Anemonin Explained

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,[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, its unique biological properties give it pharmaceutical potential as an anti-inflammatory and cosmetic 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]

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.[7] 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°.[8]

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. 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.

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.[9]

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,[10] cerebral ischemia,[11] and arthritis.[12] [13] Its activity against LPS-related inflammation[14] and nitric oxide production[15] [5] contribute to its pharmaceutical potential. Anemonin also displays inhibition of melanin production in human melanocytes with mild cytotoxicity.[16]

Given its skin permeability in ethanolic solutions[17] 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.[18]

Notes and 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 . 30393208 .
  2. Kern JR, Cardellina JH . Native American medicinal plants. Anemonin from the horse stimulant Clematis hirsutissima. Journal of Ethnopharmacology . 8 . 1 . 121–123 . July 1983 . 6632934 . 10.1016/0378-8741(83)90093-4.
  3. Moriarty RM, Romain CR, Karle IL, Karle J . July 1965 . The Structure of Anemonin . Journal of the American Chemical Society . en . 87 . 14 . 3251–3252 . 10.1021/ja01092a047 . 0002-7863.
  4. Web site: Aktuelles aus der Natur . . German . 4 . 2 April 2009 . 27 November 2010 .
  5. Duan H, Zhang Y, Xu J, Qiao J, Suo Z, Hu G, Mu X . 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 . 16257161 . 10.1016/j.jep.2005.09.034.
  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 . Open Chemistry . en . 20 . 1 . 299–312 . 10.1515/chem-2022-0137 . free . 2391-5420.
  7. Karle . I. L. . Karle . J. . 1966-04-10 . The crystal and molecular structure of anemonin, C10H8O4 . Acta Crystallographica . en . 20 . 4 . 555–559 . 10.1107/S0365110X66001233 . 1966AcCry..20..555K . 0365-110X.
  8. Lustig . Ernest . Moriarty . Robert M. . July 1965 . The Estimation of the Angle of Twist for a Cyclobutane Derivative by Nuclear Magnetic Resonance . Journal of the American Chemical Society . en . 87 . 14 . 3252–3253 . 10.1021/ja01092a048 . 0002-7863.
  9. Kataoka . Hiroshi . Yamada . Kazutoshi . Sugiyama . Noboru . November 1965 . The Photo-synthesis of Anemonin from Protoanemonin . Bulletin of the Chemical Society of Japan . en . 38 . 11 . 2027 . 10.1246/bcsj.38.2027 . 0009-2673. free .
  10. Jiang L, Chi C, Yuan F, Lu M, Hu D, Wang L, Liu X . Anti-inflammatory effects of anemonin on acute ulcerative colitis via targeted regulation of protein kinase C-θ . Chinese Medicine . 17 . 1 . 39 . March 2022 . 35346284 . 8962473 . 10.1186/s13020-022-00599-3 . free .
  11. Jia D, Han B, Yang S, Zhao J . 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 . June 2014 . 24443273 . 10.1007/s12031-013-0217-z . 255492187 .
  12. Hou H, Peng Q, Wang S, Zhang Y, Cao J, Deng Y, Wang Y, Sun WC, Wang HB . 6 . Anemonin Attenuates RANKL-Induced Osteoclastogenesis and Ameliorates LPS-Induced Inflammatory Bone Loss in Mice via Modulation of NFATc1 . Frontiers in Pharmacology . 10 . 1696 . 2020 . 32116686 . 10.3389/fphar.2019.01696 . 7025528 . free .
  13. 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 . 6 . Anemonin attenuates osteoarthritis progression through inhibiting the activation of IL-1β/NF-κB pathway . Journal of Cellular and Molecular Medicine . 21 . 12 . 3231–3243 . December 2017 . 28643466 . 5706500 . 10.1111/jcmm.13227 .
  14. Xiao K, Cao ST, Jiao LE, Lin FH, Wang L, Hu CH . Anemonin improves intestinal barrier restoration and influences TGF-β1 and EGFR signaling pathways in LPS-challenged piglets . Innate Immunity . 22 . 5 . 344–352 . July 2016 . 27189428 . 10.1177/1753425916648223 . 12372791 . free .
  15. Lee TH, Huang NK, Lai TC, Yang AT, Wang GJ . Anemonin, from Clematis crassifolia, potent and selective inducible nitric oxide synthase inhibitor . Journal of Ethnopharmacology . 116 . 3 . 518–527 . March 2008 . 18281171 . 10.1016/j.jep.2007.12.019 .
  16. Huang YH, Lee TH, Chan KJ, Hsu FL, Wu YC, Lee MH . 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 . February 2008 . 17766092 . 10.1016/j.jdermsci.2007.07.008 .
  17. Ning Y, Rao Y, Yu Z, Liang W, Li F . Skin permeation profile and anti-inflammatory effect of anemonin extracted from weilingxian . Die Pharmazie . 71 . 3 . 134–138 . March 2016 . 27183707 .
  18. CN101759706B. Method for manufacturing anemonin. 2012-01-11. 王琳. 范淦彬.

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