Editing Cantharidin (section)

==Chemistry==

===Structure and nomenclature===
Cantharidin, from the Greek ''kantharis'', for beetle,<ref>{{cite book | title = A Dictionary of Entomology | date = 2011 | publisher = CABI | page = 253}}</ref> is an odorless, colorless [[natural product]] with solubility in various organic solvents,{{specify|date=December 2015}} but only slight solubility in water.<ref name = veterinary>{{cite book | vauthors = Schmitz DG | veditors = Aiello SE, Moses MA | year = 2013 | title = The Merck Veterinary Manual | chapter = Overview of Cantharidin Poisoning (Blister Beetle Poisoning) | location = Kenilworth, NJ, USA | publisher = Merck Sharp & Dohme | isbn = 978-0911910612 | chapter-url = https://www.merckvetmanual.com/mvm/toxicology/cantharidin_poisoning/overview_of_cantharidin_poisoning.html | access-date = 14 December 2015 | archive-date = 22 December 2015 | archive-url = https://web.archive.org/web/20151222103819/https://www.merckvetmanual.com/mvm/toxicology/cantharidin_poisoning/overview_of_cantharidin_poisoning.html | url-status = dead }}</ref> Its skeleton is [[tricyclic]], formally, a tricyclo-[5.2.1.0<sup>2,6</sup>]decane skeleton. Its functionalities include a [[Organic acid anhydride|carboxylic acid anhydride]] (−CO−O−CO−) substructure in one of its rings, as well as a bridging [[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&nbsp;mg, ''E. maculata'' contains 0.7&nbsp;mg, and ''E. immaculata'' contains 4.8&nbsp;mg per beetle; males also contain higher levels than females.<ref>{{cite journal | vauthors = Capinera JL, Gardner DR, Stermitz FR | title = Cantharidin Levels in Blister Beetles (Coleoptera: Meloidae) Associated with Alfalfa in Colorado | journal = Journal of Economic Entomology | year = 1985 | volume = 78 | issue = 5 | pages = 1052–1055 |doi=10.1093/jee/78.5.1052 }}</ref>

Males of ''[[Berberomeloe majalis]]'' have higher level of cantharidin per beetle: 64.22 ± 51.28&nbsp;mg/g (dry weight) and 9.10 ± 12.64&nbsp;mg/g (d. w.). Cantharidin content in [[haemolymph]] is also higher in males (80.9 ± 106.5&nbsp;μg/g) than in females (20.0 ± 41.5&nbsp;μg/g).<ref name=Bravo2017>{{cite journal| vauthors = Bravo C, Mas-Peinado P, Bautista LM, Blanco G, Alonso JC, García-París M |title=Cantharidin is conserved across phylogeographic lineages and present in both morphs of Iberian ''Berberomeloe'' blister beetles (Coleoptera, Meloidae)|journal=Zoological Journal of the Linnean Society|year=2017|volume=180|issue=4|pages=790–804|doi=10.1093/zoolinnean/zlw016|hdl=10261/153832|hdl-access=free}}</ref>

===Laboratory synthesis===
There have been multiple synthetic approaches to achieve cantharidin in the lab. A common strategy employed by different total synthesis methods is to begin with a [[Diels-Alder]] cycloaddition reaction to form the six-membered ring.<ref>{{cite journal | vauthors = Dauben WG, Kessel CR, Takemura KH | title = Simple, efficient total synthesis of cantharidin via a high-pressure Diels-Alder reaction | journal = Journal of the American Chemical Society | volume = 102 | issue = 22 | pages = 6893–6894 | date = 15 October 1980 | doi = 10.1021/ja00542a060 | bibcode = 1980JAChS.102.6893D }}</ref><ref>{{cite web | vauthors = Davidson MG, Eklov BM, Wuts P, Loertscher BM, Schow SR | title = Synthesis of cantharidin | date = 11 April 2019 | url = https://patents.google.com/patent/WO2019070980A2/en | language = en }}</ref><ref>{{cite web | title = Novel green environment-friendly synthesis process of cantharidin | date = 17 May 2017 | url = https://patents.google.com/patent/CN106674248A/en | language = en }}</ref> The starting material often utilizes a furan as the diene, giving the formation of a bicyclic ring. 

[[File:Synthetic Approach to Cantharidin.jpg|thumb|center|415px|Most total syntheses of cantharidin start with a Diels-Alder reaction.]]

===Biosynthesis===
The complete mechanism of the [[biosynthesis]] of cantharidin is unknown. Its framework formally consists of two [[isoprene]] units.<ref>{{cite book | title = Secondary-Metabolite Biosynthesis and Metabolism | veditors = Petroski RJ, McCormick SP | publisher = Springer Science & Business Media | date = 2012 | isbn = 978-0-306-44309-1 }}</ref> However, [[feeding studies]] indicate that the biosynthetic process is more complicated, and not a simple product of [[geranyl pyrophosphate]] or related ten-carbon parent structure, as the seeming [[monoterpene]] nature would suggest. Instead, there is a [[farnesol]] (15-carbon) precursor from which certain carbon segments are later excised.<ref>{{cite journal | vauthors = Jiang M, Lü S, Zhang Y | title = The Potential Organ Involved in Cantharidin Biosynthesis in Epicauta chinensis Laporte (Coleoptera: Meloidae) | journal = Journal of Insect Science | volume = 17 | issue = 2 | pages = 52 | date = January 2017 | pmid = 28423415 | pmc = 5633858 | doi = 10.1093/jisesa/iex021 }}</ref>

[[File:Cantharidin biosynthesis2.png|thumb|center|415 px|Biosynthesis from farnesol ⁠— ⁠bonds to be formed and major atoms to be added are in {{color|blue|blue}}; while bonds to be broken and atoms/structural segments to be removed are in {{color|red|red}}.]]

Biosynthesis utilizing farnesol as a key intermediate is further supported by experiments in which key genes whose transcripts are expected to participate in the biosynthesis pathway were interfered with by [[RNA interference]] methods. The [[mevalonate]] pathway ([[MVA pathway]]) is responsible for producing [[isoprenoids]] in many organisms, including farnesol.<ref>{{cite journal | vauthors = Kaneko M, Togashi N, Hamashima H, Hirohara M, Inoue Y | title = Effect of farnesol on mevalonate pathway of Staphylococcus aureus | journal = The Journal of Antibiotics | volume = 64 | issue = 8 | pages = 547–549 | date = August 2011 | pmid = 21772307 | doi = 10.1038/ja.2011.49 }}</ref>  Interference with two genes that participate in the MVA pathway, methyl farnesoate epoxidase (EcMFE) and juvenile hormone epoxide hydrolase (EcJHEH) inhibited the biosynthesis of cantharidin in male blister beetles.<ref>{{cite journal | vauthors = Jiang M, Lü S, Zhang Y | title = Characterization of Juvenile Hormone Related Genes Regulating Cantharidin Biosynthesis in Epicauta chinensis | journal = Scientific Reports | volume = 7 | issue = 1 | pages = 2308 | date = 23 May 2017 | pmid = 28536442 | pmc = 5442126 | doi = 10.1038/s41598-017-02393-w | bibcode = 2017NatSR...7.2308J }}</ref>