Cantharidin

Cantharidin

200px
Names
IUPAC names 2,6-Dimethyl-4,10-dioxatricyclo- [5.2.1.02,6]decane-3,5-dione
Other names Cantharidin, Spanish Fly
Identifiers
CAS Number	56-25-7 N
ChEMBL	ChEMBL48449 N
ChemSpider	2297293 Y
Jmol 3D model	Interactive image
KEGG	C16778 N
UNII	IGL471WQ8P Y
InChI InChI=1S/C10H12O4/c1-9-5-3-4-6(13-5)10(9,2)8(12)14-7(9)11/h5-6H,3-4H2,1-2H3/t5-,6+,9-,10+ Y Key: DHZBEENLJMYSHQ-YUMGAWCOSA-N Y
SMILES O=C2OC([C@@]1(C)[C@@H]3CC[C@@H](O3)[C@]12C)=O
Properties
Chemical formula	C10H12O4
Molar mass	196.20 g/mol
Density	1.41 g/cm3
Melting point	212 °C (414 °F; 485 K)
Vapor pressure	{{{value}}}
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YN ?)
Infobox references

Cantharidin is a odorless, colorless terpene secreted by many species of blister beetles, including broadly in genus Epicauta, and in species Lytta vesicatoria (Spanish fly). False blister beetles, cardinal beetles, and soldier beetles also produce cantharidin. Poisoning from the substance is a significant veterinary concern, especially in horses by Epicauta species, and in humans it also can also be poisonous if taken internally (where the origin is most often experimental self-exposure). Externally, cantharidin is a potent vesicant (blistering agent), exposure to which can cause severe chemical burns. Properly dosed and applied, the same properties have been used for effective topical medications for some conditions.

Chemistry

Structure and nomenclature

Cantharidin, from the Greek kantharis, for beetle, is an odorless, colorless natural product with solubility in various organic solvents, but only slightly solubility in water. It is a monoterpene, and so contains in its framework two isoprene units derived by biosynthesis from two equivalents of isopentenyl pyrophosphate. (The complete mechanism of the biosynthesis of cantharidin is currently unknown.) Its skeleton is tricyclic, formally, a tricyclo-[5.2.1.02,6]decane skeleton. Its functionalities include an carboxylic acid anydride (-CO-O-CO-) substructure in one of its rings, as well as a cyclic ether in its bicyclic ring system.

Distribution and availability

The level of cantharidin in blister beetles can be quite variable. Among blister beetles of the genus Epicauta in Colorado, E. pennsylvanica contains about 0.2 mg, E. maculata contains 0.7 mg, and E. immaculata contains 4.8 mg per beetle; males also contain higher levels than females.

History

Hycleus lugens, an aposematically colored beetle, secretes cantharidin.

Cantharidin was first isolated in 1810 by Pierre Robiquet, a French chemist then living in Paris, from Lytta vesicatoria. Robiquet demonstrated that cantharidin was the actual principle responsible for the aggressively blistering properties of the coating of the eggs of that insect, and established that cantharidin had definite toxic properties comparable in degree to those of the most virulent poisons known in the 19th century, such as strychnine. It is an odorless and colorless solid at room temperature. It is secreted by the male blister beetle and given to the female as a copulatory gift during mating. Afterwards, the female beetle covers her eggs with it as a defense against predators.

There are are many examples in historical sources that reference preparations of this natural product:

• According to Tacitus, it was used by the empress Livia, wife of Augustus Caesar to entice members of the imperial family or dinner guests to commit sexual indiscretions (thus providing her information to hold over them).
• Henry IV (1050–1106) is said to have consumed Spanish fly.
• In 1572, Ambroise Paré wrote an account of a man suffering from "the most frightful satyriasis" after taking a potion composed of nettles and cantharides.
• In the 1670s, Spanish fly was mixed with dried mole's and bat's blood for a love charm made by the magician La Voisin.
• Cantharides are reported to have became fashionable in the 18th century, e.g., being known as pastilles Richelieu in France, and are said to have been slipped into the food of Louis XIV to secure the king's lust for Madame de Montespan.
• Marquis de Sade is said to have given aniseed-flavored pastilles laced with Spanish fly to two prostitutes at an orgy in 1772, poisoning and nearly killing them. He was sentenced to death for that, and sodomy, but later reprieved on appeal.

Veterinary issues

Poisoning from catharidin is a significant veterinary concern, especially in horses by Epicauta species; species infesting feedstocks depend on region—e.g., Epicauta pennsylvanica (black blisterbeetle) in the U.S. midwest and E. occidentalis, temexia, and vittata species (striped blister beetles) in the U.S. southwest—where the concentrations of the agent in each can vary substantially. Beetles feed on weeds and occasionally move into crop fields used to produce livestock feeds (e.g., alfalfa), where they are found to cluster and find their way into baled hay, e.g., a single flake (4-5 in. section) may have several hundred insects, or none at all. Horses are very sensitive to the cantharidin produced by beetle infestations: the LD₅₀ for horses is roughly 1 mg/kg of the horse's body weight. Horses may be accidentally poisoned when fed bales of fodder with blister beetles in them.

Great bustards, a strongly polygynous bird species, are not immune to the toxicity of cantharidin; they become intoxicated after ingesting blister beetles; however, cantharidin has activity also against parasites that infect them.

Human medical issues

General risks

As a blister agent, cantharidin has the potential to cause adverse effects when used medically; for this reason, it has been included in a list of "problem drugs" used by dermatologists and emergency personnel. However, when compounded properly and applied in the clinic topically by a medical provider familiar with its effects and uses, cantharidin can be safely and effectively used to treat some benign skin lesions like warts and molluscum.

When ingested by humans, the LD₅₀ is around 0.5 mg/kg, with a dose of as little as 10 mg being potentially fatal. Ingesting cantharidin can initially cause severe damage to the lining of the gastrointestinal and urinary tracts, and may also cause permanent renal damage. Symptoms of cantharidin poisoning include blood in the urine, abdominal pain, and rarely prolonged erections.

Risks of aphrodisiac use

Main article: Spanish fly

Cantharidin has been used since ancient times as an aphrodisiac, possibly because its physical effects were perceived to mimic those of sexual arousal, and because it can cause priapism. The extreme toxicity of cantharidin makes any use as an aphrodisiac highly dangerous. As a result, it is illegal to sell (or use) cantharidin or preparations containing it without a prescription in many countries.

Other uses

Diluted solutions of cantharidin can be used as a topical medication to remove warts and tattoos and to treat the small papules of Molluscum contagiosum.

Research

Mechanism of action

Cantharidin is absorbed by the lipid membranes of epidermal cells, causing the release of serine proteases, enzymes that break the peptide bonds in proteins. This causes the disintegration of desmosomal plaques, cellular structures involved in cell-to-cell adhesion, leading to detachment of the tonofilaments that hold cells together. The process leads to the loss of cellular connections (acantholysis) and ultimately blistering of the skin. Lesions heal without scarring.

Bioactivities

Topical treatment with cantharidin appears to have some effect in an animal model of cutaneous leishmaniasis. In addition to topical medical applications, cantharidin and its analogues may have activity against cancer cells. Laboratory studies with cultured tumor cells suggest that this activity may be the result of PP2A inhibition.

Popular culture

Natural products preparations containing cantharidin appear frequently in popular media. Examples include:

• The I Spy, where Bill Cosby joked about co-star Robert Culp's having tried to obtain some when in Spain, where a Spanish cab driver responded to a request for it, asking them in turn for "American Fly" (emphasizing the idea of Spanish fly as a universal male fantasy).
• The compound was mentioned in the 1986 Beastie Boys song, "Brass Monkey", as being mixed in the title drink as an aphrodisiac between the narrator (Ad-Rock, Mike D, MCA) and a girl at a party.

Further reading

• Dupuis, Gérard & Berland, Nicole (2004). "Cantharidin: Origin and synthesis," Lille, FR: Lycée Faidherbe, see [1], accessed 13 December 2015.

External links

• Cantharidin
• Molecule of the Month
• Cantharidin Revisited: Blistering Defense of an Ancient Medicine