Isoquinoline and Benzylisoquinoline Alkaloids
Alkaloids that possess an isoquinoline skeleton are among the most common of all alkaloids. These are derived from a 3,4-dihydroxytyramine (dopamine) precursor that undergoes a Schiff base addition with aldehydes of different origin. At least 4000 compounds of this structural type are known.
The simplest type of isoquinoline alkaloids is based on carbonyl compounds such as glyoxylic acid,
pyruvic acid, and an aldehyde derived from leucine. The second major structural type, benzylisoquinoline
alkaloids (BIQ) and tetrahydrobenzylisoquinoline alkaloids (THBIQ) is based a 3,4-dihydroxytyramine
(dopamine) precursor and an aldehyde derived from tyrosine, 4-hydroxyphenylacetaldehyde. A third group,
includine emetine and a series of structurally related alkaloids, involves the same amine precursor
condensing with secologanin, an iridoid monoterpene.
Isoquinoline alkaloids
These alkaloids are mostly found in the Cactaceae, but in some other families as well. About 130 isoquinoline alkaloids are known. They are derived from a 3,4-dihydroxytyramine (dopamine) precursor and have an isoquinoline skeleton.
The skeleton is based on a 3,4-dihydroxytyramine (dopamine) precursor and carbonyl compounds such as glyoxylic acid, pyruvic acid, and an aldehyde derived from leucine.
The biosynthesis of mescaline, another alkaloid of similar structure found in certain members of the Cactaceae, is discussed in a previous chapter.
In contrast to benzylisoquinoline alkaloids (see below), the biosynthesis of isoquinoline alkaloids usually involves the interaction of an amine and a keto acid, rather than interaction of an amine and an aldehyde. Ring closure to form compounds such as anhalamine involves methionine. The related alkaloid pellotine is derived from pyruvate. A carboxylic acid of similar structure, peyoruvic acid, suffers oxidative decarboxylation and serves as a precursor for other isoquinoline alkaloids. The order of methoxylation and oxidation steps varies. In some cases, the 3,4-dihydroxytyramine (dopamine) precursor may be modified before reaction with the carbonyl compound.
Lophocereine has a five-carbon unit inserted into the nitrogen-containing ring. The carbonyl precursor is probably 4-methyl-2-oxopentanoic acid that arises by transamination of leucine.
Isoquinoline alkaloids sometimes occur as dimers and oligomers. For example, pilocereine is formed from coupling of isoquinoline units.
Isoquinoline alkaloids are most common in the cactus family, Cactaceae, but also are found in the Chenopodiaceae, Fabaceae, Musaceae, Nympheaceae, and Sterculiaceae.
In contrast to mescaline, isoquinoline alkaloids lack hallucinogenic activity. They are toxic to many animals, however.
Many species of Drosophila live in association with certain cactus species. They feed on
rotting limbs and have a requirement for schottenol, a steroidal compound that occurs in the cacti.
Specificity of cactus-insect associations in enforced by the combination of alkaloids present. The system
also involves yeasts that are involved in modifying steroidal glycosides present.
Benzylisoquinoline or BIQ alkaloids
About 4000 BIQ alkaloids are known. There are many important structural types. Many BIQ alkaloids are important in medicine. Others are highly toxic. Some are used as arrow poisons. BIQ alkaloids are found in a number of related families and a few others. They are found in the Annonaceae, Aristolochiaceae, Berberidaceae, Eupomatiaceae, Hernandiaceae, Fabaceae, Fumariaceae, Lauraceeae, Magnoliaceae, Menispermaceae, Monimiaceae, Nelumbonaceae, Papaveraceae, Ranunculaceae, Winteraceae, Euphorbiaceae (Croton), Rhamnaceae, Phellinaceae, Symplocaceae, Rutaceae, Combretaceae, Araliaceae, Apiaceae, Caprifoliaceae, Rubiaceae, and Araceae. Several of these family records need confirmed.
The biosynthesis of these compounds is based on a 3,4-dihydroxytyramine (dopamine) precursor and the
aldehyde, 4-hydroxyphenylacetaldehyde. Both parts of the molecule are derived from tyrosine.
Tetrahydrobenzylisoquinoline or THBIQ alkaloids
The simplest alkaloids of this series are those in which the nitrogen-containing ring is completely saturated. These alkaloids are found in almost all families that contain BIQ alkaloids. About 100 compounds of this type are known. The most important compound from a biosynthetic point of view is (+)-reticuline. This alkaloid is a presursor of several other groups of alkaloids. (+)- or (S)-Reticuline is converted to (-)- or (R)-reticuline, which is, in turn, a major precursor of other alkaloid groups.
Benzylisoquinoline (BIQ) and tetrahydrobenzylisoquinoline (THBIQ) alkaloids are formed from a 3,4-dihydroxytyramine (dopamine) precursor and the aldehyde, 4-hydroxyphenylacetaldehyde.
Much of the biosynthetic work on this group of alkaloids was done in the laboratory of Meinhard Zenk in Munich. The use of cell free extracts has permitted this group to isolate and characterize all eight enzymes involved in the conversion of dopamine and 4-hydroxyphenylacetaldehyde to (S)-reticuline and hence to berberine.
(S)-Norcoclaurine is the first compound formed in this series. Although norlaudanosoline was previously reported to be the initial precursor, this is now generally not considered to be the case.
(S)-Reticuline is transported into vacuoles of the plant Fumaria capreolata, Fumariaceae. This transport involves an active ATP-requiring, stereospecific carrier system that transports only the S)-enantiomer.
A related aromatized alkaloid of this series, papaverine, is important from a pharmacological
point of view. This compound inhibits aldol reductase, GABA, and glucose response in chemosensory
cells and phosophodiesterase. In vivo, this alkaloid decreases the tonus of smooth muscle
increases coronary artery flow, and causes dilation. Papaverine has a beneficial effect on
angina pectoris.
Aporphine alkaloids
The simplest derivatives of the THBIQ alkaloids are the aporphine alkaloids. At least 650 are known and they occur widely in the families that have BIQ alkaloids.
Aporphine alkaloids arise by o, p-couplings involving free radicals. Rotation about the single bond to which the benzyl group is attached before cyclization gives rise to two series of aporphine alkaloids, represented by bulbocapnine and by glaucine. The methylation pattern is of great importance in aporphine alkaloid biosynthesis.
Most aporphine alkaloids are toxic. They exhibit antagonistic effects to dopamine. Because they
interact at dopamine receptors, many have anticonvulsant activity. Glaucine induces narcosis and
convulsions in animals. Isoboldine inhibits aldol reductase. Taspine is known for wound healing
properties.
Aristolactams and aristolochic acid
This group of compounds is mainly found in the genus Aristolochia, Aristolochiaceae. Several
of the compounds are not actually alkaloids, but contain organic nitro groups. They are, however,
derived from benzylisoquinoline alkaloid precursors. Aristolochic acid is a common representative of
this group of compounds. This compound has antitumor activity, but is also carcinogenic.
Proaporphine alkaloids
The formation of alkaloids of similar structure to those of the aporphine group, such as stephanine, laureline, and isothebaine, is more complicated. The ortho- or para- oxygen function required for direct oxidative coupling is absent in the probable precursor. Cyclization of these alkaloids requires the intermediacy of proaporphine alkaloids, such as orientalinone. The formation of aporphine alkaloids with apparently anomalous structures appears to occur by dienone-phenol or dienol-benzene rearrangements. Ring expansion to yield aporphine alkaloids then occurs. Laureline arises via such a pathway.
Proaporphine alkaloids are known from the Euphorbiaceae, Lauraceae, Menispermaceae, Monimiaceae,
Nelumbonaceae, and Papaveraceae.
Hasubanan alkaloids
About 40 alkaloids of this group are derived from sinoacutine, which, in turn, arises from (S-reticuline. In Sinomenium acutum, Menispermaceae, sinoacutine is the precursor of sinomenine, a compound epimeric to morphine. Hasubanonine-like alkaloids are known from Sinomenium and Stephania Menispermaceae. Although these alkaloids are similar in structure to morphine alkaloids, they have quite distinct biological properties.
Morphine alkaloids
Poppies (Papaver somniferum, Papaveraceae) have long been used as medicinal plants, food plants, and drugs of abuse. Morphine alkaloids are found in many members of the genus Papaver, but codeine and morphine are only found in Papaver somniferum, and in one other species, Papaver ??, that may be a wild ancestor of Papaver somniferum. Another species, Papaver bracteatum contains thebaine.
Opium is made by lacerating immature capsules of the plant. Crude opium contains 12-14% morphine, although over 40 alkaloids are known from opium. a-narcotine (noscapine) also is a major component (4-8%). Most codeine is prepared by methylation of morphine.
Heroin, the diacetyl derivative of morphine, is not naturally occurring.
Although many have tried to produce morphine and related compounds in tissue culture or cell culture systems, the usual product is sanguinarine.
Morphine alkaloids are derived from (-)- or (R)-reticuline by series of reactions involving an oxidative coupling reaction. Radioactive labelling experiments have established the series o reactions from thebaine to codeine to morphine.
Morphine suppresses some central nervous functions, but stimulates others. This alkaloid produces
analgesia, drowsiness, changes in mood, and mental clouding. Analgesia occurs without loss of
consciousness. Morphine and its analogs are powerful suspressants of the cough center (antitussives).
Protoberbereine alkaloids
The protoberberine alkaloids are one of the most widely distributed groups of BIQ alkaloids. Approximately 100 alkaloids of this series are known. They occur in at least 10 plant families: Alangiaceae, Annonaceae, Berberidaceae, Fabaceae (Erythrina), Fumariaceae, Lauraceae, Menispermaceae, Papaveraceae, Ranunculaceae, and Rutaceae. Berberine is also produced by several cell cultures.
(S)-Reticuline is converted into berberine. The additional methylene group of berberine alkaloids has been demonstrated to come from methionine and is often called "the berberine bridge". The "berberine bridge enzyme" converts (S)-reticuline into (S)-scoulerine. The N- metyl group is transformed into an iminium function by oxidation and followed by ring closure. (S)-Scoulerine is the first tetrahydroberberine alkaloid formed. This compound is methylated and aromatized to produce columbamine. Columbamine gives rise to berberine by formation of a methylenedioxy ring. These enzymes are highly specific. From (+)-reticuline to berberine, 4 enzymes are involved. (8 all together from the initial precursors). Berberine, in turn, is a precursor to other alkaloids of the series, e.g., jatorrhizine.
Berberine has general antimicrobial, trypanocidal, antiamebic, antifungal, anthelminthic,
leishmanicidal, and tuberculostatic properties. In inhibits reverse transcriptase, intercalates
with DNA, and inhibits aldose reductase. It is widely used for treatment of malaria, amoebiasis and
leishmaniasis.
Protopine alkaloids
Berberine or protoberine alkaloids may be converted into protopine alkaloids. Cytochrome P-450- dependent enzymes introduce two methylenedioxy bridges into (S)-scoulerine to form (S)-stylopine. This compound is a precursor of protopine, phthalideisoquinoline, and benzophenanthridine alkaloids.
Allocryptotine produces antiarrhythmic effects in humans. It also is useful as an oxytocic.
Protopine has smooth-muscle relaxant, hypotensive, and antimicrobial activity against Gram-positive
bacteria as well as ocytocic properties.
Benzophenanthradine alkaloids
Approximately 30 alkaloids of this skeletal type, principally from the Papaveraceae, are known. They are synthized in the protoplasm. These alkaloids arise from a protoberberine precursor by fission of the C-6-N bond and recyclization. The biogenetic sequence leading to chelidonine in Chelidonium majus is established. Sanguinarine is a common product of tissue cultures of papaveraceous plants.
Benzophenanthradine alkaloids are found in the Fumariaceae, Papaveraceae, and Rutaceae, and possibly in two additional families.
Chelerythrine and sanguinarine have antifungal, antiacterial, anti-inflammatory, and antitumor effects.
These two alkaloids are used in human medicine. Several alkaloids of this series intercalate with DNA.
Nitidine also inhibits reverse transcriptase, DNA polymerase, tRNA methyltransferase, and Na+-
K+-ATPase. Sanguinarine uncouples respiration and oxidative phosphorylation in mitochondria
and phytosynthetic photophosphorylation. Because of its antiplaque properties, it has been incorporated
into some toothpastes.
Phthalideisoquinoline alkaloids
Phthalideisoquinoline alkaloids are commonly found in the Papaveraceae, and occasionally in the Berberidaceae and Ranunculaceae. The pathway for a-narcotine (noscapine) in Papaver somniferum involves (S)-reticuline and (S)-scoulerine. Narcotine possesses antitussive activity, depresses smooth muscles, and is not (despite its name) a narcotic.
The active principle of goldenseal (Hydrastis canadensis, Ranunculaceae),
b-hydrastine, is a phthalideisoquinoline alkaloid. The plant is used to
treat inflammation of the mucous membranes.
Pavine and isopavine (Argemone) alkaloids
Various species of Argemone, Eschscholtzia, and Thalictrum contain pavine
(about 20) and isopavine (about 10) alkaloids. They are modified benzylisoquinoline alkaloids.
Bisbenzylisoquinoline alkaloids
Intermolecular coupling of BIQ alkaloids also occurs. At least 400 alkaloids of this type are known. These involve BIQ, THBIQ, aporphine, and pavine precursors. These alkaloids are often linked by diphenylether bridges. The majority are derived from norcoclaurine or a methylated precursor. Only a few of these arise by C-C coupling. Bisbenzylisoquinoline alkaloids occur in many of the same families as BIQ alkaloids.
Many of these alkaloids have antimicrobial properties. At least two types have antitumor properties.
Tetrandrine and thalicarpine have such activity. However, tetrandrine is too toxic for human use.
Thalicarpine also has blood pressure lowering activity. Chondrodendrine inhibits growth of
Leishmania.
Curare
Curare is a mixture of plant products that is used to poison the tips of arrows for hunting and sometimes for warfare. Many different plant combinations have been used, but plants of BIQ and bisbenzylisoquinoline alkaloid-containing families are common. Tube curares are those stored in bamboo tubes. Many of these are prepared from Chondrodendron tomentosum, Menispermaceae. Most of the active components are bisbenzylisoquinoline alkaloids. The major active alkaloid, tubocurarine, is a quaternary species.
Injection of tubocurarine rapidly blocks neruomuscular action causing respiratory failure and death.
A paralyzing dose for a human is about 3-7 mg. The compound is used in smaller doses to enhance
the action of anesthetics because it causes relaxation of abdominal muscles without inhibiting the
normal action of the intestines. The drug is inactive orally.
Erythrina alkaloids
At least 60 complex alkaloids derived from BIQ precursors are found in the genera Erythrina, Fabaceae, and Cocculus, Menispermaceae.
They are products of a lengthy pathway involving a dienone-phenol rearrangement and several additional rearrangement steps.
Many of these alkaloids possess curare-like action and interact with acetylcholine receptors.
Related Images
Bisbenzylisoquinoline Alkaloids
Proaporphine and Aporphine Alkaloid Formation
Phthalideisoquinoline Alkaloids
Seco-Phthalideisoquinoline Alkaloids
Major types of Benzylisoquinoline Alkaloids
Precursors of Isoquinoline and Benzylisoquinoline Alkaloids
Lecture Slides
Plants with Isoquinoline
Alkaloids
Plants with Benzylisoquinoline
Alkaloids
© David S. Seigler, Plant Biology 363, Plant Secondary Metabolism, Department of Plant Biology,
265 Morrill Hall, 505 S. Goodwin Ave., University of Illinois, Urbana, Illinois 61801, USA.
217-333-7577. seigler@life.uiuc.edu.
