Protoanemonin (sometimes called anemonol or ranunculol) is a

toxin A toxin is a naturally occurring poison produced by metabolic activities of living cells or organisms. They occur especially as proteins, often conjugated. The term was first used by organic chemist Ludwig Brieger (1849–1919), derived ...

whose glyosidic precursor

ranunculin Ranunculin is a glycoside found in many members of the Ranunculaceae, buttercup family, including species of Helleborus, Anemone, Clematis and most commonly Ranunculus. Glycosides are common in plants, where they serve as defense mechanisms again ...

is found in many plants of the buttercup family (Ranunculaceae). When the plant is wounded or macerated,

is enzymatically broken down into

glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...

and protoanemonin. This toxin's ability to inhibit both

gram positive In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. The Gram stain i ...

and

gram negative Gram-negative bacteria are bacteria that, unlike gram-positive bacteria, do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. Their defining characteristic is that their cell envelope consists of ...

bacteria is linked to the presence of a 5-membered

lactone Lactones are cyclic carboxylic esters. They are derived from the corresponding hydroxycarboxylic acids by esterification. They can be saturated or unsaturated. Lactones are formed by lactonization, the intramolecular esterification of the corresp ...

ring with a highly reactive double bond system.

Biological pathway

Toxicity

Protoamenonin has

vesicant A blister agent (or vesicant) is a chemical compound that causes severe skin, eye and mucosal pain and irritation in the form of severe chemical burns resulting in fluid filled blisters. Named for their ability to cause vesication, blister a ...

properties, which cause rashes or blistering upon contact with the skin or

mucosa A mucous membrane or mucosa is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It ...

. Ingesting large amounts of the toxin despite its bitter taste can cause

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

, vomiting,

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...

spasm A spasm is a sudden involuntary contraction of a muscle, a group of muscles, or a hollow organ, such as the bladder. A spasmodic muscle contraction may be caused by many medical conditions, including dystonia. Most commonly, it is a musc ...

s, acute

hepatitis Hepatitis is inflammation of the liver parenchyma, liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), Anorexia (symptom), poor appetite ...

jaundice Jaundice, also known as icterus, is a yellowish or, less frequently, greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving ...

, or

paralysis Paralysis (: paralyses; also known as plegia) is a loss of Motor skill, motor function in one or more Skeletal muscle, muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory d ...

in animals and humans.

Safety

At room temperature, protoanemonin spontaneously

dimerize In chemistry, dimerization is the process of joining two identical or similar Molecular entity, molecular entities by Chemical bond, bonds. The resulting bonds can be either strong or weak. Many symmetrical chemical species are described as dim ...

s into the potentially therapeutic compound anemonin, which can then be hydrolyzed into a

dicarboxylic acid In organic chemistry, a dicarboxylic acid is an organic compound containing two carboxyl groups (). The general molecular formula for dicarboxylic acids can be written as , where R can be aliphatic or aromatic.Boy Cornils, Peter Lappe "Dicarbox ...

. As such, plants containing glycosidic precursors of protoanemonin are considered safe for humans to handle and

livestock Livestock are the Domestication, domesticated animals that are raised in an Agriculture, agricultural setting to provide labour and produce diversified products for consumption such as meat, Egg as food, eggs, milk, fur, leather, and wool. The t ...

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

ring. 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. 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. 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, while a novel catalytic oxidation of silvan required extreme conditions. 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 Triethylamine is the chemical compound with the formula N(CH2CH3)3, commonly abbreviated Et3N. Like triethanolamine and the tetraethylammonium ion, it is often abbreviated TEA. It is a colourless volatile liquid with a strong fishy odor remini ...

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%.

References

{{reflist, refs= {{cite book, editor1-first=PH, editor1-last=List, editor2-first=L, editor2-last=Hörhammer, title=Hagers Handbuch der pharmazeutischen Praxis, edition=4, publisher=Springer Verlag, year=1979, language=German, isbn=3-540-07738-3 {{cite book, editor1-first=Artur, editor1-last=Berger, editor2-first=Helmut, editor2-last=Wachter, title=Hunnius Pharmazeutisches Wörterbuch, edition=8, publisher=Walter de Gruyter Verlag, year=1998, language=German, isbn=3-11-015793-4 {{cite book, first1=Hermann, last1=Römpp, first2=Jürgen, last2=Falbe, first3=Manfred, last3=Regitz, title=Römpp Lexikon Chemie, edition=9, publisher=Georg Thieme Verlag, location=Stuttgart, year=1992, language=German Handbuch der organischen Chemie
Leopold Gmelin {{in lang, de {{cite journal , last1=Bai , first1=Yili , last2=Benn , first2=Michael , last3=Majak , first3=Walter , last4=McDiamid , first4=Ruth , title=Extraction and HPLC Determination of Ranunculin in Species of the Buttercup Family , journal=Journal of Agricultural and Food Chemistr , date=August 15, 1996 , volume=44 , issue=8 , pages=2235–2238 , doi=10.1021/jf950626m , bibcode=1996JAFC...44.2235B , url=https://doi.org/10.1021/jf950626m , access-date=March 28, 2025, url-access=subscription {{cite journal , last1=Baer , first1=Harold , last2=Holden , first2=Margaret , last3=Seegal , first3=Beatrice , title=The Nature of the Antibacterial Agent from Anemone Pulsatilla , journal=Journal of Biological Chemistry , date=January 1, 1946 , volume=162 , issue=1 , pages=65–68 , doi=10.1016/S0021-9258(17)41459-1 , doi-access=free {{cite journal , last1=Grundmann , first1=Christoph , last2=Kober , first2=Ehrenfried , title=An Improved Synthesis of Protoanemonin , journal=Journal of the American Chemical Society , date=April 1, 1955 , volume=77 , issue=8 , pages=2331–2332 , doi=10.1021/ja01613a092 , bibcode=1955JAChS..77.2332G , url=https://doi.org/10.1021/ja01613a092 , access-date=May 5, 2025, url-access=subscription {{cite journal , last1=Shaw , first1=Elliott , title=A Synthesis of Protoanemonin. The Tautomerism of Acetylacrylic Acid and of Penicillic Acid , journal=Journal of the American Chemical Society , date=December 1946 , volume=68 , issue=12 , pages=2510–2513 , doi=10.1021/ja01216a024 , pmid=20282388 , bibcode=1946JAChS..68.2510S , url=https://doi.org/10.1021/ja01216a024 , access-date=May 4, 2025, url-access=subscription Furanones Plant toxins Ranunculaceae Vinylidene compounds