Anemonin

Last updated
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

<span class="mw-page-title-main">Ranunculaceae</span> Family of eudicot flowering plants

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.

<span class="mw-page-title-main">Interleukin 10</span> Anti-inflammatory cytokine

Interleukin 10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine. In humans, interleukin 10 is encoded by the IL10 gene. IL-10 signals through a receptor complex consisting of two IL-10 receptor-1 and two IL-10 receptor-2 proteins. Consequently, the functional receptor consists of four IL-10 receptor molecules. IL-10 binding induces STAT3 signalling via the phosphorylation of the cytoplasmic tails of IL-10 receptor 1 + IL-10 receptor 2 by JAK1 and Tyk2 respectively.

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

Imperatorin is a furocoumarin and a phytochemical that has been isolated from Urena lobata L. (Malvaceae), Angelica archangelica, Angelica dahurica, Glehnia littoralis, Saposhnikovia divaricata, Cnidium monnieri, Incarvillea younghusbandii, and Zanthoxylum americanum mill. It is biosynthesized from umbelliferone, a coumarin derivative.

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

Umbelliferone, also known as 7-hydroxycoumarin, hydrangine, skimmetine, and beta-umbelliferone, is a natural product of the coumarin family.

<span class="mw-page-title-main">CXCR4</span> Protein

C-X-C chemokine receptor type 4 (CXCR-4) also known as fusin or CD184 is a protein that in humans is encoded by the CXCR4 gene. The protein is a CXC chemokine receptor.

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

Helenalin, or (-)-4-Hydroxy-4a,8-dimethyl-3,3a,4a,7a,8,9,9a-octahydroazuleno[6,5-b]furan-2,5-dione, is a toxic sesquiterpene lactone which can be found in several plants such as Arnica montana and Arnica chamissonis Helenalin is responsible for the toxicity of the Arnica spp. Although toxic, helenalin possesses some in vitro anti-inflammatory and anti-neoplastic effects. Helenalin can inhibit certain enzymes, such as 5-lipoxygenase and leukotriene C4 synthase. For this reason the compound or its derivatives may have potential medical applications.

Interleukin 27 (IL-27) is a member of the IL-12 cytokine family. It is a heterodimeric cytokine that is encoded by two distinct genes, Epstein-Barr virus-induced gene 3 (EBI3) and IL-27p28. IL-27 is expressed by antigen presenting cells and interacts with a specific cell-surface receptor complex known as IL-27 receptor (IL-27R). This receptor consists of two proteins, IL-27Rɑ and gp130. IL-27 induces differentiation of the diverse populations of T cells in the immune system and also upregulates IL-10.

<span class="mw-page-title-main">Ursolic acid</span> Pentacyclic chemical compound found in fruits

Ursolic acid, is a pentacyclic triterpenoid identified in the epicuticular waxes of apples as early as 1920 and widely found in the peels of fruits, as well as in herbs and spices like rosemary and thyme.

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

Emodin (6-methyl-1,3,8-trihydroxyanthraquinone) is a chemical compound, of the anthraquinone family, that can be isolated from rhubarb, buckthorn, and Japanese knotweed. Emodin is particularly abundant in the roots of the Chinese rhubarb, knotweed and knotgrass as well as Hawaii ‘au‘auko‘i cassia seeds or coffee weed. It is specifically isolated from Rheum palmatum L. It is also produced by many species of fungi, including members of the genera Aspergillus, Pyrenochaeta, and Pestalotiopsis, inter alia. The common name is derived from Rheum emodi, a taxonomic synonym of Rheum australe, and synonyms include emodol, frangula emodin, rheum emodin, 3-methyl-1,6,8-trihydroxyanthraquinone, Schüttgelb (Schuttgelb), and Persian Berry Lake.

<span class="mw-page-title-main">Toll-like receptor 4</span> Cell surface receptor found in humans

Toll-like receptor 4 (TLR4), also designated as CD284, is a key activator of the innate immune response and plays a central role in the fight against bacterial infections. TLR4 is a transmembrane protein of approximately 95 kDa that is encoded by the TLR4 gene.

<span class="mw-page-title-main">Lymphocyte antigen 96</span> Protein-coding gene in the species Homo sapiens

Lymphocyte antigen 96, also known as "Myeloid Differentiation factor 2 (MD-2)," is a protein that in humans is encoded by the LY96 gene.

<span class="mw-page-title-main">Ladderane</span>

In chemistry, a ladderane is an organic molecule containing two or more fused cyclobutane rings. The name arises from the resemblance of a series of fused cyclobutane rings to a ladder. Numerous synthetic approaches have been developed for the synthesis of ladderane compounds of various lengths. The mechanisms often involve [2 + 2] photocycloadditions, a useful reaction for creating strained 4-membered rings. Naturally occurring ladderanes have been identified as major components of the anammoxosome membrane of the anammox bacteria, phylum Planctomycetota.

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

Nuciferine is an alkaloid found within the plants Nymphaea caerulea and Nelumbo nucifera.

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

Protocatechuic acid (PCA) is a dihydroxybenzoic acid, a type of phenolic acid. It is a major metabolite of antioxidant polyphenols found in green tea. It has mixed effects on normal and cancer cells in in vitro and in vivo studies.

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

Tetrandrine, a bis-benzylisoquinoline alkaloid, is a calcium channel blocker. It is isolated from the plant Stephania tetrandra, and other Chinese and Japanese herbs.

<span class="mw-page-title-main">NLRP11</span> Protein-coding gene in the species Homo sapiens

NOD-like receptor family pyrin domain containing 11 is a protein that in humans is encoded by the NLRP11 gene located on the long arm of human chromosome 19q13.42. NLRP11 belongs to the NALP subfamily, part of a large subfamily of CATERPILLER. It is also known as NALP11, PYPAF6, NOD17, PAN10, and CLR19.6

<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.

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

Bufothionine is a sulfur-containing compound which is present in the bufotoxins secreted by the parotoid gland of certain toads of the genera Bufo and Chaunus. This specific compound can be found in the skin of certain species of toad such as the Asiatic Toad, Chaunus arunco, Chaunus crucifer, Chaunus spinulosus, and Chaunus arenarum.

Regulatory B cells (Bregs or Breg cells) represent a small population of B cells that participates in immunomodulation and in the suppression of immune responses. The population of Bregs can be further separated into different human or murine subsets such as B10 cells, marginal zone B cells, Br1 cells, GrB+B cells, CD9+ B cells, and even some plasmablasts or plasma cells. Bregs regulate the immune system by different mechanisms. One of the main mechanisms is the production of anti-inflammatory cytokines such as interleukin 10 (IL-10), IL-35, or transforming growth factor beta (TGF-β). Another known mechanism is the production of cytotoxic Granzyme B. Bregs also express various inhibitory surface markers such as programmed death-ligand 1 (PD-L1), CD39, CD73, and aryl hydrocarbon receptor. The regulatory effects of Bregs were described in various models of inflammation, autoimmune diseases, transplantation reactions, and in anti-tumor immunity.

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