Swainsonine

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Swainsonine
Swainsonine Formula V.1.svg
Identifiers
CAS number 72741-87-8 N
PubChem 51683
ChemSpider 46788 YesY
UNII RSY4RK37KQ YesY
DrugBank DB02034
KEGG C10173 YesY
ChEBI CHEBI:9367 N
ChEMBL CHEMBL371197 YesY
Jmol-3D images Image 1
Properties
Molecular formula C8H15NO3
Molar mass 173.21 g mol−1
Melting point 143-144 °C
Solubility in water 10 mg/1 mL
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 N (verify) (what is: YesY/N?)
Infobox references

Swainsonine is an indolizidine 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[1]) it also is a significant cause of economic losses in livestock industries, particularly in North America.

Pharmacology[edit]

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[edit]

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[edit]

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.[2]

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.[2]

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.[2]

Livestock losses[edit]

Because chronic intoxication with swainsonine causes a variety of neurological disorders in livestock,[3] 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).[4]

Potential uses[edit]

Swainsonine is an anti-cancer drug with potential for treating glioma[5] and gastric carcinoma.[6] However, a phase II clinical trial of GD0039 (a hydrochloride salt of swainsonine) in 17 patients with renal carcinoma was discouraging.[7] Swainsonine's activity against tumors is attributed to its stimulation of macrophages.[8]

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.[9][10] Swainsonine may promote restoration of bone marrow damaged by some types of cancer treatments.[11][12]

Swainsonine is an appetite suppressant.[13]

See also[edit]

References[edit]

  1. ^ 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. 
  2. ^ a b c Harris, Constance M.; Bruce C. Campbell, Russell J. Molyneux, and 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
  3. ^ "THE DARLING PEA.". The Sydney Morning Herald (NSW : 1842 - 1954) (NSW: National Library of Australia). 14 May 1897. p. 5. Retrieved 16 May 2014. 
  4. ^ 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. 
  5. ^ 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 : International Journal of Phytotherapy and Phytopharmacology 16 (11): 1070–4. doi:10.1016/j.phymed.2009.02.012. PMID 19427771. 
  6. ^ 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 : International Journal of Phytotherapy and Phytopharmacology 14 (5): 353–9. doi:10.1016/j.phymed.2006.08.003. PMID 17097281. 
  7. ^ 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. 
  8. ^ 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. 
  9. ^ 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. 
  10. ^ 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. 
  11. ^ 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. 
  12. ^ 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. Retrieved 2009-05-15. 
  13. ^ Pritchard DH, Huxtable CR, Dorling PR (March 1990). "Swainsonine toxicosis suppresses appetite and retards growth in weanling rats". Research in Veterinary Science 48 (2): 228–30. PMID 2110378.