Lupinine

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Lupinine
Names
Preferred IUPAC name
[(1R,9aR)-Octahydro-2H-quinolizin-1-yl]methane
Identifiers
3D model (
JSmol
)
3DMet
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard
 100.006.944 Edit this at Wikidata
EC Number
  • 207-638-0
KEGG
UNII
  • InChI=1S/C10H19NO/c12-8-9-4-3-7-11-6-2-1-5-10(9)11/h9-10,12H,1-8H2/t9-,10+/m0/s1 checkY
    Key: HDVAWXXJVMJBAR-VHSXEESVSA-N checkY
  • InChI=1/C10H19NO/c12-8-9-4-3-7-11-6-2-1-5-10(9)11/h9-10,12H,1-8H2/t9-,10+/m0/s1
    Key: HDVAWXXJVMJBAR-VHSXEESVBK
  • OC[C@H]1[C@@H]2N(CCC1)CCCC2
Properties
C10H19NO
Molar mass 169.268 g·mol−1
Melting point 68 to 69 °C (154 to 156 °F; 341 to 342 K)
Boiling point 269 to 270 °C (516 to 518 °F; 542 to 543 K)
Hazards
GHS labelling:
GHS07: Exclamation mark
Warning
H302, H312, H332
P261, P264, P270, P271, P280, P301+P312, P302+P352, P304+P312, P304+P340, P312, P322, P330, P363, P501
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 ?)

Lupinine is a

lupins) of the flowering plant family Fabaceae.[1] The scientific literature contains many reports on the isolation and synthesis of this compound as well as a vast number of studies on its biosynthesis from its natural precursor, lysine.[2][3] Studies have shown that lupinine hydrochloride is a mildly toxic acetylcholinesterase inhibitor and that lupinine has an inhibitory effect on acetylcholine receptors.[4][5] The characteristically bitter taste of lupin beans, which come from the seeds of Lupinus plants, is attributable to the quinolizidine alkaloids which they contain, rendering them unsuitable for human and animal consumption unless handled properly.[6][7] However, because lupin beans have potential nutritional value due to their high protein content,[8] efforts have been made to reduce their alkaloid content through the development of "sweet" varieties of Lupinus.[9][10]

Toxicity

Lupinine is a hepatotoxin prevalent in the seeds of leguminous herbs of the genus Lupinus.[9] Lupinine and other quinolizidine alkaloids give a bitter taste to naturally growing lupin flowers.[5] Due to the toxicity of quinolizidine alkaloids, lupin beans are soaked overnight and rinsed to remove some of their alkaloid content.[7] However, when the cooking and rinsing procedure is insufficient, 10 grams of seeds are able to liberate as much as 100 milligrams of lupinine.[11]

The neurotoxicity of lupinine has been known within veterinary medical circles for some time due to the use of lupins as a forage feed for grazing livestock since it has high protein content.[9] It[clarification needed][citation needed] is found to produce lupinosis, which is a morbid, and often fatal condition that results in acute atrophy of liver function and which affects domestic animals such as cattle and sheep.[9] When ingested by humans, quinolizidine alkaloid poisoning causes trembling, shaking, excitation, as well as convulsions.[12] Lupinine, in addition to being orally toxic to mammals, is also an insect antifeedant as well as a growth inhibitor for the grasshopper.[13]

Relative toxicity

Quinolizidine alkaloids in lupins

Lupinine, in comparison to other quinolizidine alkaloids commonly found in lupins, such as lupanine and sparteine, shows a lower toxicity. Lupinine, with a minimal lethal dose of 28–30 mg/kg and a toxic dose of 25–28 mg/kg, is about 85 percent as toxic as d-lupanine and about 90% as toxic as sparteine. The relative toxicity of lupinine with other quinolizidine alkaloids commonly found in lupins is shown in the table below.[14]

Relative Toxicity of Quinolizidine Alkaloids
Substance Minimal Lethal Dose (mg/Kg)[14] Toxic Dose (mg/Kg)[14]
Lupinine 28-30 25-28
Lupanine 22-25 21-24
Sparteine 23-30 21-31

Mechanism of action

Structural comparison of lupinine and acetylcholine

Studies on the hydrochloride of lupinine have shown it to be a reversible inhibitor of acetylcholinesterases.[4] Lupinine, a nitrogen-containing heterocycle, has a structure similar to the ammonium "head" of the acetylcholinesterase endogenous agonist, acetylcholine.[15] At physiological pH, the amine of lupinine is protonated which leads to ion-ion interaction with the acetylcholinesterase anionic site in the same manner as the ammonium on acetylcholine interacts.[15] Previous studies of reversible ammonium inhibitors similar to lupinine have shown that the ammonium groups (corresponding to the protonated amine of lupinine) enter the gorge of the active center of the acetylcholinesterase in the region of the Trp84 residue.[4] This leads to the formation of an enzyme-sorption complex with the anionic portion of the acetylcholinesterase located on the active site of lupinine, namely the amine.[15] This complex blocks the access of acetylcholine to the active center which decreases the catalytic hydrolysis and subsequent breakdown of acetylcholine by acetylcholinesterase.[15] Enzyme inactivation leads to an accumulation of acetylcholine in the body, hyperstimulation of both the muscarinic and nicotinic acetylcholine receptors, as well as subsequent disruption of neurotransmission.[16] However, it was found that the time of incubation did not affect the inhibition, leading to the conclusion that lupinine is a reversible inhibitor.[4]

Studies have also shown that lupinine has a binding affinity for both muscarinic and nicotinic acetylcholine receptors. Lupinine was found to have an IC50 value of >500 μM for nicotinic receptors and an IC50 value of 190 μM for muscarinic receptors. However, it has yet to be determined whether this affinity is agonistic or antagonistic in nature.[17]

Synthesis

Biosynthesis of lupinine

Biological

Lupinine is naturally biosynthesized from l-lysine in the Lupinus genes of plants along with various other quinolizidine alkaloids. In the biosynthetic process, lysine is first decarboxylated into cadaverine, which is then oxidatively deaminated to the corresponding aldehyde. The aldehyde is then spontaneously cyclized into two tautmers which couple through an aldol type mechanism in which the allylic amine attacks the iminium, forming a dissymmetric dimeric intermediate which is then hydrated. The primary amine is then oxidized and an intramolecular condensation occurs, giving the quinolizidinealdehyde. The aldehyde is then reduced to an alcohol, giving, enantioselectively, (-)- lupinine.[3][18]

Synthetic

Lupinine has a

stereoisomers of lupinine, and containing many references to earlier work in this field, was published by Ma and Ni.[20] Another total synthesis of specific note due to the enantioselectivity and limited number of steps is by Santos et al. In 2010, Santos et al. synthesized enantioselective (-)- lupinine in 36% yield over eight steps using a double Mitsunobu Reaction.[21] First, they employed asymmetric addition of the starting materials using a Lewis acid, followed by treatment with a reducing agent and a base. This gave the (R,R)-alcohol. This configuration was inverted using a Mitsunobu reaction followed by hydrolysis, affording the (R,S) configuration of the alcohol. The alcohol was then reduced with alane, underwent another Mitsunobu reaction, was hydrolyzed to the acid and finally reduced to (-)-lupinine via alane reduction.[21]

Total retrosynthesis of lupinine by Santos et al.

Isolation

One of the earliest isolations of lupinine, from Lupinus palmeri collected in Utah, USA, is that reported by Couch, who was able to obtain crystalline lupinine without the use of

chromatographic techniques.[22]

Applications

Drawing of a culicine mosquito larva

Pest control

Lupinine is an insect antifeedant.

filarial worms, and avian malaria.[23][24]

Botany

Lupins are often found growing with Castilleja (Indian paintbrush) which uses lupins as a host and confers lupinine and other alkaloids to itself. This works in tandem with the increase in nitrogen fixation to increase parasitic reproduction rates and potentially reduce herbivory activity; however, studies have shown mixed results in the efficacy of alkaloid transfer in prevention of herbivory activity.[25]

Regulations

The European Chemicals Agency (ECA) labels lupinine under the hazard statement codes H302, H312, and H332, which indicate that lupinine is harmful if swallowed, harmful in contact with skin, and harmful if inhaled, respectively. It is given a GHS07 labeling which indicates its acute oral toxicity is category 4.[26]

See also

References

  1. ISSN 0031-9422
    .
  2. ^
    PMID 6042140
    .
  3. ^
    ISSN 0008-4042
    .
  4. ^
    S2CID 25689578
    .
  5. ^
    doi:10.17590/20170530-142504. {{cite journal}}: Cite journal requires |journal= (help
    )
  6. S2CID 82321535
    .
  7. ^
    OCLC 910979700.{{cite book}}: CS1 maint: location missing publisher (link
    )
  8. PMID 6651228
    .
  9. ^
    OCLC 39764034.{{cite book}}: CS1 maint: others (link
    )
  10. PMID 7212919
    .
  11. ^ Kirkensgaard, Kristine (2017-12-11). "Lupinine - the chemical stopping you from eating Lupin". natoxaq.ku.dk. Retrieved 2018-04-27.
  12. PMID 18324702
    .
  13. ^
    OCLC 34281328.{{cite book}}: CS1 maint: others (link
    )
  14. ^ a b c Couch, James (1926). "Relative Toxicity of the Lupine Alkaloids". Journal of Agricultural Research. XXXII: 51–67.
  15. ^
    S2CID 30640524
    .
  16. PMID 24179466
    .
  17. PMID 7798968
    .
  18. S2CID 46220343
    .
  19. ISSN 0368-1769
    .
  20. PMID 15224338
    .
  21. ^
    ISSN 0039-7881
    .
  22. doi:10.1021/ja01326a067
    .
  23. ISSN 1938-291X
    .
  24. PMID 24140295
    .
  25. ISSN 0012-9658
    .
  26. ^ "Classifications - CL Inventory". www.echa.europa.eu. Retrieved 2018-04-25.

External links

  • Media related to Lupinine at Wikimedia Commons
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