Swainsonine

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Swainsonine
Swainsonine Formula V.1.svg
Names
Preferred IUPAC name
(1S,2R,8R,8aR)-Octahydroindolizine-1,2,8-triol
Other names
Tridolgosir
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.123.531 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • InChI=1S/C8H15NO3/c10-5-2-1-3-9-4-6(11)8(12)7(5)9/h5-8,10-12H,1-4H2/t5-,6-,7-,8-/m1/s1 Yes check.svgY
    Key: FXUAIOOAOAVCGD-WCTZXXKLSA-N Yes check.svgY
  • InChI=1/C8H15NO3/c10-5-2-1-3-9-4-6(11)8(12)7(5)9/h5-8,10-12H,1-4H2/t5-,6-,7-,8-/m1/s1
    Key: FXUAIOOAOAVCGD-WCTZXXKLBP
  • InChI=1S/C8H15NO3/c10-5-2-1-3-9-4-6(11)8(12)7(5)9/h5-8,10-12H,1-4H2/t5-,6-,7-,8-/m1/s1
    Key: FXUAIOOAOAVCGD-WCTZXXKLSA-N
  • C1C[C@H]([C@@H]2[C@@H]([C@@H](CN2C1)O)O)O
Properties
C8H15NO3
Molar mass 173.2
Melting point 143 to 144 °C (289 to 291 °F; 416 to 417 K)
10 mg/1 mL
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Swainsonine is an indolizidine alkaloid. It is a potent inhibitor of Golgi alpha-mannosidase II, an immunomodulator, and a potential chemotherapy drug. [1] As a toxin in locoweed (likely its primary toxin [2] ) it also is a significant cause of economic losses in livestock industries, particularly in North America. It was first isolated from Swainsona canescens . [3]

Contents

Pharmacology

Swainsonine inhibits glycoside hydrolases, specifically those involved in 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.[ citation needed ]

The pharmacological properties of this product have not been fully investigated.[ citation needed ]

Sources

Some plants[ which? ] do not produce the toxic compound itself; they are host of endophytic fungi which produces swainsonine.[ citation needed ]

Fungal Sources
FamilyFungi
Pleosporaceae Undifilum oxytropis [4]
Clavicipitaceae Metarhizium anisopliae [5]
Plant sources
FamilyPlants
Fabaceae Swainsona canescens , Astragalus earlei , A. mollissimus , A. pubentissimus , A. lentiginosis , A. wootoni , A. nothoxys , A. tephrodes , A. humistratus [6] [7] [3]
Convolvulaceae Jacquemontia corymbulosa , Ipomoea verbascoidea , I. subincana , I. megapotamica , I. rosea , I. carnea , I. sericophylla , I. riedelii [8] [9] [10] [11]
Swainsonine biosynthesis scheme Swainsonine Biosynthesis Scheme.gif
Swainsonine biosynthesis scheme

Biosynthesis

The biosynthesis of swainsonine has been investigated in the fungus Rhizoctonia leguminicola , 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. [12]

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 indolizidine 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. [12]

The biosynthetic pathway of swainsonine has also been investigated in the Diablo locoweed ( Astragalus oxyphysus ). 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. [12]

Synthesis

Despite the small size of swaisonine, the synthesis of this molecule and its analogues is quite challenging due to the presence of four chiral centers. In most cases, synthesis implies the use of sugars, chiral aminoacids as starting compounds, or chiral catalysts to induce chirality.The swainsonine synthesis was systemazed by three common precursors: 8-oxy-hexahydroindolizines, N-protected-3-oxy-2-substituted-piperidines and 2-substituted-pyrrolidine-3,4-protected-diols. [13]

Swainsonine synthesis from common precursors Swainsonine synthesis from common precursors.png
Swainsonine synthesis from common precursors

Livestock losses

Because chronic intoxication with swainsonine causes a variety of neurological disorders in livestock, [14] these plant species are known collectively as locoweeds. 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). [15]

Potential uses

Swainsonine has a potential for treating cancers such as glioma [16] and gastric carcinoma. [17] However, a phase II clinical trial of GD0039 (a hydrochloride salt of swainsonine) in 17 patients with renal carcinoma was discouraging. [18] Swainsonine's activity against tumors is attributed to its stimulation of macrophages. [19]

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. [20] [21] Swainsonine may promote restoration of bone marrow damaged by some types of cancer treatments. [22] [23]

Molecular mechanism

The inhibitory effect of swainsonine on Golgi Mannosidase II (GMII) was proposed to be due to its ability to bind in the GMII binding pocket in a similar fashion as the natural GMII substrate in its transition state. [24] Later, it was shown that the binding pattern of the swainsonine molecule resembles that of the Michaelis complex of mannose and only the protonated, charge positive swainsonine molecule binds similarly to the substrate in its transition state. [25] The actual state in which swainsonine binds in the mannosidase remains undetermined and is most likely dependent on the pH at which the enzyme operates. [25]

See also

Related Research Articles

<span class="mw-page-title-main">Mannose</span> Chemical compound

Mannose is a sugar monomer of the aldohexose series of carbohydrates. It is a C-2 epimer of glucose. Mannose is important in human metabolism, especially in the glycosylation of certain proteins. Several congenital disorders of glycosylation are associated with mutations in enzymes involved in mannose metabolism.

Locoweed is a common name in North America for any plant that produces swainsonine, an alkaloid harmful to livestock. Worldwide, swainsonine is produced by a small number of species, most of them in three genera of the flowering plant family Fabaceae: Oxytropis and Astragalus in North America, and Swainsona in Australia. The term locoweed usually refers only to the North American species of Oxytropis and Astragalus, but this article includes the other species as well. Some references may incorrectly list Datura as locoweed.

<span class="mw-page-title-main">Ergine</span> Chemical compound

Ergine, also known as d-lysergic acid amide (LSA) and d-lysergamide, is an ergoline alkaloid that occurs in various species of vines of the Convolvulaceae and some species of fungi. The psychedelic properties in the seeds of ololiuhqui, Hawaiian baby woodrose and morning glories have been linked to ergine and/or isoergine, its epimer, as it is an alkaloid present in the seeds.

<i>Astragalus</i> (plant) Genus of legumes

Astragalus is a large genus of over 3,000 species of herbs and small shrubs, belonging to the legume family Fabaceae and the subfamily Faboideae. It is the largest genus of plants in terms of described species. The genus is native to temperate regions of the Northern Hemisphere. Common names include milkvetch, locoweed and goat's-thorn. Some pale-flowered vetches are similar in appearance, but they are more vine-like than Astragalus.

<span class="mw-page-title-main">Alpha-mannosidosis</span> Medical condition

Alpha-mannosidosis is a lysosomal storage disorder, first described by Swedish physician Okerman in 1967. In humans it is known to be caused by an autosomal recessive genetic mutation in the gene MAN2B1, located on chromosome 19, affecting the production of the enzyme alpha-D-mannosidase, resulting in its deficiency. Consequently, if both parents are carriers, there will be a 25% chance with each pregnancy that the defective gene from both parents will be inherited, and the child will develop the disease. There is a two in three chance that unaffected siblings will be carriers. In livestock alpha-mannosidosis is caused by chronic poisoning with swainsonine from locoweed.

<span class="mw-page-title-main">Cyclopamine</span> Chemical compound

Cyclopamine (11-deoxojervine) is a naturally occurring steroidal alkaloid. It is a teratogenic component of corn lily, which when consumed during gestation has been demonstrated to induce birth defects, including the development of a single eye (cyclopia) in offspring. The molecule was named after this effect, which was originally observed by Idaho lamb farmers in 1957 after their herds gave birth to cycloptic lambs. It then took more than a decade to identify corn lily as the culprit. Later work suggested that differing rain patterns had changed grazing behaviours, which led to a greater quantity of corn lily to be ingested by pregnant sheep. Cyclopamine interrupts the sonic hedgehog signalling pathway, instrumental in early development, ultimately causing birth defects.

<span class="mw-page-title-main">Lycorine</span> Chemical compound

Lycorine is a toxic crystalline alkaloid found in various Amaryllidaceae species, such as the cultivated bush lily, surprise lilies (Lycoris), and daffodils (Narcissus). It may be highly poisonous, or even lethal, when ingested in certain quantities. Regardless, it is sometimes used medicinally, a reason why some groups may harvest the very popular Clivia miniata.

<span class="mw-page-title-main">MAN1B1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">MAN2A1</span> Protein-coding gene in the species Homo sapiens

Alpha-mannosidase 2 is an enzyme that in humans is encoded by the MAN2A1 gene.

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Mannosyl-oligosaccharide 1,2-alpha-mannosidase IA is an enzyme that in humans is encoded by the MAN1A1 gene.

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<i>N</i>-linked glycosylation Attachment of an oligosaccharide to a nitrogen atom

N-linked glycosylation, is the attachment of an oligosaccharide, a carbohydrate consisting of several sugar molecules, sometimes also referred to as glycan, to a nitrogen atom, in a process called N-glycosylation, studied in biochemistry. The resulting protein is called an N-linked glycan, or simply an N-glycan.

<i>Ipomoea carnea</i> Species of flowering plant

Ipomoea carnea, the pink morning glory, is a species of morning glory that grows as a bush. This flowering plant has heart-shaped leaves that are a rich green and 6–9 inches (15–23 cm) long. It can be easily grown from seeds. These seeds are toxic and it can be hazardous to cattle; the toxicity is related to the swainsonine produced by its endophytes, and to bioaccumulation of selenium in the leaves but mostly in the seeds.

<span class="mw-page-title-main">Castanospermine</span> Chemical compound

Castanospermine is an indolizidine alkaloid first isolated from the seeds of Castanospermum australe. It is a potent inhibitor of some glucosidase enzymes and has antiviral activity in vitro and in mouse models.

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Methaneseleninic acid (methylseleninic acid or MSA) is a seleninic acid with the chemical formula CH3SeO2H.

Mannosyl-oligosaccharide 1,3-1,6-α-mannosidase, also known as Golgi α-mannosidase II, is an enzyme with systematic name (1→3)-(1→6)-mannosyl-oligosaccharide α-D-mannohydrolase. It catalyses the hydrolysis of the terminal (1→3)- and (1→6)-linked α-D-mannose residues in the mannosyl-oligosaccharide Man5(GlcNAc)3.

<span class="mw-page-title-main">Kifunensine</span> Chemical compound

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<span class="mw-page-title-main">Magnoflorine</span> Chemical compound

(S)-Magnoflorine is a quaternary benzylisoquinoline alkaloid (BIA) of the aporphine structural subgroup which has been isolated from various species of the family Menispermaceae, such as Pachygone ovata,Sinomenium acutum, and Cissampelos pareira. 

References

  1. ↑ "NCATS Inxight: Drugs". drugs.ncats.io. Retrieved 2020-01-22.
  2. ↑ Stegelmeier BL, Molyneux RJ, Elbein AD, James LF (May 1995). "The lesions of locoweed (Astragalus mollissimus), swainsonine, and castanospermine in rats". Veterinary Pathology. 32 (3): 289–98. doi: 10.1177/030098589503200311 . PMID   7604496. S2CID   45016726.
  3. 1 2 Dorling PR, Huxtable CR, Colegate SM (November 1980). "Inhibition of lysosomal alpha-mannosidase by swainsonine, an indolizidine alkaloid isolated from Swainsona canescens". The Biochemical Journal . 191 (2): 649–51. doi:10.1042/bj1910649. PMC   1162258 . PMID   6786280.
  4. ↑ Lu, Hao; Quan, Haiyun; Ren, Zhenhui; Wang, Shuai; Xue, Ruixu; Zhao, Baoyu (2016). "The Genome of Undifilum oxytropis Provides Insights into Swainsonine Biosynthesis and Locoism". Scientific Reports. 6 (1): 30760. Bibcode:2016NatSR...630760L. doi: 10.1038/srep30760 . ISSN   2045-2322. PMC   4967851 . PMID   27477109.
  5. ↑ Sim, Kim Lan; Perry, David (1 September 1995). "Swainsonine production by Metarhizium anisopliae determined by means of an enzymatic assay". Mycological Research. 99 (9): 1078–1082. doi:10.1016/S0953-7562(09)80776-4.
  6. ↑ Cook D, Gardner DR, Grum D, Pfister JA, Ralphs MH, Welch KD, Green BT (February 2011). "Swainsonine and endophyte relationships in Astragalus mollissimus and Astragalus lentiginosus". Journal of Agricultural and Food Chemistry . 59 (4): 1281–7. doi:10.1021/jf103551t. PMID   21214242.
  7. ↑ Gardner, DR; Cook, D (2016). "Analysis of Swainsonine and Swainsonine N-Oxide as Trimethylsilyl Derivatives by Liquid Chromatography-Mass Spectrometry and Their Relative Occurrence in Plants Toxic to Livestock". J Agric Food Chem. 64 (31): 6156–62. doi:10.1021/acs.jafc.6b02390. PMID   27436221.
  8. ↑ Cook D, Beaulieu WT, Mott IW, Riet-Correa F, Gardner DR, Grum D, Pfister JA, Clay K, Marcolongo-Pereira C (April 2013). "Production of the alkaloid swainsonine by a fungal endosymbiont of the Ascomycete order Chaetothyriales in the host Ipomoea carnea". Journal of Agricultural and Food Chemistry . 61 (16): 3797–803. doi:10.1021/jf4008423. PMID   23547913.
  9. ↑ Barbosa, Rossemberg C.; Riet-Correa, Franklin; Lima, Everton F.; Medeiros, Rosane M.T.; Guedes, Karla M.R.; Gardner, Dale R.; Molyneux, Russell J.; Melo, Lúcio E.H. de (2007). "Experimental swainsonine poisoning in goats ingesting Ipomoea sericophylla and Ipomoea riedelii (Convolvulaceae)". Pesquisa Veterinária Brasileira. 27 (10): 409–414. doi: 10.1590/S0100-736X2007001000004 . ISSN   0100-736X.
  10. ↑ Mendonça, Fábio S.; Silva Filho, Givaldo B.; Chaves, Hisadora A.S.; Aires, Lorena D.A.; Braga, Thaiza C.; Gardner, Dale R.; Cook, Daniel; Buril, Maria T. (2018). "Detection of swainsonine and calystegines in Convolvulaceae species from the semiarid region of Pernambuco". Pesquisa Veterinária Brasileira. 38 (11): 2044–2051. doi: 10.1590/1678-5150-pvb-5945 . ISSN   1678-5150.
  11. ↑ Mendonça FS, Albuquerque RF, Evêncio-Neto J, Freitas SH, Dória RG, Boabaid FM, Driemeier D, Gardner DR, Riet-Correa F, Colodel EM (January 2012). "Alpha-mannosidosis in goats caused by the swainsonine-containing plant Ipomoea verbascoidea". Journal of Veterinary Diagnostic Investigation . 24 (1): 90–5. doi: 10.1177/1040638711425948 . PMID   22362938.
  12. 1 2 3 Harris, Constance M.; Bruce C. Campbell; Russell J. Molyneux; Thomas M. Harris (1988). "Biosynthesis of swainsonine in the diablo locoweed (Astragalus oxyphyrus)". Tetrahedron Letters. 29 (38): 4815–4818. doi:10.1016/S0040-4039(00)80616-4. Closed Access logo transparent.svg
  13. 1 2 Drogalin, Artem (2022-07-21). "Advances in the Chemistry of (−)-D-Swainsonine". ChemistrySelect. 7 (27). doi:10.1002/slct.202201905. ISSN   2365-6549. S2CID   250930070.
  14. ↑ "THE DARLING PEA". The Sydney Morning Herald . National Library of Australia. 14 May 1897. p. 5. Retrieved 16 May 2014.
  15. ↑ Panter KE, James LF, Stegelmeier BL, Ralphs MH, Pfister JA (February 1999). "Locoweeds: effects on reproduction in livestock". Journal of Natural Toxins. 8 (1): 53–62. PMID   10091128.
  16. ↑ Sun JY, Yang H, Miao S, Li JP, Wang SW, Zhu MZ, Xie YH, Wang JB, Liu Z, Yang Q (May 2009). "Suppressive effects of swainsonine on C6 glioma cell in vitro and in vivo". Phytomedicine. 16 (11): 1070–4. doi:10.1016/j.phymed.2009.02.012. PMID   19427771.
  17. ↑ Sun JY, Zhu MZ, Wang SW, Miao S, Xie YH, Wang JB (May 2007). "Inhibition of the growth of human gastric carcinoma in vivo and in vitro by swainsonine". Phytomedicine. 14 (5): 353–9. doi:10.1016/j.phymed.2006.08.003. PMID   17097281.
  18. ↑ Shaheen PE, Stadler W, Elson P, Knox J, Winquist E, Bukowski RM (December 2005). "Phase II study of the efficacy and safety of oral GD0039 in patients with locally advanced or metastatic renal cell carcinoma". Investigational New Drugs. 23 (6): 577–81. doi:10.1007/s10637-005-0793-z. PMID   16034517. S2CID   33471927.
  19. ↑ Das PC, Roberts JD, White SL, Olden K (1995). "Activation of resident tissue-specific macrophages by swainsonine". Oncology Research. 7 (9): 425–33. PMID   8835286.
  20. ↑ Oredipe OA, Furbert-Harris PM, Laniyan I, Green WR, Griffin WM, Sridhar R (November 2003). "Mice primed with swainsonine are protected against doxorubicin-induced lethality". Cellular and Molecular Biology (Noisy-le-Grand, France). 49 (7): 1089–99. PMID   14682391.
  21. ↑ Oredipe OA, Furbert-Harris PM, Laniyan I, Green WR, Griffin WM, Sridhar R (November 2003). "Coadministration of swainsonine and doxorubicin attenuates doxorubicin-induced lethality in mice". Cellular and Molecular Biology (Noisy-le-Grand, France). 49 (7): 1037–48. PMID   14682385.
  22. ↑ Oredipe OA, Furbert-Harris PM, Laniyan I, Griffin WM, Sridhar R (October 2003). "Limits of stimulation of proliferation and differentiation of bone marrow cells of mice treated with swainsonine". International Immunopharmacology. 3 (10–11): 1537–47. doi:10.1016/S1567-5769(03)00186-3. PMID   12946451.
  23. ↑ Klein JL, Roberts JD, George MD, Kurtzberg J, Breton P, Chermann JC, Olden K (April 1999). "Swainsonine protects both murine and human haematopoietic systems from chemotherapeutic toxicity". British Journal of Cancer. 80 (1–2): 87–95. doi:10.1038/sj.bjc.6690326. PMC   2363022 . PMID   10389983.
  24. ↑ Petersen, Luis; Ardèvol, Albert; Rovira, Carme; Reilly, Peter J. (23 June 2010). "Molecular Mechanism of the Glycosylation Step Catalyzed by Golgi α-Mannosidase II: A QM/MM Metadynamics Investigation". Journal of the American Chemical Society. 132 (24): 8291–8300. doi:10.1021/ja909249u. PMID   20504027.
  25. 1 2 Sladek, V.; Kóňa, J.; Tokiwa, H. (2017). "In silico analysis of interaction pattern switching in ligand⋯receptor binding in Golgi α-mannosidase II induced by the protonated states of inhibitors". Physical Chemistry Chemical Physics. 19 (19): 12527–12537. Bibcode:2017PCCP...1912527S. doi:10.1039/c7cp01200d. PMID   28470253.
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