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Sparteine

Sparteine
(−)-Sparteine.svg
Clinical data
Synonyms(6R,8S,10R,12S)-7,15-diazatetracyclo[7.7.1.02,7.010,15]heptadecane
AHFS/Drugs.comInternational Drug Names
ATC code
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard100.001.808 Edit this at Wikidata
Chemical and physical data
FormulaC15H26N2
Molar mass234.380 g/mol 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)
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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

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] The breakdown of this mechanism is shown in figure 1; however, the intermediates, as mentioned before, were not isolated.

Figure 1. Mechanistic Biosynthesis of Sparteine

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 (Figure 2).,[9][10][11] 7-oxosparteine requires four units of pyruvate as the NH2 acceptors and produces four molecules of alanine (Figure 3). Both lysine decarboxylase and the quinolizidine skeleton-forming enzyme are localized in chloroplasts.[12]

Figure 2.Biosynthesis of sparteine showing proposed ring cyclization steps
Figure 3.Schematic Biosynthesis of Sparteine with OS

See also

References

  1. ^ Dewick, P.M. (2009). Medicinal Natural Products, 3rd. Ed. Wiley. p. 311.
  2. ^ Golebiewski, W.M., Spenser (1988). "Biosynthesis of the lupine alkaloids. II. Sparteine and lupanine". Can. J. Chem. 66 (7): 1734–1748. doi:10.1139/v88-280.CS1 maint: multiple names: authors list (link)
  3. ^ Rana, J., Robins, D.J. (1983). "Quinolizidine alkaloid biosynthesis: incorporation of [1-amino-15N,1-13C]cadaverine into sparteine". J. Chem. Soc., Chem. Commun. 22 (22): 1335–6. doi:10.1039/c39830001335.CS1 maint: multiple names: authors list (link)
  4. ^ Fraser, A.M., Robins, D.J. (1984). J. Chem. Soc., Chem. Commun. 22: 1147–9. Missing or empty |title= (help)CS1 maint: multiple names: authors list (link)
  5. ^ a b 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.CS1 maint: multiple names: authors list (link)
  7. ^ Wink, M. (1987). "Quinolizidine Alkaloids: Biochemistry, Metabolism, and Function in Plants and Cell Suspension Cultures". Planta Medica. 53 (6): 509–514. doi:10.1055/s-2006-962797.
  8. ^ Wink, M., Hartmann, T. (1979). "Cadaverine--pyruvate transamination: the principal step of enzymatic quinolizidine alkaloid biosynthesis in Lupinus polyphyllus cell suspension cultures". FEBS Letters. 101 (2): 343–346. doi:10.1016/0014-5793(79)81040-6. PMID 446758.CS1 maint: multiple names: authors list (link)
  9. ^ a b 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.CS1 maint: multiple names: authors list (link)
  10. ^ a b Atta-ur-Rahman (Ed.) (1995). Natural Products Chemistry. 15. Elsevier. p. 537. ISBN 978-0-444-42691-8.CS1 maint: extra text: authors list (link)
  11. ^ a b Roberts, M., Wink, M. (Eds.) (1998). Alkaloids: Biochemistry, Ecology, and Medicinal Applications. Plenum Press. pp. 112–114.CS1 maint: multiple names: authors list (link) CS1 maint: extra text: authors list (link)
  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.CS1 maint: multiple names: authors list (link)

External links

  • Media related to Sparteine at Wikimedia Commons