Protoanemonin

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Protoanemonin[1]
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Names
Preferred IUPAC name
5-Methylidenefuran-2(5H)-one
Other names
4-Methylenebut-2-en-4-olide
Identifiers
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3D model (JSmol)
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  • InChI=1S/C5H4O2/c1-4-2-3-5(6)7-4/h2-3H,1H2 checkY
    Key: RNYZJZKPGHQTJR-UHFFFAOYSA-N checkY
  • InChI=1/C5H4O2/c1-4-2-3-5(6)7-4/h2-3H,1H2
    Key: RNYZJZKPGHQTJR-UHFFFAOYAD
  • C=C1C=CC(=O)O1
Properties
C5H4O2
Molar mass 96.085 g·mol−1
Appearance Pale yellow oil
Boiling point 73[2] °C (163 °F; 346 K)
Hazards
Lethal dose or concentration (LD, LC):
190 mg·kg−1 (mouse)[3]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Template:Chembox Footer/trackingTemplate:Short description

Protoanemonin (sometimes called anemonol or ranunculol[4]) is a toxin whose glycosidic precursor ranunculin is found in many plants of the buttercup family (Ranunculaceae). When the plant is wounded or macerated, ranunculin is enzymatically broken down into glucose and protoanemonin.[5][6] This toxin's ability to inhibit both gram positive and gram negative bacteria is linked to the presence of a 5-membered lactone ring with a highly reactive double bond system.[7]

Biological pathway

File:Ranunculin skeletal.svg ranunculin
↓ – glucose (maceration, enzymatically)
File:Protoanemonine.svg protoanemonin
↓ dimerization (spontaneous)
File:Anemonin.svg anemonin
↓ hydrolyzation
File:Anemoninsäure.svg 4,7-dioxo-2-decenedioic acid

Toxicity

Protoamenonin has vesicant properties, which cause rashes or blistering upon contact with the skin or mucosa.[6] Ingesting large amounts of the toxin despite its bitter taste can cause nausea, vomiting, dizziness, spasms, acute hepatitis, jaundice, or paralysis in animals and humans.[6][8][9][10][11]

Safety

At room temperature, protoanemonin spontaneously dimerizes into the potentially therapeutic compound anemonin, which can then be hydrolyzed into a dicarboxylic acid.[5][12][13] As such, plants containing glycosidic precursors of protoanemonin are considered safe for humans to handle and livestock to eat after being properly harvested and dried into hay. The hydrolization product of anemonin- anemoninic acid- is also non-toxic but lacks its potentially therapeutic antimicrobial activity, having lost the highly reactive unsaturated lactone ring.[7] This makes anemonin of greater interest for the synthesis of therapeutic compounds.

Synthesis

A patent from 1955 describes a method for extracting protoanemonin from fresh plants, but the extract must be kept at nearly neutral pH and requires the addition of some radical scavenger to avoid spontaneous formation of anemonin.[12][14] Depending on the specific amount of added weak acid and storage temperature, solutions of extracted protoanemonin have been reported to be able to retain their potency for periods ranging from days to months.[12][15] Due to the variable stability of protoanemonin solutions obtained by complicated fresh plant extractions, reliable synthetic preparation has been pursued from many starting points. Methods starting from levulinic acid- widely used in the early 2000s- require tedious extraction steps and have been associated with difficult replication of results,[16] while a novel catalytic oxidation of silvan required extreme conditions.[17] In 2006, a paper was published detailing a convenient synthesis that proceeds through a crystal which is stable for storage at room temperature. When stirred with triethylamine overnight, this solid affords protoanemonin with an 80% yield; Kotera and colleagues balance simplicity and efficiency well, as the overall yield of protoanemonin from this 4 step synthesis is 46%.[18]

File:Deoxyribose structure.svg 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
File:Protoanemonine.svg Protoanemonin; 46% overall yield [18]

References

  1. ^ Page Module:Citation/CS1/styles.css has no content.Römpp, Hermann; Falbe, Jürgen; Regitz, Manfred (1992). Römpp Lexikon Chemie (in German) (9 ed.). Stuttgart: Georg Thieme Verlag. ISBN 3137349095.{{cite book}}: CS1 maint: unrecognized language (link)
  2. ^ Page Module:Citation/CS1/styles.css has no content.Haynes, William M.; Lide, David R.; Bruno, Thomas J. (2014). "3". CRC Handbook of Chemistry and Physics (95th ed.). Boca Raton, Florida: CRC Press. p. 370. ISBN 9781482208689. OCLC 908078665.
  3. ^ Page Module:Citation/CS1/styles.css has no content.Martín, ML; San Román, L; Domínguez, A (1990). "In vitro activity of protoanemonin, an antifungal agent". Planta Medica. 56 (1): 66–9. Bibcode:1990PlMed..56...66M. doi:10.1055/s-2006-960886. PMID 2356244. S2CID 260283223. The LD50 of protoanemonin in male Swiss albino mice was 190 mg/kg.
  4. ^ Page Module:Citation/CS1/styles.css has no content.List, PH; Hörhammer, L, eds. (1979). Hagers Handbuch der pharmazeutischen Praxis (in German) (4 ed.). Springer Verlag. ISBN 3-540-07738-3.{{cite book}}: CS1 maint: unrecognized language (link)
  5. ^ a b Page Module:Citation/CS1/styles.css has no content.Berger, Artur; Wachter, Helmut, eds. (1998). Hunnius Pharmazeutisches Wörterbuch (in German) (8 ed.). Walter de Gruyter Verlag. ISBN 3-11-015793-4.{{cite book}}: CS1 maint: unrecognized language (link)
  6. ^ a b c Page Module:Citation/CS1/styles.css has no content.Bai, Yili; Benn, Michael; Majak, Walter; McDiamid, Ruth (August 15, 1996). "Extraction and HPLC Determination of Ranunculin in Species of the Buttercup Family". Journal of Agricultural and Food Chemistry. 44 (8): 2235–2238. Bibcode:1996JAFC...44.2235B. doi:10.1021/jf950626m. Retrieved March 28, 2025.
  7. ^ a b Page Module:Citation/CS1/styles.css has no content.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.
  8. ^ Page Module:Citation/CS1/styles.css has no content."Helleborus niger". Gardener Toolbox. North Carolina State University Extension. Retrieved April 30, 2025.
  9. ^ Page Module:Citation/CS1/styles.css has no content.Yilmaz, Bulent; Yilmaz, Barış; Aktaş, Bora; Unlu, Ozan; Roach, Emir Charles (2015-02-27). "Lesser celandine (pilewort) induced acute toxic liver injury: The first case report worldwide". World Journal of Hepatology. 7 (2): 285–288. doi:10.4254/wjh.v7.i2.285. ISSN 1948-5182. PMC 4342611. PMID 25729484.
  10. ^ Page Module:Citation/CS1/styles.css has no content.Verbraucherschutz, Bundesamt für (2014-09-12). List of Substances of the Competent Federal Government and Federal State Authorities: Category "Plants and plant parts". Springer. ISBN 9783319107325.
  11. ^ Page Module:Citation/CS1/styles.css has no content.Lewis, Robert Alan (1998-03-23). Lewis' Dictionary of Toxicology. CRC Press. ISBN 9781566702232.
  12. ^ a b c Page Module:Citation/CS1/styles.css has no content.Cuny, Eckehard (September 12, 2023). "Bioactive Ingredients of Helleborus niger L. (Christmas Rose): The Renaissance of an Old Medicinal Herb—A Review". Natural Product Communications. 18 (9). doi:10.1177/1934578X231201053.
  13. ^ Handbuch der organischen Chemie, Leopold Gmelin Template:In lang
  14. ^ Page Module:Citation/CS1/styles.css has no content.Gäbelein, K. "Verfahren zur Gewinnung therapeutisch wervoller, haltbarer Protoanemoninpräparate (Process for obtaining therapeutically useful, stable protoanemonine preparations)". Hermes Fabrik pharm Präparate. doi:10.1177/1934578X231201053. Retrieved May 4, 2025.
  15. ^ Page Module:Citation/CS1/styles.css has no content.Grundmann, Christoph; Kober, Ehrenfried (April 1, 1955). "An Improved Synthesis of Protoanemonin". Journal of the American Chemical Society. 77 (8): 2331–2332. Bibcode:1955JAChS..77.2332G. doi:10.1021/ja01613a092. Retrieved May 5, 2025.
  16. ^ Page Module:Citation/CS1/styles.css has no content.Shaw, Elliott (December 1946). "A Synthesis of Protoanemonin. The Tautomerism of Acetylacrylic Acid and of Penicillic Acid". Journal of the American Chemical Society. 68 (12): 2510–2513. Bibcode:1946JAChS..68.2510S. doi:10.1021/ja01216a024. PMID 20282388. Retrieved May 4, 2025.
  17. ^ Page Module:Citation/CS1/styles.css has no content.Lovel, Irina; Goldberg, Yuri; Shymanska, Mariya (January 1, 1990). "A Novel Synthesis of Protoanemonin by the Catalytic Vapour-phase Oxidation of Silvan". Journal of the Chemical Society (16): 1079–1080. doi:10.1039/C39900001079. Retrieved May 4, 2025.
  18. ^ a b Page Module:Citation/CS1/styles.css has no content.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. Retrieved May 4, 2025.
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