Sparteine

Sparteine
Clinical data
Other names(6R,8S,10R,12S)-7,15-diazatetracyclo[7.7.1.02,7.010,15]heptadecane
AHFS/Drugs.comInternational Drug Names
ATC code
Identifiers
IUPAC name
  • (7α,9α)-sparteine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.001.808 Edit this at Wikidata
Chemical and physical data
FormulaC15H26N2
Molar mass234.387 g·mol−1
3D model (JSmol)
Density1.02 g/cm3
Melting point30 °C (86 °F)
Boiling point325 °C (617 °F)
Solubility in water3.04 mg/mL (20 °C)
SMILES
  • C1CCN2C[C@@H]3C[C@H]([C@H]2C1)CN4[C@H]3CCCC4
InChI
  • InChI=1S/C15H26N2/c1-3-7-16-11-13-9-12(14(16)5-1)10-17-8-4-2-6-15(13)17/h12-15H,1-11H2/t12-,13-,14-,15+/m0/s1 checkY
  • Key:SLRCCWJSBJZJBV-ZQDZILKHSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Sparteine is a class 1a antiarrhythmic agent; a sodium channel blocker. It is an alkaloid and can be extracted from scotch broom. It is the predominant alkaloid in Lupinus mutabilis, and is thought to chelate the bivalent cations calcium and magnesium. It is not FDA approved for human use as an antiarrhythmic agent, and it is not included in the Vaughan Williams classification of antiarrhythmic drugs.

It is also used as a chiral ligand in organic chemistry, especially in syntheses involving organolithium reagents.

Biosynthesis

Originally proposed biosynthesis pathway of sparteine

Sparteine is a lupin alkaloid containing a tetracyclic bis-quinolizidine ring system derived from three C5 chains of lysine, or more specifically, L-lysine.[1] The first intermediate in the biosynthesis is cadaverine, the decarboxylation product of lysine catalyzed by the enzyme lysine decarboxylase (LDC).[2] Three units of cadaverine are used to form the quinolizidine skeleton. The mechanism of formation has been studied enzymatically, as well as with tracer experiments, but the exact route of synthesis still remains unclear.

Tracer studies using 13C-15N-doubly labeled cadaverine have shown three units of cadaverine are incorporated into sparteine and two of the C-N bonds from two of the cadaverine units remain intact.[3] The observations have also been confirmed using 2H NMR labeling experiments.[4]

Enzymatic evidence then showed that the three molecules of cadaverine are transformed to the quinolizidine ring via enzyme bound intermediates, without the generation of any free intermediates. Originally, it was thought that conversion of cadaverine to the corresponding aldehyde, 5-aminopentanal, was catalyzed by the enzyme diamine oxidase.[5] The aldehyde then spontaneously converts to the corresponding Schiff base, Δ1-piperideine. Coupling of two molecules occurs between the two tautomers of Δ1-piperideine in an aldol-type reaction. The imine is then hydrolyzed to the corresponding aldehyde/amine. The primary amine is then oxidized to an aldehyde followed by formation of the imine to yield the quinolizidine ring.[5]

Via 17-oxosparteine synthase

More recent enzymatic evidence has indicated the presence of 17-oxosparteine synthase (OS), a transaminase enzyme.[6][7][8][9][10][11] The deaminated cadaverine is not released from the enzyme, thus is can be assumed that the enzyme catalyzes the formation of the quinolizidine skeleton in a channeled fashion .[9][10][11] 7-oxosparteine requires four units of pyruvate as the NH2 acceptors and produces four molecules of alanine. Both lysine decarboxylase and the quinolizidine skeleton-forming enzyme are localized in chloroplasts.[12]

Biosynthesis of sparteine by 17-oxosparteine synthase
Proposed ring cyclization steps
Overall schematic

See also

  • Lupinus
  • Lupin poisoning

References

  1. ↑ Dewick PM (2009). Medicinal Natural Products, 3rd. Ed. Wiley. p. 311.
  2. ↑ Golebiewski WM, Spenser ID (1988). "Biosynthesis of the lupine alkaloids. II. Sparteine and lupanine". Canadian Journal of Chemistry. 66 (7): 1734–1748. doi:10.1139/v88-280.
  3. ↑ Rana J, Robins DJ (1983). "Quinolizidine alkaloid biosynthesis: incorporation of [1-amino-15 N, 1-13 C] cadaverine into sparteine". Journal of the Chemical Society, Chemical Communications (22): 1335–6. doi:10.1039/c39830001335.
  4. ↑ Fraser AM, Robins DJ (1984). J. Chem. Soc., Chem. Commun. 22: 1147–9. {{cite journal}}: Missing or empty |title= (help)
  5. 1 2 Aniszewski T (2007). Alkaloids - Secrets of Life, 1st Ed. Elsevier. pp. 98–101.
  6. ↑ Wink M, Hartmann T (1984). Enzymology of Quinolizidine Alkaloid Biosynthesis; Natural Products Chemistry: Zalewski and Skolik (Eds.). pp. 511–520.
  7. ↑ Wink M (December 1987). "Quinolizidine alkaloids: biochemistry, metabolism, and function in plants and cell suspension cultures". Planta Medica. 53 (6): 509–14. doi:10.1055/s-2006-962797. PMID 17269092.
  8. ↑ Wink M, Hartmann T (May 1979). "Cadaverine--pyruvate transamination: the principal step of enzymatic quinolizidine alkaloid biosynthesis in Lupinus polyphyllus cell suspension cultures". FEBS Letters. 101 (2): 343–6. doi:10.1016/0014-5793(79)81040-6. PMID 446758.
  9. 1 2 Perrey R, Wink M (1988). "On the Role of Δ1-Piperideine and Tripiperideine in the Biosynthesis of Quinolizidine Alkaloids". Z. Naturforsch. 43 (5–6): 363–369. doi:10.1515/znc-1988-5-607.
  10. 1 2 Atta-ur-Rahman (Ed.) (1995). Natural Products Chemistry. Vol. 15. Elsevier. p. 537. ISBN 978-0-444-42691-8.
  11. 1 2 Roberts M, Wink M, eds. (1998). Alkaloids: Biochemistry, Ecology, and Medicinal Applications. Plenum Press. pp. 112–114.
  12. ↑ Wink M, Hartmann T (1980). "Enzymatic Synthesis of Quinolizidine Alkaloids in Lupin Chloroplasts". Z. Naturforsch. 35 (1–2): 93–97. doi:10.1515/znc-1980-1-218.
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