Chemistry:Anemonin

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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,[1] and Clematis hirsutissima.[2] Originally isolated in 1792 by M. Heyer,[3] It is the dimerization product of the toxin protoanemonin.[4] One of the likely active agents in plants used in Chinese medicine as an anti-inflammatory[5] and Native American medicine as a horse stimulant,[2] 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.[3] When a plant from this family is injured, a β-glucosidase cleaves ranunculin, liberating protoanemonin from glucose as a defense mechanism.[6] This butenolide readily dimerizes in aqueous media to form a single cyclodimer.[3]

Biosynthesis pathway

250px ranunculin
↓ – glucose (plant wounded)
150px protoanemonin
↓ dimerization (spontaneous)
150px 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.[3]

Despite multiple stereochemical possibilities, X-ray crystallography of solid anemonin in 1965 revealed that the two butenolide rings exclusively possess a trans relationship.[3][7] 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.[3]

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.[8]

Pharmaceutical potential

Though Anemonin and protoanemonin share antibiotic activity, Anemonin is anti-inflammatory rather than an irritant like its parent monomer.[9] Anemonin has been demonstrated to have activity which prevents or decreases LPS-induced cytokine release,[10][11] nitric oxide production[12] and oxidative cell damage, which are thought to be responsible for the anti-inflammatory effect of certain herbs used in traditional Chinese medicine.[5] In fact, many studies have demonstrated anemonin's potential for the treatment of inflammatory and cardiovascular diseases including cerebral ischemia[13],ulcerative colitis,[14][5] arthritis[15]and inflammatory bone loss. [10]

Given its skin permeability in ethanolic solutions[16] 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,[17] 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. [3] 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. [18] The findings of an investigation by Kataoka and colleagues in 1965 implied that this dimerization may be mediated by visible light. [8]

Kotera Synthesis

160px 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
150px Protoanemonin; 46% overall yield [18]
↓ dimerization (spontaneous, may be sped up by light)
150px anemonin

References

  1. ↑ Teodora, Neag; Neli Kinga, Olag; Daniela, Hanganu; Daniela, Benedec; Pripon, Flavia; Aurel, Ardelean; Claudia, Toma (2018). "Anemonin Content of Four Different Ranunculus Species". Pakistan Journal of Pharmaceutical Sciences 31 (5(Supplementary)): 2027–2032. PMID 30393208. https://pesquisa.bvsalud.org/portal/resource/pt/emr-199590. 
  2. ↑ 2.0 2.1 "Native American medicinal plants. Anemonin from the horse stimulant Clematis hirsutissima". Journal of Ethnopharmacology 8 (1): 121–123. July 1983. doi:10.1016/0378-8741(83)90093-4. PMID 6632934. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 "The Structure of Anemonin" (in en). Journal of the American Chemical Society 87 (14): 3251–3252. July 1965. doi:10.1021/ja01092a047. ISSN 0002-7863. 
  4. ↑ "Aktuelles aus der Natur" (in German). TU Graz. 2 April 2009. p. 4. http://www.orgc.tugraz.at/hoegroup/naturst/Akt_2009_04_02.pdf. 
  5. ↑ 5.0 5.1 5.2 "Effect of anemonin on NO, ET-1 and ICAM-1 production in rat intestinal microvascular endothelial cells". Journal of Ethnopharmacology 104 (3): 362–366. April 2006. doi:10.1016/j.jep.2005.09.034. PMID 16257161. 
  6. ↑ Pirvu, Lucia; Stefaniu, Amalia; Neagu, Georgeta; Pintilie, Lucia (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" (in en). Open Chemistry 20 (1): 299–312. doi:10.1515/chem-2022-0137. ISSN 2391-5420. 
  7. ↑ Karle, I. L.; Karle, J. (1966-04-10). "The crystal and molecular structure of anemonin, C10H8O4" (in en). Acta Crystallographica 20 (4): 555–559. doi:10.1107/S0365110X66001233. ISSN 0365-110X. Bibcode: 1966AcCry..20..555K. https://scripts.iucr.org/cgi-bin/paper?S0365110X66001233. 
  8. ↑ 8.0 8.1 Kataoka, Hiroshi; Yamada, Kazutoshi; Sugiyama, Noboru (November 1965). "The Photo-synthesis of Anemonin from Protoanemonin" (in en). Bulletin of the Chemical Society of Japan 38 (11): 2027. doi:10.1246/bcsj.38.2027. ISSN 0009-2673. 
  9. ↑ Baer, Harold; Holden, Margaret; Seegal, Beatrice (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. 
  10. ↑ 10.0 10.1 "Anemonin Attenuates RANKL-Induced Osteoclastogenesis and Ameliorates LPS-Induced Inflammatory Bone Loss in Mice via Modulation of NFATc1". Frontiers in Pharmacology 10: 1696. 2020. doi:10.3389/fphar.2019.01696. PMID 32116686. 
  11. ↑ Xiao, Kan; Cao, Shu Ting; Jiao, Le Fei; Lin, Fang Hui; Wang, Li; Hu, Cai Hong (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. https://doi.org/10.1177/1753425916648223. 
  12. ↑ 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. https://doi.org/10.1016/j.jep.2007.12.019. 
  13. ↑ Jia, Dong; Han, Bin; Yang, Shaowei; Zhao, Junying (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. https://link.springer.com/article/10.1007/s12031-013-0217-z. 
  14. ↑ Jiang, Lu; Chi, Chunhua; Yuan, Fang; Lu, Meiqi; Hu, Dongquing; Wang, Lin; Liu, Xiaoming (March 28, 2022). "Anti-inflammatory effects of anemonin on acute ulcerative colitis via targeted regulation of protein kinase C-θ". Chinese Medicine 17 (39). doi:10.1186/s13020-022-00599-3. 
  15. ↑ Wang, Zuquiang; Huang, Junluan; Zhou, Siru; Luo, Fengtao; Xu, Wei; Wang, Quan; Tan, Qiaoyang; Chen, Liang et al. (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. https://doi.org/10.1111/jcmm.13227. 
  16. ↑ "Skin permeation profile and anti-inflammatory effect of anemonin extracted from weilingxian". Die Pharmazie 71 (3): 134–138. March 2016. PMID 27183707. 
  17. ↑ & 范淦彬"Method for manufacturing anemonin" patent CN101759706B, issued 2012-01-11
  18. ↑ 18.0 18.1 Crey, Caroline; Dumy, Pascal; Lhomme, Jean; Kotera, Mitsuharu (2003). "A Convenient Synthesis of Protoanemonin". Synthetic Communications 33 (21): 3727–3732. doi:10.1081/SCC-120025181. https://doi.org/10.1081/SCC-120025181. Retrieved May 4, 2025. 



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