View source for 4-Hydroxycoumarins

{{Short description|Group of anticoagulant drugs}}
{{about|the class of anticoagulants|the parent compound|4-Hydroxycoumarin}}
{{Hatnote group|1=
{{Redirect|Coumadins|the medication known by the trade name "Coumadin"|Warfarin}}
{{Distinguish|text=the broader class of [[coumarin derivatives]], or "coumarins"}}
}}
[[File:Rattenvergifwaarschuwing edit.JPG|thumb|Warning label on a tube of "brown rat" poison laid on a dike of the [[Scheldt]] river in Steendorp, Belgium. The tube contains [[bromadiolone]], a second-generation ("super-warfarin") anticoagulant. The label in Dutch states, in part: '''Contains an anticoagulant with prolonged activity. Antidote Vitamin K1.''']] 
'''4-Hydroxycoumarins''' are a class of [[vitamin K antagonist]] (VKA) anticoagulant drug molecules. Chemically, they are [[derivative (chemistry)|derived]] from [[coumarin]] by adding a [[hydroxy group]] at the [[Locant|4 position]] to obtain [[4-hydroxycoumarin]], then adding a large [[aromatic]] substituent at the 3-position (the ring-carbon between the hydroxyl and the carbonyl). The large 3-position substituent is required for anticoagulant activity.

The primary mechanism of the 4-hydroxycoumarin drugs is the inhibition of [[vitamin K epoxide reductase]]. These compounds are not direct antagonists (in the pharmaceutical sense) of vitamin K, but rather act to deplete reduced vitamin K in tissues. For this reason vitamin K antagonizes their effect, and this has led to the loose terminology of "vitamin K antagonist".

==Origin==
{{further|Warfarin#History}}
{{also|Coumarin derivatives}}
Although 4-hydroxycoumarin itself is not an anticoagulant, it is an important fungal metabolite from the precursor [[coumarin]], which is also not an anticoagulant, and its production leads to further fermentative production of the natural anticoagulant [[dicoumarol]].<ref>{{cite book |author-last1=Low Dog |author-first1=Tieraona |author-last2=Markham |author-first2=Merry Jennifer |chapter=Dietary Supplements and Hemostasis |title=Consultative Hemostasis and Thrombosis |date=2007 |publisher=Elsevier Health Sciences |location=Philadelphia, PA |isbn=9781437710601 |edition=2nd |page=564 |url=https://books.google.com/books?id=sr7CU__45dEC&q=%22coumarin+drugs%22 |doi=10.1016/B978-141602401-9.10033-1}}</ref> This happens in the presence of naturally occurring [[formaldehyde]], which allows attachment of a second 4-hydroxycoumarin molecule through the linking carbon of the formaldehyde, to the 3-position of the first 4-hydroxycoumarin molecule, giving the [[semi-dimer]] the motif of the drug class. Dicoumarol appears in spoiled [[silage]] of [[sweet clover]] and is considered a natural [[mycotoxin]] substance of combined plant and fungal origin.<ref>Bye, A., King, H. K., 1970. The biosynthesis of 4-hydroxycoumarin and dicoumarol by Aspergillus fumigatus Fresenius. Biochemical Journal 117, 237-245.</ref> The identification of dicoumarol in 1940 was the precursor to development of the 4-hydroxycoumarin class of drugs.

==Effects==
The synthetic drugs in the 4-hydroxycoumarin class are all noted primarily for their use as [[anticoagulants]], though they can have several additional effects. All affect the normal metabolism of [[vitamin K]] in the body by inhibiting the enzyme [[vitamin K epoxide reductase]] which recycles vitamin K to active form. As such, these compounds form the most important and widely used subset of [[vitamin K antagonist]] drugs, but other such drugs exist which do not have the 4-hydroxycoumarin structure. All the vitamin K antagonist agents diminish the amount of available vitamin K in the body, and thus inhibit the action of vitamin K-dependent enzymes that are critically involved in the production of active forms of certain [[clotting factors]], and certain other metabolic processes involving the binding of [[calcium]] ion.
[[File:K1 vitamin Mechanism of Action.svg|thumb|left|500px|Mechanism of action for K1-vitamin.]]
{{Clear}}

==Drugs and poisons in the class==
The simplest synthetic molecule in the 4-hydroxycoumarin class is [[warfarin]], in which the aromatic 3-position substituent is a simple [[phenyl group]]. So called "super-warfarins" or second-generation anticoagulants in this class, were developed as [[rodenticides]] for rodents that have developed warfarin resistance. The second generation agents have even larger [[lipid-soluble]] substituents at the 3-position (e.g. [[brodifacoum]]), a chemical change that causes their [[Half-life (biology)|half-lives]] in the body to be greatly increased (sometimes to months). The rodenticide chemicals are sometimes incorrectly referred to as "coumadins" rather than 4-hydroxycoumarins ("Coumadin" is a brand name for [[warfarin]]). They are also referred to as "coumarins," in reference to their derivation, although this term also may be deceptive since [[coumarin]] itself, as noted, is not active in clotting, and is used mostly as a perfumery agent.

Pharmaceutical examples of 4-hydroxycoumarin pharmaceuticals include: 
* [[acenocoumarol]]
* [[dicoumarol]]
* [[ethyl biscoumacetate]]
* [[phenprocoumon]]
* [[warfarin]]

Compounds in this class have also been used as pesticides, specifically [[rodenticide]]s. They act by causing the affected animal to hemorrhage, causing it to seek water, and thus leave dwellings to die outdoors.

The second-generation [[vitamin K antagonist]] agents, used only in this fashion as poisons (because their duration of action is too long to be used as pharmaceuticals) include:

* [[coumatetralyl]]
* [[difenacoum]]
* [[flocoumafen]]
* [[bromadiolone]]
* [[tioclomarol]]
* [[brodifacoum]] ("[[d-CON]]" etc.)

== Structures==
:{| class="wikitable" style="text-align:center; font-size:90%"
|-
| [[File:Cumarin2.svg|100px]]
| [[File:4-HC Struktur.svg|100px]]
| [[File:Dicumarol.svg|180px]]
|-
| [[Coumarin]] <br><small>This molecule does not affect coagulation</small>|| [[4-Hydroxycoumarin]]<br><small>This molecule does not affect coagulation, but is a known '''[[carcinogen]]''' in diesel fumes and tobacco smoke; in the latter, it probably derives from combustion of the [[tobacco additive]] coumarin.</small> || [[Dicumarol]]<br/><small>This molecule was the first discovered 4-hydroxycoumarin anticoagulant. It is a dimer type structure connected at the 3 ring position.</small>
|-
| [[File:Phenprocoumon.svg|140px]]
| [[File:Warfarin.svg|140px]]
| [[File:Acenocoumarol.svg|180px]]
|-
| [[Phenprocoumon]]<br/>([[anticoagulant]]) || [[Warfarin]]<br/>Most commonly used '''anticoagulant''' pharmaceutical|| [[Acenocoumarol]]<br/>(anticoagulant)
|-
| [[File:Tecarfarin skeletal.svg|200px]]
|-
| [[Tecarfarin]] (experimental anticoagulant)
|}

:{| class="wikitable" style="text-align:center; font-size:90%"
|-
| [[File:Brodifacoum.svg|240px]]
| [[File:Bromadiolone structure.svg|240px]]
|-
| [[Brodifacoum]]<br/><small>This molecule is a second-generation anticoagulant with a large 3-position substituent which causes it to be retained in fatty tissues for longer times than first-generation compounds and pharmaceuticals.</small> ([[rodenticide]])|| [[Bromadiolone]]<br/>(rodenticide)
|-
| [[File:Coumatetralyl.svg|140px]]
| [[File:Difenakum structure.svg|140px]]
|-
|[[Coumatetralyl]]<br/>(rodenticide) || [[Difenacoum]]<br/>(rodenticide)
|-
| [[File:Flocoumafen.svg|200px]]
|-
|[[Flocoumafen]]<br/>(rodenticide)
|}

==See also==
*[[Vitamin K antagonist]]

==References==
{{reflist}}

==External links==
* {{MeshName|4-hydroxycoumarins}}
* [https://www.organic-chemistry.org/abstracts/literature/667.shtm Synthesis]

{{coumarin}}

{{DEFAULTSORT:Hydroxycoumarins, 4-}}
[[Category:4-Hydroxycoumarins| ]]<!-- The [[Warfarin]] "article is about the anticoagulation medication. For the rodenticide often called "coumarins", see 4-hydroxycoumarins." -->
[[Category:Coumarin drugs]]
[[Category:Rodenticides]]