9.0 Alkaloids9.0 Alkaloids
HO
O
NCH3
HO
HH
Morphine N
N
H
CH3O
HO
H
Quinine
RA Macahig
FM Dayrit
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
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.
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
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)
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)
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
• 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)
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
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.
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.
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
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
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
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.
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)
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
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
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
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
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
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.
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
9.0 Alkaloids (Dayrit) 24
Ornithine comes from glutamic acid.
HO2CH2N CO2H
glutamic acid
H2N CO2H
OHC
N CO2H N CO2H
CO2HOH2NH2N CO2HH2N
ornithine
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
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
#
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
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)
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
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
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
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
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
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*
*
* * *
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
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.
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
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]
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
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
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
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
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
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
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
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
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)
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]
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
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
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
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
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
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)
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)
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
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
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
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)
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.
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
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
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.
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.
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
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.
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.
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
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)
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
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
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
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
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.
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.
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)
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)