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Mesembrine

(Redirected from Total synthesis of mesembrine)

Mesembrine is an alkaloid primarily derived from the plant Sceletium tortuosum, commonly known as kanna. This compound is noted for its psychoactive properties, particularly as a serotonin reuptake inhibitor, which contributes to its potential use in treating mood disorders and anxiety. Mesembrine has garnered interest in both traditional medicine and modern pharmacology, where it is explored for its effects on enhancing mood and cognitive function. The plant itself has a long history of use by indigenous peoples in southern Africa, who utilized it for its mood-enhancing and stress-relieving effects, often consuming it in various forms such as teas or chews.[1][2][3][4]

Mesembrine
Clinical data
Drug classSerotonin reuptake inhibitor; PDE4 inhibitor
Legal status
Legal status
  • US: Unscheduled
Identifiers
  • (3aS,7aS)-3a-(3,4-Dimethoxyphenyl)-1-methyl-2,3,4,5,7,7a-hexahydroindol-6-one
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC17H23NO3
Molar mass289.375 g·mol−1
3D model (JSmol)
  • CN1CC[C@@]2([C@H]1CC(=O)CC2)C3=CC(=C(C=C3)OC)OC
  • InChI=1S/C17H23NO3/c1-18-9-8-17(7-6-13(19)11-16(17)18)12-4-5-14(20-2)15(10-12)21-3/h4-5,10,16H,6-9,11H2,1-3H3/t16-,17-/m1/s1
  • Key:DAHIQPJTGIHDGO-IAGOWNOFSA-N

Mesembrine has also been identified in Mesembryanthemum cordifolium, Delosperma echinatum, and Oscularia deltoides.[5]

Pharmacology

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Mesembrine has been shown to act as a serotonin reuptake inhibitor (Ki = 1.4 nM), and has also been found to behave as a weak inhibitor of the enzyme phosphodiesterase 4 (PDE4) (Ki = 7,800 nM).[6] A concentrated mesembrine extract of Sceletium tortuosum may exert antidepressant effects by acting as a monoamine releasing agent.[7] As such, mesembrine likely plays a dominant role in the antidepressant effects of kanna.[8]

Rat studies have evaluated effects of kanna extract, finding analgesic and antidepressant potential.[9] No adverse results were noted for a commercial extract up to 5000 mg/kg daily in rats.[10]

Structure

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Mesembrine was first isolated and characterized by Bodendorf et al. in 1957.[11] It is a tricyclic molecule with two bridgehead chiral carbons located between the five-membered and six-membered rings. The naturally occurring form of mesembrine produced by plants is the levorotatory isomer, (−)-mesembrine, where the carbon atoms at positions 3a and 7a both have the S configuration (3aS,7aS).[12]

Total synthesis

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Because of its structure and bioactivity, mesembrine has been a target for total synthesis over the past 40 years. Over 40 total syntheses have been reported for mesembrine, most of which focused on different approaches and strategies for the construction of the bicyclic ring system and the quaternary carbon.

 
Shamma's route for total synthesis of (±)-mesembrine
 
Yamada's asymmetric total synthesis of (+)-mesembrine

The first total synthesis of mesembrine was reported by Shamma, et al.[13] in 1965. This route has 21 steps, which was among the longest synthetic routes for mesembrine. Key steps involve the construction of the six-membered ketone ring by Diels-Alder reaction, α-allylation for synthesis of the quaternary carbon, and conjugate addition reaction for the final five-membered ring closure. The final product from this route is a racemic mixture of (+)- and (-)-mesembrine.

In 1971, Yamada et al.[14] reported the first asymmetric total synthesis of (+)-mesembrine. This synthesis introduced the quaternary carbon atom through an asymmetric Robinson annulation reaction, which was mediated by a chiral auxiliary derived from L-proline. In the final step, an intramolecular aza-Michael addition produced the fused pyrrolidine ring system.

References

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  1. ^ Van Wyk BE, Wink M (2017). Medicinal plants of the world: an illustrated scientific guide to important medicina plants and theier uses (Second ed.). CABI. p. 226. ISBN 978-1-78639-325-8.
  2. ^ Smith MT, Crouch NR, Gericke N, Hirst M (March 1996). "Psychoactive constituents of the genus Sceletium N.E.Br. and other Mesembryanthemaceae: a review". Journal of Ethnopharmacology (Review). 50 (3): 119–130. doi:10.1016/0378-8741(95)01342-3. PMID 8691846.
  3. ^ Krstenansky JL (January 2017). "Mesembrine alkaloids: Review of their occurrence, chemistry, and pharmacology". Journal of Ethnopharmacology (Review). 195: 10–19. doi:10.1016/j.jep.2016.12.004. PMID 27939420.
  4. ^ Makolo F, Viljoen A, Veale CG (October 2019). "Mesembrine: The archetypal psycho-active Sceletium alkaloid". Phytochemistry (Review). 166: 112061. doi:10.1016/j.phytochem.2019.112061. PMID 31299396.
  5. ^ Smith MT, Field CR, Crouch NR, Hirst M (January 1998). "The Distribution of Mesembrine Alkaloids in Selected Taxa of the Mesembryanthemaceae and their Modification in the Sceletium Derived 'Kougoed'". Pharmaceutical Biology. 36 (3): 173–179. doi:10.1076/phbi.36.3.173.6350.
  6. ^ Harvey AL, Young LC, Viljoen AM, Gericke NP (October 2011). "Pharmacological actions of the South African medicinal and functional food plant Sceletium tortuosum and its principal alkaloids". Journal of Ethnopharmacology. 137 (3): 1124–1129. doi:10.1016/j.jep.2011.07.035. PMID 21798331.
  7. ^ Coetzee DD, López V, Smith C (January 2016). "High-mesembrine Sceletium extract (Trimesemine™) is a monoamine releasing agent, rather than only a selective serotonin reuptake inhibitor". Journal of Ethnopharmacology. 177: 111–116. doi:10.1016/j.jep.2015.11.034. PMID 26615766.
  8. ^ Stafford GI, Pedersen ME, van Staden J, Jäger AK (October 2008). "Review on plants with CNS-effects used in traditional South African medicine against mental diseases". Journal of Ethnopharmacology. 119 (3): 513–537. doi:10.1016/j.jep.2008.08.010. PMID 18775771.
  9. ^ Loria MJ, Ali Z, Abe N, Sufka KJ, Khan IA (August 2014). "Effects of Sceletium tortuosum in rats". Journal of Ethnopharmacology. 155 (1): 731–735. doi:10.1016/j.jep.2014.06.007. PMID 24930358.
  10. ^ Murbach TS, Hirka G, Szakonyiné IP, Gericke N, Endres JR (December 2014). "A toxicological safety assessment of a standardized extract of Sceletium tortuosum (Zembrin®) in rats". Food and Chemical Toxicology. 74: 190–199. doi:10.1016/j.fct.2014.09.017. PMID 25301237.
  11. ^ Bodendorf K, Krieger W (October 1957). "[Alkaloids of Mesembryanthemum tortuosum]". Archiv der Pharmazie und Berichte der Deutschen Pharmazeutischen Gesellschaft (in German). 290 (10): 441–448. doi:10.1002/ardp.19572901002. PMID 13471008.
  12. ^ Coggon P, Farrier DS, Jeffs PW, McPhail AT (1970). "Absolute configuration of mesembrine and related alkaloids: X-ray analysis of 6-epimesembranol methiodide". Journal of the Chemical Society B: Physical Organic: 1267–1271. doi:10.1039/J29700001267.
  13. ^ Shamma M, Rodriguez HR (1965). "The total synthesis of (±)-mesembrine". Tetrahedron Letters. 6 (52): 4847–4851. doi:10.1016/S0040-4039(01)89046-8.
  14. ^ Yamada SI, Otani G (January 1971). "Total synthesis of (+)-mesembrine by asymmetric synthesis with amino acid". Tetrahedron Letters. 12 (16): 1133–1136. doi:10.1016/S0040-4039(01)96647-X.

Further reading

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