particular to alkaloid biosynthesis.

+

tryptamine from tyrosine

phenylethylaminefrom phenylalanine

NNH2

R C

O

H+

NH2

D. Pictet-Springler

N

R

N

R

R C

O

H

NN

R

NN

Rtryptophan

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9.0 Alkaloids (Dayrit) 22

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 being introduced in a late step.

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9.0 Alkaloids (Dayrit) 23

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).

N

pyrrolidine

N

N

tropane

N

pyrrolizidine

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9.0 Alkaloids (Dayrit) 24

Ornithine comes from glutamic acid.

HO2CH2N CO2H

glutamic acid

H2N CO2H

OHC

N CO2H N CO2H

CO2HOH2NH2N CO2HH2N

ornithine

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9.0 Alkaloids (Dayrit) 25

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.

ornithine

H2N CO2HH2N

putrescine

H2NH2N

-CO2

1. -CO2

2. pyridoxal* #

NH2 N

CH

N

POOH

CH3H

#

*H+

H+

*#

NH2 N

CH2

N

POOH

CH3

N NH

CH2

N

POOH

CH3

CH3

#

*

[CH3]

+H2C

CCH3

O

_

*#

N

CH3

O

hygrine

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9.0 Alkaloids (Dayrit) 26

Tropane alkaloids from ornithine. Consistent with what has been observed, labeling shows that the biosynthesis is regiospecific.

ornithine

H2N CO2HH2N

# #

N

CH3

O

hygrine

H2C

NH3C

O

#

_

+

N

O

H3C

tropinone

tropine

NH3C

OH

H

NH3C

OH

H

PhCH

CH2OH

HO2C

tropic acid

NH3C

H

O

CCH

Ph

CH2OHOatropine

NH3C

OH

H

CO2H

ecgonine

benzoic acid

NH3C

O

H

CO2H

CPh

O

#

#

#

cocaine

#

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9.0 Alkaloids (Dayrit) 27

Pyrrolizidine alkaloids from ornithine. Pyrrolizidine alkaloids are common in the butterflies Senecio and Crotolaria species.

NH2

CO2H

NH2

-CO2

ornithine

NH2

NH2

putrescine

NH2

CHO

H2N

OHC

dimerize N

CHO

NH2

1. pyridoxal 2. +2[H]

NH

CH

CHOO

_

NH

CHOOH

N

HOOH

retronecine

N

OO

OO

HH3C

HOOH

retrorsine

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9.0 Alkaloids (Dayrit) 28

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.

N

HOOH

retronecine

generalizedpyrrolizidine

N

OO

OO

[O]

inlepidoptera retronecine-N-oxide

N

HOOH

O _+

[O]

danaidal

N

CHO

N

CHOHO H

hydroxydanaidal

N

CH3O

danaidone

sex phermones inlepidoptera

inmammalian liver

-2[H]

N

HOOH

N

HO

+

alkylating agent (carcinogenic)

CHO

HO

E-4-hydroxyhex-2-enal

(bound to liver, toxic)

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9.0 Alkaloids (Dayrit) 29

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 -mannosidase; 3, 4, and 6 showed potent inhibitory activity toward rat lysosomal -glucosidase; and alkaloid 5 was a moderate inhibitor of - and -mannosidases. (Haraguchi, et al., J. Agric. Food Chem. 2003, 51, 4995-5000.)

NOH

OHH

HO

Swainsonine ( 1) 2-epi-Lentiginosine ( 2)

NOH

OHH

HN

HO

HO

OH

OH

Calystegine B1 (3)

HN

HO

OH

OHOH

Calystegine B2 (4)

HN

HO

OH

OHOH

Calystegine B3 (5) Calystegine C1 (6)

HN

HO

HO

OH

OHOH

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9.0 Alkaloids (Dayrit) 30

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.

piperidine

N

homotropane quinolizidine

N

N

N

Page 31: 9.0 Alkaloids

Alkaloids from lysine. 1-Piperidine and pellieterine are key intermediates to this group of alkaloids.

1-piperidine

NH3C

O

N

H

H2N CO2HH2N

lysine

SCoA

O O

_

N

O

CSCoA

O

+

N

O

-CO2

(-)-pelletierine

H2C

NH3C

O

1. [CH3]

2. [O]_

+

-pelletierine

N

CH3

NH

+

+

N

O

N

anaferine

N

O

NCH3

anahygrine

N

O

N

N

cernuine

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9.0 Alkaloids (Dayrit) 32

Quinolizidine alkaloids have the characteristic fused 6,6-bicyclic group and are derived from lysine. Lupinine is a dimeric metabolite while sparteine is trimeric.

NH2

NH2

CO2H

lysine

NH2

NH2

cadaverine

NH2

CH

O

N

OH

NH2

OHC

lupinine

N

NH2

NH2

OHC

N

N

H

H

sparteine

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9.0 Alkaloids (Dayrit) 33

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.

*

*

**

N

OHconhydrine coniine

N*

*

* *

-coniceine

**

*

*NOH2N

*

*

* ***

*

*HO O O

* SCoA

O

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9.0 Alkaloids (Dayrit) 34

Polyketide-derived piperidine alkaloids. Some alkaloids having the piperidine-type structure are not derived from lysine.

coccinelline

N

H

H H

a heptaketide

-CO2

HO2C

O

O

O

O

O

O

The European ladybug ( Coccinella septempunctata ) produces this tricylic defense substance.

-CO2**

N

penidine

*SCoA

O

*O O

CO2H*

*

* * *

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9.0 Alkaloids (Dayrit) 35

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

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9.0 Alkaloids (Dayrit) 36

Alkaloids from phenylalanine/tyrosine. Structurally, there are six main types.

NH21. Simple phenylethylamines.

NH2

+ NH

R

R CHO

2. Phenylethylamine + alkyl aldehyde or ketone.

NH

OHC

+NH2

3. Phenylethylamine + benzaldehyde (Ar-C 1).

NH

OHC

NH2

4. Phenylethylamine + Ar-C2.

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9.0 Alkaloids (Dayrit) 37

Alkaloids from phenylalanine/tyrosine. Structurally, there are six main types.

NH

OHC

NH2

5. Phenylethylamine + Ar-C3.

6. Phenylethylamine + secologanin.

NH2

O

OHC

O-Glc

CH3OC

O

NH

O

CH3OC

O-Glc

O

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9.0 Alkaloids (Dayrit) 38

Alkaloids from phenylalanine/ tyrosine: Simple phenylethylamines. Biosynthesis of this group involves simply loss of the carboxylic acid carbon. Some important members of this group are the hallucinogenic compound mescaline and the drug epinephrine.

NH2

HO

NH2

HOCO2H

-CO2

tyrosine tyramine hordenine

N(CH3)2

HO

Hordenine is produced by the barleyplant. It is released in the roots andacts to kill competing plants, inparticular weeds. It is an allelopathicagent.

DOPA

NH2

HOCO2H

HO

dopamine

NH2

HO

HO

[O]

-CO2

NH2

HO

HO

OCH3

1. [O]2. [CH3]

mescaline

Mescaline is the hallucinogeniccompound in the peyote cactus(Lophophora williamsii). It is

produced together with a numberof other phenylethylamines.

NH2

HO

HO

OH

norepinephrine

epinephrine

NH(CH3)

HO

HO

OH Epinephrine is also a cactus alkaloid. It is also a human hormone secreted by the adrenal medulla which acts to increase theheart rate, blood pressure and carbohydratemetabolism. It is also known as adrenalin.

[CH3]

[O]

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9.0 Alkaloids (Dayrit) 39

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.

NH2HO

HO

dopamine

CO 2H

NH2

leucine

CO 2H

O

1.

2. [CH3]

lophocerine

NHCH3HO

CH3O Lophocerin was isolated fromthe cactus Lophocerus schotti.

NH2CH3O

CH3O

OH

OHC CO 2Hglyoxylic acid

NH2CH3O

CH3O

CO2HOH

peyoxylic acid

-CO2

anhalamine

NH2CH3O

CH3O

OH

H3C C

O

CO2H pyruvicacid

NH2CH3O

CH3O

OH CH3

pellotine

-CO2

peyoruvic acid

NH2CH3O

CH3O

CO2HOH H3C

HO2C CO2H

NH2

HO2C CO2H

O

glutamic acid

NCH3O

CH3O

OH

O

peyoglutan

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9.0 Alkaloids (Dayrit) 40

Alkaloids from phenylalanine / tyrosine + Ar-C1. Phenylethylamine couples with Ar-C1 (benzaldehyde) via a Pictet-Springler condensation. This is followed by oxidation of the phenol.

.

O

NH

CH3O

O

O

NH

CH3O

O

.

. .

.

O

NH

CH3O

O

[O]

o-methylnorbelladine

HO

NH

CH3O

HO

CHOHO

CH3O

-CO2NH2

HO

NH2HO

CO2H

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9.0 Alkaloids (Dayrit) 41

Alkaloids from phenylalanine / tyrosine + Ar-C1. The two oxidized rings can couple via different folding conformations leading to para-para, para-ortho or ortho-para coupling.

galanthamine

NCH3

CH3O

OH

O

1. p-o2. [CH3]

.

.

O

NHO

CH3O

p-p

oxocrine

N

O

O

O

NH

O

O

CH3O

. .

NH

O

O

CH3O

lycorine

N

O

O

OH

HO

O

NHCH3O

HO

o-p

.

.

O

NH

CH3O

O

O

NH

CH3O

O

.

. .

.

O

NH

CH3O

O

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9.0 Alkaloids (Dayrit) 42

Alkaloids from phenylalanine / tyrosine + Ar-C1. (overview) Coupling of the radical intermediates in different folding conformations leads to para-para, para-ortho and ortho-para couplings. This is a theme that is repeated for other alkaloids with similar structural characteristics.

The alkaloid families that comprise this group include the Amaryllidaceae and Mesembrine species.

galanthamine

NCH3

CH3O

OH

O

1. p-o2. [CH3]

.

.

O

NHO

CH3O

p-p

oxocrine

N

O

O

O

NH

O

O

CH3O

. .

NH

O

O

CH3O

lycorine

N

O

O

OH

HO

O

NHCH3O

HO

o-p

.

.

O

NH

CH3O

O

O

NH

CH3O

O

.

. .

.

O

NH

CH3O

O

[O]

o-methylnorbelladine

HO

NH

CH3O

HO

CHOHO

CH3O

-CO2NH2

HO

NH2HO

CO2H

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9.0 Alkaloids (Dayrit) 43

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.

N

HO

HO

OH

OH

NH2

HO

HO

CO2HNH2

HO

HO

DOPA

-CO2

pyridoxalpyrophosphate

HO

HO

CO2H

O

-CO2

1,2-dehydrolaudanosoline

1. +2[H](2. 2x [CH3])

NR

RO

HOH

OR

OH

(S)-norlaudanosoline, R = H(S)-reticuline, R=CH3

1. -2[H]2. 4x [CH3]

N

CH3O

CH3O

OCH3

OCH3

papaverine

Page 44: 9.0 Alkaloids

Alkaloids from phenylalanine / tyrosine + Ar-C2. The Aprophine alkaloids are produced by oxidation of reticuline. Various isomeric radical intermediates are formed.

CH3O

NCH3

O

CH3O

H

O

.

.

C

A

B

C

BA

C

BA

B

A

C

.

.

CH3O

O

NCH3

O

CH3O

H

.

.

NCH3

CH3O

OH

CH3O

O

NCH3

CH3O

OH

CH3O

O.

. .

.

NCH3

CH3O

OH

CH3O

O

NCH3

CH3O

OH

CH3O

O

.

...

NCH3

CH3O

OH

CH3O

O

[O]

(S)-reticuline

NCH3

CH3O

HOH

CH3O

HO

Page 45: 9.0 Alkaloids

45

Alkaloids from phenylalanine / tyrosine + Ar-C2. Four regiochemical couplings are observed: ortho-ortho, ortho-para, para-ortho, and para-para.

bulbocarpine

NCH3

O

OH

CH3O

CH3O

NCH3

CH3O

OH

CH3O

O

o-o

.

.

NCH3

CH3O

OH

CH3O

O

isoboldine

NCH3

CH3O

OH

CH3O

OH

NCH3

CH3O

OH

CH3O

O

o-p

.

.

NCH3

CH3O

OH

CH3O

O

thebaine (to the morphine alkaloids)

1. 2[H]2. -H2O

CH3O

O

NCH3

CH3O

H

p-o

CH3O

O

NCH3

O

CH3O

H

H

B

A

C

.

.

CH3O

O

NCH3

O

CH3O

H

sebiferine

OCH3

H

CH3O

O

NCH3

CH3O

p-p

CH3O

NCH3

O

CH3O

H

O

.

.

C

A

B

Page 46: 9.0 Alkaloids

Alkaloids from phenylalanine / tyrosine + Ar-C2. The Aprophine alkaloids are produced by radical coupling of the benzylisoquinoline system of reticuline.

sebiferine

OCH3

H

CH3O

O

NCH3

CH3O

thebaine (to the morphine alkaloids)

1. 2[H]2. -H2O

CH3O

O

NCH3

CH3O

H

p-pp-o

CH3O

O

NCH3

O

CH3O

H

H

CH3O

NCH3

O

CH3O

H

O

.

.

C

A

BB

A

C

.

.

CH3O

O

NCH3

O

CH3O

H

isoboldine

NCH3

CH3O

OH

CH3O

OH

NCH3

CH3O

OH

CH3O

O

o-p

.

.

NCH3

CH3O

OH

CH3O

O

bulbocarpine

NCH3

O

OH

CH3O

CH3O

NCH3

CH3O

OH

CH3O

O

o-o

.

.

NCH3

CH3O

OH

CH3O

O

Page 47: 9.0 Alkaloids

9.0 Alkaloids (Dayrit) 47

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, 8:280–291)

Page 48: 9.0 Alkaloids

9.0 Alkaloids (Dayrit) 48

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.

thebaine codeine

HO

O

NCH3

HO

HH

morphine

CH3O

O

NCH3

CH3O

H

CH3O

O

NCH3

HO

HH

1. -[CH3]

2. +2[H]

-[CH3]

Page 49: 9.0 Alkaloids

9.0 Alkaloids (Dayrit) 49

Alkaloids from phenylalanine / tyrosine + Ar-C2. Coupling using the N-methyl group.

N-CH3

CH3O

HO

OH

OCH3

H

(S)-reticuline

-H-N

CH3O

HOH

OCH3

O-H

CH2

+

N

CH3O

HOH

OCH3

OH

(S)-scoulerine(S)-canadine

N

O

OH

OCH3

OCH3

N

O

O

OCH3

OCH3

berberine

+

[O]

N

O

OH

O

O

(S)-stylopine

N

O

OH

O

O

CH3

[CH3]

+

N

O

O

O

O

CH3

O

protopine

Page 50: 9.0 Alkaloids

9.0 Alkaloids (Dayrit) 50

Alkaloids from phenylalanine / tyrosine + Ar-C3. This group is homologous to the benzyltetrahydro-isoquinolines (dopamine + C2). The biosynthetic steps are assumed to be similar.

autumnaline(cf. re ticuline)

HO

HO

CO2H1. pyrido xalpyropho sphate

2. +2[H]

3. -H2O

-CO2

DOPA

NH 2

HO

HO

NH 2

HO

HO

CO2H

NC H3

CH3O

HO

CH3O

CH3O

OH

[CH3 ]

CH 3O

CH3O

NC H3

CH 3O

H

OCH3

O

p-oC

BA

B

A

C

.

.

CH 3O

O

NC H3

O

CH 3O

H

OCH3

o-p

NC H3

CH3O

OH

O

CH3O

CH3O

.

.

.

.

[O]

o-methyland ro cymb ine

NC H3

CH3O

O

CH3O

CH3O

O

NC H3

CH3O

HO

CH3O

CH3O

OH

multif loramine

Page 51: 9.0 Alkaloids

9.0 Alkaloids (Dayrit) 51

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.

NH2HO

HO

dopamine

+

O

OHC

H3COC

O-Glc

Osecologanin

NHHO

HO

O

O-Glc

H3COCO

NHHO

HO

O

O-H

H3COCO

-Glc

Page 52: 9.0 Alkaloids

9.0 Alkaloids (Dayrit) 52

Alkaloids from phenylalanine / tyrosine + secologanin.

emetine

NCH3O

CH3O

HNOH

OH

H

NH2HO

HO

proemetine

NCH3O

CH3O

O

H

H

1. H+

2. -CO23. 2[CH3]4. [H]

+NHO

HO

O

H3COCO

H

NHHO

HO

O

H3COC

CHO

O

H

2

alangiside

+Glc

NHO

HO

O

HO

O-Glc

NHO

HO

O

OH

O

H

H

H+

H+

NHHO

HO

O

CO2H

O

H

HH

1

21

NHHO

HO

O

O

H3COCO

H

H

NHHO

HO

O

O-H

H3COCO

Page 53: 9.0 Alkaloids

9.0 Alkaloids (Dayrit) 53

Alkaloids from tryptophan: the indole alkaloids

• The indole alkaloids are derived from tryptophan and are found in both plants and microorganisms. They comprise the single largest group of alkaloids, accounting for almost one-fourth of all alkaloids isolated. Many of the members of this group are biologically active and some possess very important medicinal properties. Among the best known sources are: Catharanthus, Curare, Rauwolfia, and Vinca plant species and the ergot fungi.

• The indole alkaloids can be classified as follows:

1. Simple indole alkylamines

2. Simple -carbolines

3. Tryptophan + C5

4. Tryptamine + secologanin

Page 54: 9.0 Alkaloids

9.0 Alkaloids (Dayrit) 54

Indole alkaloids. Structural groups..

N

N

1. Simple indole alkylamines.

may be saturatedor aromatic

NN

R

OHC

R

+

N

N

2. Simple -carbolines: indole + aldehyde (Pictet-Springer condensation)

Page 55: 9.0 Alkaloids

9.0 Alkaloids (Dayrit) 55

Indole alkaloids. Structural groups..

CO2H

NH2

N

OPP

3. Tryptophan + C 5 (ergolines).

N

NH2

CO2H+

NN

O

O-Glc

CH3OCO

+

CHO

OCH3OC

O-Glc

O

N

NH2

4. Tryptamine + secologanine. (Pictet-Springer condensation)

Page 56: 9.0 Alkaloids

9.0 Alkaloids (Dayrit) 56

Simple indole alkaloids. Decarboxylation of tryptophan yields serotonin, a neurotransmitter; methylation yields bufotenin, a hallucinogenic compound isolated from toadstools.

N

NH2

HO

HN

NH2

CO2H

H

1. -CO2

2. [O]

5-hydroxytryptamine (serotonin)

N

N(CH3)2

HO

H

[CH3]

bufotenin

N

HO

N

CH3

CH3 CH3

eseroline

Page 57: 9.0 Alkaloids

9.0 Alkaloids (Dayrit) 57

Simple indole alkaloids. Bishler-Napieralski condensation of tryptamine with simple alkyl groups yields the b-carbolines. The harmanes are CNS stimulants.

N

N

NNH

H3C CO2HH3CC

CO2H

ON

N

CH3

-CO2

harmane

Page 58: 9.0 Alkaloids

9.0 Alkaloids (Dayrit) 58

Ergot alkaloids. Condensation with C5 DMAPP. This group of metabolites is produced by the fungus Claviceps purpurea and includes the hallucinogen lysergic acid.

+

N

NH2

CO2H

H

OPP CO2H

NH2

N

H

CO2H

NH2

N

O

H

[O]

_

N

H

HO2C NH2

HO

N

H

HO NH2

OPP

1. -CO2

2. [O], +OPP1. [CH3]

2. [O]

N

H

NCH3

HO2C

lysergic acid

Page 59: 9.0 Alkaloids

Indole alkaloids: tryptophan + secologanin. More than 1,100 compounds from this group of mixed metabolites have been identified. They occur predominantly in Loganiaciae, Apocynaceae, and Rubiaceae. This figure gives the major skeletal types.

NN

O

Vincosan (D-type)

NN

NN

O

Coryanthean (C-type)

NN

Reserpine Valleseachotaman (V-type)

NN

NN

Eburnan (E-type)

N

N

Strychnan (S-type)

N

N

Aspidospermatan (A-type)

N

N

Plumeran (P-type)

N

N

Ibogan (I-type)

Page 60: 9.0 Alkaloids

Indole alkaloids: tryptophan + secologanin. The Vincosan alkaloids yield straight-forward incorporation of secologanin.

NNH

OCH3OC

O-Glc

OOCH3OC

CHO

O

H

H

O-Glc

NNH2

+

strictosidine vincoside

NNH

OCH3OC

O-Glc

O

+

H+

-Glc

NNH

OCH3OC

O-H

O

NNH

CHO

OHCH3OC

O

NNH

OHCH3OC

O

CHO

NN

OHCH3OC

O

+

NN

OCH3OC

O

H

H

catharanthine

+2[H]

ajmalicine

NN

OCH3OC

O

H

H

• Loss of glucose enables more extensive structural changes to occur. The glycoside is hypothesized to act as a protecting group.

• Many alkaloids are formed from strictosidine.

Page 61: 9.0 Alkaloids

9.0 Alkaloids (Dayrit) 61

Indole alkaloids: tryptophan + secologanin. Loss of glucose initiates the chemical transformation. Reserpine is a tranquilizer and sedative isolated from the roots of Rauwolfia serpentina.

NNH

OCH3OC

O-Glc

Ostrictosidine

1. -Glc2. H+

3. double bond isomerization4. bond rotation

NNH

CHO

OCH3OC

O H

NN

OCH3OC

O H

H

+

NN

OCH3OC

O H

NN

CH3OC

O OH

H

H

+

NN

CH3OC

O OH

H

H

-yohimbine

NN

CH3OC

O OCH3

H

H

O

H

O

OCH3

OCH3

OCH3

reserpine

Page 62: 9.0 Alkaloids

9.0 Alkaloids (Dayrit) 62

Indole alkaloids: tryptophan + secologanin. Strychnine (from the seeds of Strychnos nux-vomica) was used in medicine as a CNS stimulant. At higher doses, it was used as poison for humans and rodents.

NNH

OCH3OC

O-Glc

Ostrictosidine

NN

OHCH3OC

O

H

geissoschizine

NN

CHOCH3OC

O

HH+

NN

CHO

CH3OC

O

H

+

_

N

N

CHOCH3OC

O

H1. [O]2. -CH2O

[O]

NH

N

HOCH3OC

O

CH3COS-CoA

NH

N

HOO

CoAS

O

N

N

OO

strychnine

Page 63: 9.0 Alkaloids

9.0 Alkaloids (Dayrit) 63

NNH

OCH3OC

O-Glc

O

H

strictosidine corynantheal

NN

CHO

H

NN

H

O-H

O

H

[O]

NN

CHO

H HO

H

1. -H2O

2. +2[H]3. "X"

NN

CHO

H

X

H2O

NH2

N

CHO

H

X

O

NH2

CHO

O

NX

N

NO

cinchonidinone

N

NHO

RH

quinine, R=OCH3

cinchonidine, R=H

quinidine, R=OCH3

cinchonine, R=H

N

N

RHO

H

1. -H2O

2. -"HX"

Indole alkaloids: tryptophan + secologanin. The cinchona alkaloids (from the bark of Cinchona spp.) involve extensive rearrangement.Quinine was used as an antimalarial drug.

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9.0 Alkaloids (Dayrit) 64

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.

Page 65: 9.0 Alkaloids

9.0 Alkaloids (Dayrit) 65

Quinoline alkaloids. Except for the cinchona alkaloids, the quinoline alkaloids are mixed metabolites being derived from anthranilic acid, which belongs to the shikimate group, and polyketides.

N

OH

NH2

O

O

CO2H

arborinine

N

O

OCH3

OH

OCH3

CH3

1. [O]2. [CH3]

N

O

OH

H

OH

NH2

O

O

SCoAO

O

skimmianine

N O

OCH3

OCH3

CH3O

3. [O]4. [CH3]

PPO1.

2. [CH3]

N

O

H

O

SCoA

O O

SCoA

O OO

SCoA

O O

NH2 SCoA

O

O

anthranilic acid

CO2H

NH2

shikimate

Page 66: 9.0 Alkaloids

9.0 Alkaloids (Dayrit) 66

The terpene alkaloids. The sequence of addition of nitrogen into the terpene is suggested to be: R-CH2-OH R-CHO R-CH2-NH2 (where R is a terpene metabolite).

dehydroskythanthine

NCH3

H

actidine

N

OH

NH2

pyridoxamine[O]CHO

OHOH-

OH

OPP

1. [O]2. OPP

geraniol OPP

OPP

A. Monoterpene alkaloids.

Page 67: 9.0 Alkaloids

9.0 Alkaloids (Dayrit) 67

The terpene alkaloids. Steroidal alkaloids are formed from completed steroids. Solasidine and tomatidine occur in potatoes and tomatoes, respectively.

solasidine tomatidine

25S

CHO

O

O

NH2

N CH3

HO

O

N CH3

25R

HO

O

NCH3

NCH3

O

NH2

CHO

O cholesterolHO

B. Steroidal alkaloids.

Page 68: 9.0 Alkaloids

9.0 Alkaloids (Dayrit) 68

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.

N

CO2H

nicotinic acidN

NCH3

(-) nicotine

Page 69: 9.0 Alkaloids

9.0 Alkaloids (Dayrit) 69

Nicotinic acid. In plants, nicotinic acid is biosynthesized from tryptophan.

N

NH2

CO2H

tryptophan

[O]

N

NH2

CO2H

CH

O

OH

-CH2O

NH2

NH2

CO2H

O

[O], Baeyer-Villiger

[O] [O]

CO2H

NH2

OH

3-hydroxyanthranilic acid

CO2H

NH2

OHO

[O]

CO2H

NH2

OH

O

OHC

HO2C

CO2H

NH2

cis trans

OHC

CO2H

H2N CO2H N

CO2H

CO2H N

CO2H

quinolinic acid nicotinic acid

A. Biosynthesis from tryptophan (in plants)

Page 70: 9.0 Alkaloids

9.0 Alkaloids (Dayrit) 70

Nicotinic acid. In bacteria, nicotinic acid is biosynthesized from glyceraldehyde + aspartic acid.B. Biosynthesis from glyceraldehyde + aspartic acid (C 3 + C4) (in bacteria)

OPP

CH

HO

O H2N CO2

-

CO2

-_

N

CO2H

CO2H

nicotinic acidquinolinic acid

N

CO2H

N

CO2H

CO2H

Page 71: 9.0 Alkaloids

9.0 Alkaloids (Dayrit) 71

Nicotinic acid. Mimosine, which resembles phenylalanine, is a toxin found in grass which is used as animal feed.

N

C-NH2

O

nicotinamide

A. Various nicotine alkaloids

N

C-OGlc

O

Glc

+

buchanine

N

O

OH

CO2H

NH2

mimosine

Mimosine, a -pyridone which is found inMimosa species, is toxic to animals. Notethat it is a -amino acid and is believed tomimic phenylalanine, tyrosine or DOPA.

OH

OH

CO2H

NH2

Page 72: 9.0 Alkaloids

9.0 Alkaloids (Dayrit) 72

Nicotinic acid. Biosynthesis of nicotine. Nicotine is a ganglionic cholinergic-receptor agonist. Chronic ingestion of nicotine often results in psychological addiction and physical dependence.

B. Biosynthesis of nicotine (Nicotiana alkaloids).

N

CO2H

-CO2

N

N

NCH3

+

H2NH2N CO2H

ornithine

N

NCH3

(-) nicotine

N

lysine

H2NH2N CO2H

anabasine

N

N

N

N

anatabine

Page 73: 9.0 Alkaloids

9.0 Alkaloids (Dayrit) 73

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.

N

N

N

N

O

H3C

O

CH3

CH3

Caffeine

N

N

N

N

HO

O

XanthinePurine

N

N

N

N

H

Theophylline

N

N

N

N

O

H3C

O

CH3

H

Theobromine

N

N

N

N

O

H

O

CH3

CH3

Page 74: 9.0 Alkaloids

9.0 Alkaloids (Dayrit) 74

The methylxanthines (caffeine, theophylline and theobromine) are CNS stimulants and smooth muscle relaxants. Research into their physiological mechanisms are continuing research topics.

98

76

5

432

1

Caffeine

CH3

CH3

O

H3C

O

N

CH

NCC

CN

C

N

Caffeine

C1 fragments

asparticacid

CO2

amide N of glutamine

CH3

CH3

O

H3C

O

N

CH

NCC

CN

C

N

glycine, NH2CH2CO2H

C1 fragments

1

2 3 4

56

78

9

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.

Page 75: 9.0 Alkaloids

9.0 Alkaloids (Dayrit) 75

Summary

• Structurally, the alkaloids are a very diverse group; the only unifying characteristic is the presence of an amine.

• The origin of the carbons in alkaloids include the aliphatic amino acids (ornithine and lysine), aromatic amino acids (phenylalanine, tyrosine and tryptophan, which arises from shikimic acid via phenylpropanoids), anthranilic acid (from shikimic acid), polyketides, and terpenes.

Page 76: 9.0 Alkaloids

9.0 Alkaloids (Dayrit) 76

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 and

Erythrina) Tryptophan + DMAPP: (e.g., ergot alkaloids) Tryptophan + secologanin: (Vinca, Catharanthus, Strychnos,

Cinchona) Steroidal alkaloids Nicotinic acid: (Nicotiana) Xanthine alkaloids: (Coffea, Camelia, Theobroma)

Page 77: 9.0 Alkaloids

9.0 Alkaloids (Dayrit) 77

Overview of alkaloid biosynthesis. The biogenetic location of the xanthines is diverse and not included here.

glucose

aliphatic amino acids

lysine,ornithine

aliphatic alkaloids:pyrrolidine, tropane,pyrrolizidine;piperidine, quinolizidine

shikimate

phenylalanine,tyrosine,tryptophan

anthranilicacid

aromatic alkaloids:phenylethylamine,isoquinoline,betalin; indole,carboline, quinoline,nicotinic acid

quinoline

polyketide

piperidine

mevalonic acid

terpene alkaloids:monoterpene,steroidal

C5-OPP,

secologanin

(to aromaticalkaloids)