Anemonin

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Contents

Anemonin
Anemonin Structural Formulae.svg
Anemonin 3D ball.png
Names
IUPAC names
trans-4,7-Dioxadispiro[4.0.46.25]dodeca-1,9-diene-3,8-dione
trans-1,7-Dioxadispiro[4.0.4.2]dodeca-3,9-diene-2,8-dione [1]
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
PubChem CID
UNII
  • InChI=1S/C10H8O4/c11-7-1-3-9(13-7)5-6-10(9)4-2-8(12)14-10/h1-4H,5-6H2 Yes check.svgY
    Key: JLUQTCXCAFSSLD-UHFFFAOYSA-N Yes check.svgY
  • C1CC2(C13C=CC(=O)O3)C=CC(=O)O2
Properties
C10H8O4
Molar mass 192.170 g·mol−1
AppearanceColourless, odourless solid
Density 1.45g/cm3
Melting point 158 [1]  °C (316 °F; 431 K)
Boiling point 535.7 °C (996.3 °F; 808.9 K) @ 760mmHg
low
Solubility in chloroform very soluble [1]
Hazards
Flash point 300.7 °C (573.3 °F; 573.8 K)
Lethal dose or concentration (LD, LC):
150 mg·kg−1 (mouse, IP)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Anemonin is a dibutenolide natural product found in members of the buttercup family (Ranunculaceae) such as Helleborus niger , Ranunculus bulbosus , R. ficaria , R. sardous , R. sceleratus , [2] and Clematis hirsutissima . [3] Originally isolated in 1792 by M. Heyer, [4] It is the dimerization product of the toxin protoanemonin. [5] One of the likely active agents in plants used in Chinese medicine as an anti-inflammatory [6] and Native American medicine as a horse stimulant, [3] its unique biological properties give it pharmaceutical potential as an anti-inflammatory agent.

Biosynthetic origins

Anemonin is a homodimer formed from two protoanemonin subunits. Protoanemonin is formed from the enzymatic cleavage of ranunculin upon crushing plant matter. [4] When a plant from this family is injured, a β-glucosidase cleaves ranunculin, liberating protoanemonin from glucose as a defense mechanism. [7] This butenolide readily dimerizes in aqueous media to form a single cyclodimer. [4]

Biosynthesis pathway

Ranunculin skeletal.svg ranunculin
↓ – glucose (plant wounded)
Protoanemonina.svg protoanemonin
↓ dimerization (spontaneous)
Anemonin.svg anemonin

Chemical structure and proposed mechanism of formation

Based on the spontaneous dimerization observed following synthesis of protoanemonin by Asahina in 1920, it was assumed that the two butenolide rings of anemonin have a cis or head-to-head stereochemistry. The highly selective formation of the dimer was explained by a stable diradical intermediate; it was expected that after an initial carbon-carbon bond forming step the free electrons would be delocalized through the adjacent double bonds. [4]

Despite multiple stereochemical possibilities, X-ray crystallography of solid anemonin in 1965 revealed that the two butenolide rings exclusively possess a trans relationship. [4] [8] Destabilizing dipole-dipole interactions disfavor the transition state where the two rings adopt a cis conformation, leading to selectivity for the more stable trans relationship. [4]

The formation of anemonin from protoanemonin is most likely a photochemical process. A study by Kataoka and colleagues comparing the dimerization of protoanemonin in the presence and absence of UV radiation from a mercury lamp found a 75% yield with radiation and a very poor yield without. It is not mentioned whether light was excluded from this control reaction; the low yield of anemonin may have arisen from visible light-mediated dimerization of protoanemonin. [9]

Pharmaceutical potential

Though Anemonin and protoanemonin share antibiotic activity, Anemonin is anti-inflammatory rather than an irritant like its parent monomer. [10] Anemonin has been demonstrated to have activity which prevents or decreases LPS-induced cytokine release, [11] [12] nitric oxide production [13] and oxidative cell damage, which are thought to be responsible for the anti-inflammatory effect of certain herbs used in traditional Chinese medicine. [6] In fact, many studies have demonstrated anemonin's potential for the treatment of inflammatory and cardiovascular diseases including cerebral ischemia [14] ,ulcerative colitis, [15] [6] arthritis [16] and inflammatory bone loss. [11]

Given its skin permeability in ethanolic solutions [17] and its anti-inflammatory properties, anemonin may be a good candidate for topical formulations as an arthritis medication.

Synthetic preparation

Extraction from fresh plants has been suggested as a method for industrial-scale preparation of anemonin, [18] but the long and complicated procedures required to achieve a pure extract favors the use of synthetic approaches. This is especially true given that methods of synthesizing protoanemonin from several commercially available starting materials already exist, and anemonin is its spontaneously formed dimer. [4] Kotera's efficient synthesis of protoanemonin from 2-Deoxy-D-ribose can be employed, then the product held at room temperature overnight to allow dimerization to anemonin. [19] The findings of an investigation by Kataoka and colleagues in 1965 implied that this dimerization may be mediated by visible light. [9]

Kotera Synthesis

Deoxyribose structure.svg 2-Deoxy-D-ribose
↓ HCl, MeOH
21-O-Methyl-2-Deoxy-D-ribose
↓ TolCl/pyridine
3
↓ MCPBA/ BF3-OEt2
4Crystalline solid; 58% overall yield
↓ 5eq. NEt3 (stirred overnight)80% yield
Protoanemonine.png Protoanemonin; 46% overall yield [19]
↓ dimerization (spontaneous, may be sped up by light)
Anemonin.svg anemonin

References

  1. 1 2 3 William M. Haynes (2016). CRC Handbook of Chemistry and Physics (97th ed.). Boca Raton: CRC Press. pp. 3–26. ISBN   978-1-4987-5429-3.
  2. ↑ Teodora N, Neli Kinga O, Daniela H, Daniela B, Pripon F, Aurel A, Claudia T (2018). "Anemonin Content of Four Different Ranunculus Species". Pakistan Journal of Pharmaceutical Sciences. 31 (5(Supplementary)): 2027–2032. PMID   30393208.
  3. 1 2 Kern JR, Cardellina JH (July 1983). "Native American medicinal plants. Anemonin from the horse stimulant Clematis hirsutissima". Journal of Ethnopharmacology. 8 (1): 121–123. doi:10.1016/0378-8741(83)90093-4. PMID   6632934.
  4. 1 2 3 4 5 6 7 Moriarty RM, Romain CR, Karle IL, Karle J (July 1965). "The Structure of Anemonin". Journal of the American Chemical Society. 87 (14): 3251–3252. doi:10.1021/ja01092a047. ISSN   0002-7863.
  5. ↑ "Aktuelles aus der Natur" (PDF) (in German). TU Graz. 2 April 2009. p. 4. Retrieved 27 November 2010.[ permanent dead link ]
  6. 1 2 3 Duan H, Zhang Y, Xu J, Qiao J, Suo Z, Hu G, Mu X (April 2006). "Effect of anemonin on NO, ET-1 and ICAM-1 production in rat intestinal microvascular endothelial cells". Journal of Ethnopharmacology. 104 (3): 362–366. doi:10.1016/j.jep.2005.09.034. PMID   16257161.
  7. ↑ Pirvu L, Stefaniu A, Neagu G, Pintilie L (2022-01-01). "Studies on Anemone nemorosa L. extracts; polyphenols profile, antioxidant activity, and effects on Caco-2 cells by in vitro and in silico studies". Open Chemistry. 20 (1): 299–312. doi: 10.1515/chem-2022-0137 . ISSN   2391-5420.
  8. ↑ Karle IL, Karle J (1966-04-10). "The crystal and molecular structure of anemonin, C10H8O4" . Acta Crystallographica. 20 (4): 555–559. Bibcode:1966AcCry..20..555K. doi:10.1107/S0365110X66001233. ISSN   0365-110X.
  9. 1 2 Kataoka H, Yamada K, Sugiyama N (November 1965). "The Photo-synthesis of Anemonin from Protoanemonin". Bulletin of the Chemical Society of Japan. 38 (11): 2027. doi: 10.1246/bcsj.38.2027 . ISSN   0009-2673.
  10. ↑ Baer H, Holden M, Seegal B (January 1, 1946). "The Nature of the Antibacterial Agent from Anemone Pulsatilla". Journal of Biological Chemistry. 162 (1): 65–68. doi: 10.1016/S0021-9258(17)41459-1 .
  11. 1 2 Hou H, Peng Q, Wang S, Zhang Y, Cao J, Deng Y, et al. (2020). "Anemonin Attenuates RANKL-Induced Osteoclastogenesis and Ameliorates LPS-Induced Inflammatory Bone Loss in Mice via Modulation of NFATc1". Frontiers in Pharmacology. 10: 1696. doi: 10.3389/fphar.2019.01696 . PMC   7025528 . PMID   32116686.
  12. ↑ Xiao K, Cao ST, Jiao LF, Lin FH, Wang L, Hu CH (May 12, 2016). "Anemonin improves intestinal barrier restoration and influences TGF-β1 and EGFR signaling pathways in LPS-challenged piglets". Innate Immunity. 22 (5): 344–352. doi:10.1177/1753425916648223. PMID   27189428.
  13. ↑ Lee TH, Huang NK, Lai TC, Yang A, Wang GJ (March 28, 2008). "Anemonin, from Clematis crassifolia, potent and selective inducible nitric oxide synthase inhibitor". Journal of Ethnopharmacology. 116 (3): 518–527. doi:10.1016/j.jep.2007.12.019.
  14. ↑ Jia D, Han B, Yang S, Zhao J (January 21, 2014). "Anemonin Alleviates Nerve Injury After Cerebral Ischemia and Reperfusion (I/R) in Rats by Improving Antioxidant Activities and Inhibiting Apoptosis Pathway". Journal of Molecular Neuroscience. 53 (2): 271–279. doi:10.1007/s12031-013-0217-z.
  15. ↑ Jiang L, Chi C, Yuan F, Lu M, Hu D, Wang L, Liu X (March 28, 2022). "Anti-inflammatory effects of anemonin on acute ulcerative colitis via targeted regulation of protein kinase C-θ". Chinese Medicine. 17 (39) 39. doi: 10.1186/s13020-022-00599-3 .
  16. ↑ Wang Z, Huang J, Zhou S, Luo F, Xu W, Wang Q, Tan Q, Chen L, Wang J, Chen H, Chen L, Xie Y, Du X (June 23, 2017). "Anemonin attenuates osteoarthritis progression through inhibiting the activation of IL-1β/NF-κB pathway". Cell and Molecular Medicine. 21 (12): 3231–3243. doi:10.1111/jcmm.13227. PMC   5706500 .
  17. ↑ Ning Y, Rao Y, Yu Z, Liang W, Li F (March 2016). "Skin permeation profile and anti-inflammatory effect of anemonin extracted from weilingxian". Die Pharmazie. 71 (3): 134–138. PMID   27183707.
  18. ↑ CN101759706B,王琳&范淦彬,"Method for manufacturing anemonin",issued 2012-01-11
  19. 1 2 Crey C, Dumy P, Lhomme J, Kotera M (2003). "A Convenient Synthesis of Protoanemonin". Synthetic Communications. 33 (21): 3727–3732. doi:10.1081/SCC-120025181 . Retrieved May 4, 2025.
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