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Anemonin

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Anemonin
Skeletal formula of anemonin
Ball-and-stick model of the anemonin molecule
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
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 checkY
    Key: JLUQTCXCAFSSLD-UHFFFAOYSA-N checkY
  • C1CC2(C13C=CC(=O)O3)C=CC(=O)O2
Properties
C10H8O4
Molar mass 192.170 g·mol−1
Appearance Colourless, 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).
checkY verify (what is checkY☒N ?)

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

[edit]

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

[edit]
ranunculin
↓ – glucose (plant wounded)
protoanemonin
↓ dimerization (spontaneous)
anemonin

Chemical structure and proposed mechanism of formation

[edit]

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

[edit]

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

[edit]

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

[edit]
2-Deoxy-D-ribose
↓ HCl, MeOH
2 1-O-Methyl-2-Deoxy-D-ribose
↓ TolCl/pyridine
3
↓ MCPBA/ BF3-OEt2
4 Crystalline solid; 58% overall yield
↓ 5eq. NEt3 (stirred overnight) 80% yield
Protoanemonin; 46% overall yield [19]
↓ dimerization (spontaneous, may be sped up by light)
anemonin

References

[edit]
  1. ^ a b c 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. ^ a b 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. ^ a b c d e f g 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. ^ a b c 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. ^ a b 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.
  11. ^ a b 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. 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.
  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: 271–279.
  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).
  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.
  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. ^ a b Crey C, Dumy P, Lhomme J, Kotera M (2003). "A Convenient Synthesis of Protoanemonin". Synthetic Communications. 33 (21): 3727–3732. Retrieved May 4, 2025.
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