Anemonin

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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 tri-spirocyclic dibutenolide natural product found in members of the buttercup family (Ranunculaceae) such as 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 and cosmetic agent.

Contents

Biosynthetic origins

Protoanemonina.svg
Protoanemonin
Ranunculin skeletal.svg
Ranunculin

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]

Chemical structure and proposed mechanism of formation

Despite multiple possibilities, X-ray crystallography of the solid anemonin has revealed that the two rings exclusively possess a trans relationship. [8] The central cyclobutane ring was found to be bent to a dihedral angle of 152°. NMR spectroscopy reveals that the central ring is also twisted 9-11°. [9]

The highly selective formation of the head-to-head dimer has been rationalized through the stability of a proposed diradical intermediate; the resulting radicals after an initial carbon-carbon bond forming step are delocalized through the α,β-unsaturated system. [4] These proposed radicals could also be stabilized through the captodative effect, as they are situated between the enone and sp3-hybridized oxygen of the butenolides.

Destabilizing dipole-dipole interactions are proposed to disfavor the transition state where the two butenolide rings adopt a cis conformation, leading to selectivity of a trans relationship between the lactone rings. [4]

The formation of anemonin from protoanemonin is most likely a photochemical process. When Kataoka et. al compared the dimerization of protoanemonin in the presence and absence of radiation from a mercury lamp, they found a 75% yield with radiation and a very poor yield without radiation. It is not mentioned whether light was excluded from this control reaction; the low yield of anemonin may arise from visible light-mediated dimerization of protoanemonin. [10]

Pharmaceutical potential

Anemonin possesses anti-inflammatory properties rather than the vesicant properties of its parent monomer. Numerous studies have demonstrated anemonin’s potential in treating ulcerative colitis, [11] cerebral ischemia, [12] and arthritis. [13] [14] Its activity against LPS-related inflammation [13] [15] and nitric oxide production [16] [6] contribute to its pharmaceutical potential. Anemonin also displays inhibition of melanin production in human melanocytes with mild cytotoxicity. [17]

Given its skin permeability in ethanolic solutions [18] and its anti-inflammatory and anti-pigmentation properties, anemonin may be a good candidate for topical formulations as arthritis medications or cosmetics. An extraction method with the potential for industrial-scale preparations of anemonin may provide inroads to drug development. [19]

Related Research Articles

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Ranunculaceae is a family of over 2,000 known species of flowering plants in 43 genera, distributed worldwide.

<i>Ranunculus</i> Genus of flowering plants in the buttercup family Ranunculaceae

Ranunculus is a large genus of about 1700 to more than 1800 species of flowering plants in the family Ranunculaceae. Members of the genus are known as buttercups, spearworts and water crowfoots.

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<span class="mw-page-title-main">Umbelliferone</span> Chemical compound

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<span class="mw-page-title-main">Protoanemonin</span> Chemical compound

Protoanemonin is a toxin found in all plants of the buttercup family (Ranunculaceae). When the plant is wounded or macerated, the unstable glucoside found in the plant, ranunculin, is enzymatically broken down into glucose and the toxic protoanemonin. It is the lactone of 4-hydroxy-2,4-pentadienoic acid.

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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 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 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. ↑ Lustig E, Moriarty RM (July 1965). "The Estimation of the Angle of Twist for a Cyclobutane Derivative by Nuclear Magnetic Resonance". Journal of the American Chemical Society. 87 (14): 3252–3253. doi:10.1021/ja01092a048. ISSN   0002-7863.
  10. ↑ 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.
  11. ↑ Jiang L, Chi C, Yuan F, Lu M, Hu D, Wang L, Liu X (March 2022). "Anti-inflammatory effects of anemonin on acute ulcerative colitis via targeted regulation of protein kinase C-θ". Chinese Medicine. 17 (1): 39. doi: 10.1186/s13020-022-00599-3 . PMC   8962473 . PMID   35346284.
  12. ↑ Jia D, Han B, Yang S, Zhao J (June 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. PMID   24443273. S2CID   255492187.
  13. 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.
  14. ↑ Wang Z, Huang J, Zhou S, Luo F, Xu W, Wang Q, et al. (December 2017). "Anemonin attenuates osteoarthritis progression through inhibiting the activation of IL-1β/NF-κB pathway". Journal of Cellular and Molecular Medicine. 21 (12): 3231–3243. doi:10.1111/jcmm.13227. PMC   5706500 . PMID   28643466.
  15. ↑ Xiao K, Cao ST, Jiao LE, Lin FH, Wang L, Hu CH (July 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. S2CID   12372791.
  16. ↑ Lee TH, Huang NK, Lai TC, Yang AT, Wang GJ (March 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. PMID   18281171.
  17. ↑ Huang YH, Lee TH, Chan KJ, Hsu FL, Wu YC, Lee MH (February 2008). "Anemonin is a natural bioactive compound that can regulate tyrosinase-related proteins and mRNA in human melanocytes". Journal of Dermatological Science. 49 (2): 115–123. doi:10.1016/j.jdermsci.2007.07.008. PMID   17766092.
  18. ↑ 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.
  19. ↑ CN101759706B,王琳&范淦彬,"Method for manufacturing anemonin",issued 2012-01-11
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