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Swainsonine

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Swainsonine
Names
IUPAC name (1S,2R,8R,8aR)-1,2,3,5,6,7,8,8a-Octahydroindolizine- 1,2,8-triol
Other names Tridolgosir
Identifiers
CAS Number
3D model (JSmol)
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.123.531 Edit this at Wikidata
KEGG
PubChem CID
UNII
CompTox Dashboard (EPA)
InChI
  • 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/s1Key: FXUAIOOAOAVCGD-WCTZXXKLSA-N
  • 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/s1Key: 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/s1Key: FXUAIOOAOAVCGD-WCTZXXKLSA-N
SMILES
  • C1C(2((CN2C1)O)O)O
Properties
Chemical formula C8H15NO3
Molar mass 173.2
Melting point 143-144 °C
Solubility in water 10 mg/1 mL
Except where otherwise noted, data are given for materials in their standard state (at 25 °C , 100 kPa). ☒N verify (what is  ?) Infobox references
Chemical compound

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.

Pharmacology

Swainsonine inhibits glycoside hydrolases, 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.

Sources

Swainsonine is a natural product that has been isolated from numerous species of flowering plants 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.

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.

Swainsonine Biosynthesis Scheme

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.

Livestock losses

Because chronic intoxication with swainsonine causes a variety of neurological disorders in livestock, 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).

Potential uses

Swainsonine is an anti-cancer drug with potential for treating glioma 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 macrophages.

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.

See also

References

  1. Stegelmeier BL, Molyneux RJ, Elbein AD, James LF (1995). "The lesions of locoweed (Astragalus mollissimus), swainsonine, and castanospermine in rats". Veterinary Pathology. 32 (3): 289–98. doi:10.1177/030098589503200311. PMID 7604496. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  2. Harris, Constance M. (3 June 1988). "Biosynthesis of swainsonine in the diablo locoweed (Astragalus oxyphyrus)". Tetrahedron Letters. 29 (38): 4815–4818. doi:10.1016/S0040-4039(00)80616-4. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  3. Harris, Constance M. (3 June 1988). "Biosynthesis of swainsonine in the diablo locoweed (Astragalus oxyphyrus)". Tetrahedron Letters. 29 (38): 4815–4818. doi:10.1016/S0040-4039(00)80616-4. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  4. Harris, Constance M. (3 June 1988). "Biosynthesis of swainsonine in the diablo locoweed (Astragalus oxyphyrus)". Tetrahedron Letters. 29 (38): 4815–4818. doi:10.1016/S0040-4039(00)80616-4. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  5. Panter KE, James LF, Stegelmeier BL, Ralphs MH, Pfister JA (1999). "Locoweeds: effects on reproduction in livestock". Journal of Natural Toxins. 8 (1): 53–62. PMID 10091128. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  6. Sun JY, Yang H, Miao S, Li JP, Wang SW, Zhu MZ, Xie YH, Wang JB, Liu Z, Yang Q (2009). "Suppressive effects of swainsonine on C6 glioma cell in vitro and in vivo". Phytomedicine : International Journal of Phytotherapy and Phytopharmacology. 16 (11): 1070–4. doi:10.1016/j.phymed.2009.02.012. PMID 19427771. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. Sun JY, Zhu MZ, Wang SW, Miao S, Xie YH, Wang JB (2007). "Inhibition of the growth of human gastric carcinoma in vivo and in vitro by swainsonine". Phytomedicine : International Journal of Phytotherapy and Phytopharmacology. 14 (5): 353–9. doi:10.1016/j.phymed.2006.08.003. PMID 17097281. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. Shaheen PE, Stadler W, Elson P, Knox J, Winquist E, Bukowski RM (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. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. 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. {{cite journal}}: |access-date= requires |url= (help)CS1 maint: multiple names: authors list (link)
  10. Oredipe OA, Furbert-Harris PM, Laniyan I, Green WR, Griffin WM, Sridhar R (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. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  11. Oredipe OA, Furbert-Harris PM, Laniyan I, Green WR, Griffin WM, Sridhar R (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. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. Oredipe OA, Furbert-Harris PM, Laniyan I, Griffin WM, Sridhar R (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. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. Klein JL, Roberts JD, George MD, Kurtzberg J, Breton P, Chermann JC, Olden K (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. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  14. Pritchard DH, Huxtable CR, Dorling PR (1990). "Swainsonine toxicosis suppresses appetite and retards growth in weanling rats". Research in Veterinary Science. 48 (2): 228–30. PMID 2110378. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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