Swainsonine

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Swainsonine
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 Edit this at Wikidata
KEGG
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 checkY
    Key: FXUAIOOAOAVCGD-WCTZXXKLSA-N checkY
  • 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).
☒N verify (what is checkY☒N ?)

Swainsonine is 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]

Pharmacology

Swainsonine inhibits

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
Family Fungi
Pleosporaceae Undifilum oxytropis[4]
Clavicipitaceae
Metarhizium anisopliae[5]
Plant sources
Family Plants
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

Biosynthesis

The biosynthesis of swainsonine has been investigated in the fungus

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[13]

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

References

  1. ^ "NCATS Inxight: Drugs". drugs.ncats.io. Retrieved 2020-01-22.
  2. S2CID 45016726
    .
  3. ^
    PMID 6786280
    .
  4. PMID 27477109
    .
  5. doi:10.1016/S0953-7562(09)80776-4
    .
  6. PMID 21214242
    .
  7. PMID 27436221
    .
  8. PMID 23547913
    .
  9. ISSN 0100-736X
    .
  10. ISSN 1678-5150
    .
  11. PMID 22362938
    .
  12. ^
    doi:10.1016/S0040-4039(00)80616-4. Closed access icon
  13. ^
    S2CID 250930070
    .
  14. ^ "THE DARLING PEA". The Sydney Morning Herald. National Library of Australia. 14 May 1897. p. 5. Retrieved 16 May 2014.
  15. PMID 10091128
    .
  16. PMID 19427771
    .
  17. PMID 17097281
    .
  18. S2CID 33471927
    .
  19. PMID 8835286
    .
  20. PMID 14682391
    .
  21. PMID 14682385
    .
  22. PMID 12946451
    .
  23. PMID 10389983
    .
  24. PMID 20504027
    .
  25. ^
    PMID 28470253
    .
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