Swainsonine
Encyclopedia
Swainsonine is an indolizine
alkaloid
. It is a potent inhibitor
of Golgi alpha-mannosidase II
, an immunomodulator
, and a potential chemotherapy
drug
. As a toxin in locoweed
(likely its primary toxin) it also is a significant cause of economic losses in livestock
industries, particularly in North America
.
s, specifically N-linked glycosylation
. Disruption of Golgi alpha-mannosidase II with swainsonine induces hybrid-type glycans
. These glycans have a Man5GlcNAc2 core with processing on the 3-arm that resembles so-called complex-type glycans.
The pharmacological properties of this product have not been fully investigated.
that has been isolated from numerous species
of flowering plant
s and some fungi
(see Locoweed
). It was first isolated from Swainsona
in Australia
.
Swainsonine is extracted commercially from several species of plants and fungi, including the soil fungus Metarhizium anisopliae
. It also can be produced from total synthesis
.
, and it initially involves the conversion of lysine
into pipecolic acid
. The pyrrolidine
ring is then formed via retention of the carbon atom of the pipecolate’s carboxyl
group, as well as the coupling of two more carbon atoms from either acetate
or malonate
to form a pipecolylacetate. The retention of the carboxyl carbon is striking, since it is normally lost in the biosynthesis of most other alkaloids.
The resulting oxoindolizidine is then reduced to (1R,8aS)- 1-hydroxyindolizidine, which is subsequently hydroxylated
at the C2 carbon atom to yield 1,2-dihydroxyindolizidine. Finally, an 8-hydroxyl group is introduced through epimerization at C-8a to yield swainsonine. Schneider et. al. have suggested that oxidation occurs at C-8a to give an iminium ion
. Reduction from the β face would then yield the R configuration of swainsonine, as opposed to the S configuration of slaframine
, another indolizine alkaloid whose biosynthesis is similar to that of swainsonine during the first half of the pathway and also shown above alongside that of swainsonine. The instance at which oxidation and reduction occur with regard to the introduction of the hydroxyl groups at the C2 and C8 positions is still under investigation.
The biosynthetic pathway of swainsonine has also been investigated in the Diablo locoweed
. Through detection of (1,8a-trans)-1-hydroxyindolizidine and (1,8a-trans-1,2-cis)-1,2-dihydroxyindolizidine—two precursors of swainsonine in the fungus pathway—in the shoots of the plant, Harris et. al. proposed that the biosynthetic pathway of swainsonine in the locoweed is nearly identical to that of the fungus.
, these plant species are known collectively as locoweed
s. Other effects of intoxication include reduced appetite and consequent reduced growth in young animals and loss of weight in adults, and cessation of reproduction (loss of libido, loss of fertility, and abortion).
and gastric carcinoma
. However, a phase II clinical trial
of GD0039 (a hydrochloride salt of swainsonine) in 17 patients with renal carcinoma
was discouraging. Swainsonine's activity against tumors is attributed to its stimulation of macrophage
s.
Swainsonine also has potential uses as an adjuvant for anti-cancer drugs and other therapies in use. In mice, swainsonine reduces the toxicity of doxorubicin
, suggesting that swainsonine might enable use of higher doses of doxorubicin. Swainsonine may promote restoration of bone marrow
damaged by some types of cancer treatments.
Swainsonine is an appetite suppressant.
Indolizine
Indolizine is a heterocyclic aromatic organic compound that is an isomer of indole. It forms the structural core of a variety of alkaloids such as swainsonine.-External links:*...
alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
. It is a potent inhibitor
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
of Golgi alpha-mannosidase II
Golgi alpha-mannosidase II
Golgi α-mannosidase II is a key enzyme involved in N-linked Glycan processing. It is inhibited by small molecule swainsonine....
, an immunomodulator
Immunomodulator
An immunomodulator, also known as an immunotherapy is a substance which has an effect on the immune system.- Immunosuppressants :Inhibits immune response in organ transplantation and autoimmune diseases.- Immunostimulants :...
, and a potential chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
. As a toxin in locoweed
Locoweed
Locoweed is a common name in North America for any plant that produces swainsonine, a phytotoxin harmful to livestock. Worldwide, swainsonine is produced by a small number of species, most in three genera of the flowering plant family Fabaceae: Oxytropis and Astragalus in North America, and...
(likely its primary toxin) it also is a significant cause of economic losses in livestock
Livestock
Livestock refers to one or more domesticated animals raised in an agricultural setting to produce commodities such as food, fiber and labor. The term "livestock" as used in this article does not include poultry or farmed fish; however the inclusion of these, especially poultry, within the meaning...
industries, particularly in North America
North America
North America is a continent wholly within the Northern Hemisphere and almost wholly within the Western Hemisphere. It is also considered a northern subcontinent of the Americas...
.
Pharmacology
Swainsonine inhibits glycoside hydrolaseGlycoside hydrolase
Glycoside hydrolases catalyze the hydrolysis of the glycosidic linkage to release smaller sugars...
s, specifically N-linked glycosylation
N-linked glycosylation
N-linked glycosylation is important for the folding of some eukaryotic proteins. The N-linked glycosylation process occurs in eukaryotes and widely in archaea, but very rarely in bacteria....
. Disruption of Golgi alpha-mannosidase II with swainsonine induces hybrid-type glycans
Glycans
The term glycan refers to a polysaccharide or oligosaccharide. Glycans usually consist solely of O-glycosidic linkages of monosaccharides. For example, cellulose is a glycan composed of beta-1,4-linked D-glucose, and chitin is a glycan composed of beta-1,4-linked N-acetyl-D-glucosamine...
. These glycans have a Man5GlcNAc2 core with processing on the 3-arm that resembles so-called complex-type glycans.
The pharmacological properties of this product have not been fully investigated.
Sources
Swainsonine is a natural productNatural product
A natural product is a chemical compound or substance produced by a living organism - found in nature that usually has a pharmacological or biological activity for use in pharmaceutical drug discovery and drug design...
that has been isolated from numerous species
Species
In biology, a species is one of the basic units of biological classification and a taxonomic rank. A species is often defined as a group of organisms capable of interbreeding and producing fertile offspring. While in many cases this definition is adequate, more precise or differing measures are...
of flowering plant
Flowering plant
The flowering plants , also known as Angiospermae or Magnoliophyta, are the most diverse group of land plants. Angiosperms are seed-producing plants like the gymnosperms and can be distinguished from the gymnosperms by a series of synapomorphies...
s and some fungi
Fungus
A fungus is a member of a large group of eukaryotic organisms that includes microorganisms such as yeasts and molds , as well as the more familiar mushrooms. These organisms are classified as a kingdom, Fungi, which is separate from plants, animals, and bacteria...
(see Locoweed
Locoweed
Locoweed is a common name in North America for any plant that produces swainsonine, a phytotoxin harmful to livestock. Worldwide, swainsonine is produced by a small number of species, most in three genera of the flowering plant family Fabaceae: Oxytropis and Astragalus in North America, and...
). It was first isolated from Swainsona
Swainsona
Swainsona is a large genus of flowering plants native to Australasia. There are 85 species, all but one of which is endemic to Australia; the exception, S...
in Australia
Australia
Australia , officially the Commonwealth of Australia, is a country in the Southern Hemisphere comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands in the Indian and Pacific Oceans. It is the world's sixth-largest country by total area...
.
Swainsonine is extracted commercially from several species of plants and fungi, including the soil fungus Metarhizium anisopliae
Metarhizium anisopliae
Metarhizium anisopliae, formerly known as Entomophthora anisopliae , is a fungus that grows naturally in soils throughout the world and causes disease in various insects by acting as a parasite. Ilya I. Mechnikov named it after the insect species it was originally isolated from: the beetle...
. It also can be produced from total synthesis
Total synthesis
In organic chemistry, a total synthesis is, in principle, the complete chemical synthesis of complex organic molecules from simpler pieces, usually without the aid of biological processes. In practice, these simpler pieces are commercially available in bulk and semi-bulk quantities, and are often...
.
Biosynthesis
The biosynthesis of swainsonine has been investigated in the fungus Rhizoctonia leguminicolaRhizoctonia leguminicola
Rhizoctonia leguminicola is a fungus that is a plant pathogen that most often attaches itself to the Trifolium pratense or red clover. It is also called Black Patch Disease. The infection is first seen as small black patches on the leaves of red clover and spreads to cover the entire plant,...
, and it initially involves the conversion of lysine
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
into pipecolic acid
Pipecolic acid
Pipecolic acid is a small organic molecule which accumulates in pipecolic acidemia. It is the carboxylic acid of piperidine.It can be associated with some forms of epilepsy....
. The pyrrolidine
Pyrrolidine
Pyrrolidine, also known as tetrahydropyrrole, is an organic compound with the molecular formula C4H9N. It is a cyclic secondary amine with a five-membered heterocycle containing four carbon atoms and one nitrogen atom...
ring is then formed via retention of the carbon atom of the pipecolate’s carboxyl
Carboxylic acid
Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...
group, as well as the coupling of two more carbon atoms from either acetate
Acetate
An acetate is a derivative of acetic acid. This term includes salts and esters, as well as the anion found in solution. Most of the approximately 5 billion kilograms of acetic acid produced annually in industry are used in the production of acetates, which usually take the form of polymers. In...
or malonate
Malonate
The malonate or propanedioate ion is CH222− . Malonate compounds include salts and esters of malonic acid, such as*diethyl malonate, 2,*dimethyl malonate, 2,...
to form a pipecolylacetate. The retention of the carboxyl carbon is striking, since it is normally lost in the biosynthesis of most other alkaloids.
The resulting oxoindolizidine is then reduced to (1R,8aS)- 1-hydroxyindolizidine, which is subsequently hydroxylated
Hydroxyl
A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...
at the C2 carbon atom to yield 1,2-dihydroxyindolizidine. Finally, an 8-hydroxyl group is introduced through epimerization at C-8a to yield swainsonine. Schneider et. al. have suggested that oxidation occurs at C-8a to give an iminium ion
Iminium
An iminium salt or cation in organic chemistry has the general structure [R1R2C=NR3R4]+ and is as such a protonated or substituted imine. It is an intermediate in many organic reactions such as the Beckmann rearrangement, Vilsmeier-Haack reaction, Stephen reaction or the Duff reaction...
. Reduction from the β face would then yield the R configuration of swainsonine, as opposed to the S configuration of slaframine
Slaframine
Slaframine is a kind of piperidine or indolizidine alkaloidal mycotoxin that generally causes salivation in most of the animals. It is usually produced by the fungus Rhizoctonia leguminicola. It is a common fungal pathogen of red clover that causes black patch disease in the plant . Slaframine has...
, another indolizine alkaloid whose biosynthesis is similar to that of swainsonine during the first half of the pathway and also shown above alongside that of swainsonine. The instance at which oxidation and reduction occur with regard to the introduction of the hydroxyl groups at the C2 and C8 positions is still under investigation.
The biosynthetic pathway of swainsonine has also been investigated in the Diablo locoweed
Locoweed
Locoweed is a common name in North America for any plant that produces swainsonine, a phytotoxin harmful to livestock. Worldwide, swainsonine is produced by a small number of species, most in three genera of the flowering plant family Fabaceae: Oxytropis and Astragalus in North America, and...
. Through detection of (1,8a-trans)-1-hydroxyindolizidine and (1,8a-trans-1,2-cis)-1,2-dihydroxyindolizidine—two precursors of swainsonine in the fungus pathway—in the shoots of the plant, Harris et. al. proposed that the biosynthetic pathway of swainsonine in the locoweed is nearly identical to that of the fungus.
Livestock losses
Because chronic intoxication with swainsonine causes a variety of neurological disorders in livestockLivestock
Livestock refers to one or more domesticated animals raised in an agricultural setting to produce commodities such as food, fiber and labor. The term "livestock" as used in this article does not include poultry or farmed fish; however the inclusion of these, especially poultry, within the meaning...
, these plant species are known collectively as locoweed
Locoweed
Locoweed is a common name in North America for any plant that produces swainsonine, a phytotoxin harmful to livestock. Worldwide, swainsonine is produced by a small number of species, most in three genera of the flowering plant family Fabaceae: Oxytropis and Astragalus in North America, and...
s. Other effects of intoxication include reduced appetite and consequent reduced growth in young animals and loss of weight in adults, and cessation of reproduction (loss of libido, loss of fertility, and abortion).
Potential uses
Swainsonine is an anti-cancer drug with potential for treating gliomaGlioma
A glioma is a type of tumor that starts in the brain or spine. It is called a glioma because it arises from glial cells. The most common site of gliomas is the brain.-By type of cell:...
and gastric carcinoma
Stomach cancer
Gastric cancer, commonly referred to as stomach cancer, can develop in any part of the stomach and may spread throughout the stomach and to other organs; particularly the esophagus, lungs, lymph nodes, and the liver...
. However, a phase II clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
of GD0039 (a hydrochloride salt of swainsonine) in 17 patients with renal carcinoma
Kidney cancer
Kidney cancer is a type of cancer that starts in the cells in the kidney.The two most common types of kidney cancer are renal cell carcinoma and urothelial cell carcinoma of the renal pelvis...
was discouraging. Swainsonine's activity against tumors is attributed to its stimulation of macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s.
Swainsonine also has potential uses as an adjuvant for anti-cancer drugs and other therapies in use. In mice, swainsonine reduces the toxicity of doxorubicin
Doxorubicin
Doxorubicin INN is a drug used in cancer chemotherapy. It is an anthracycline antibiotic, closely related to the natural product daunomycin, and like all anthracyclines, it works by intercalating DNA....
, suggesting that swainsonine might enable use of higher doses of doxorubicin. Swainsonine may promote restoration of bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
damaged by some types of cancer treatments.
Swainsonine is an appetite suppressant.