4-Hydroxycoumarins belong to a class of

vitamin K antagonist Vitamin K antagonists (VKA) are a group of substances that reduce blood clotting by reducing the action of vitamin K. The term "vitamin K antagonist" is technically a misnomer, as the drugs do not directly antagonise the action of vitamin K in t ...

(VKA) anticoagulant drug molecules derived from

coumarin Coumarin () or 2''H''-chromen-2-one is an aromatic organic chemical compound with formula . Its molecule can be described as a benzene molecule with two adjacent hydrogen atoms replaced by a lactone-like chain , forming a second six-membered h ...

by adding a hydroxy group at the 4 position to obtain

4-hydroxycoumarin 4-Hydroxycoumarin is a coumarin derivative with a hydroxy group at the 4-position. Occurrence 4-Hydroxycoumarin is an important fungal metabolite from the precursor coumarin, and its production leads to further fermentative production of the nat ...

, then adding a large

aromatic In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...

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 Vitamin K epoxide reductase (VKOR) is an enzyme () that reduces vitamin K after it has been oxidised in the carboxylation of glutamic acid residues in blood coagulation enzymes. VKOR is a member of a large family of predicted enzymes that are pre ...

. 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 antagonism.

Origin

Although 4-hydroxycoumarin itself is not an anticoagulant, it is an important fungal metabolite from the precursor

, which is also not an anticoagulant, and its production leads to further fermentative production of the natural anticoagulant

dicoumarol Dicoumarol ( INN) or dicumarol (USAN) is a naturally occurring anticoagulant drug that depletes stores of vitamin K (similar to warfarin, a drug that dicoumarol inspired). It is also used in biochemical experiments as an inhibitor of reductases. ...

. This happens in the presence of naturally occurring

formaldehyde Formaldehyde ( , ) (systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section F ...

, 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

sweet clover ''Melilotus'', known as melilot, sweet clover, and kumoniga (from the Cumans),Bulgarian Folk Customs, Mercia MacDermott, pg 27 is a genus in the family Fabaceae (the same family that also includes the ''Trifolium'' clovers). Members are known a ...

silages and is considered a natural chemical substance of combined plant and fungal origin;

mycotoxin A mycotoxin (from the Greek μύκης , "fungus" and τοξίνη , "toxin") is a toxic secondary metabolite produced by organisms of kingdom Fungi and is capable of causing disease and death in both humans and other animals. The term 'mycotoxin' ...

also shares these properties.Bye, A., King, H. K., 1970. The biosynthesis of 4-hydroxycoumarin and dicoumarol by Aspergillus fumigatus Fresenius. Biochemical Journal 117, 237-245. The identification of Dicoumarol in 1940 is the precursor of the drug class known as 4-Hydroxycoumarin. See

warfarin Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent strok ...

for this history.

Effect

The synthetic drugs in the 4-hydroxycoumarin class are all noted primarily for their use as

anticoagulants Anticoagulants, commonly known as blood thinners, are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where the ...

, though they can have several additional effects. All affect the normal metabolism of

vitamin K Vitamin K refers to structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-synthesis modification of certain proteins that are required for blood coagulation ...

in the body by inhibiting the enzyme

which recycles vitamin K to active form. As such, these compounds form the most important and widely used subset of

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 Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...

ion.

Drugs and poisons in the class

The simplest synthetic molecule in the 4-hydroxycoumarin class is

, 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 Brodifacoum is a highly lethal 4-hydroxycoumarin vitamin K antagonist anticoagulant poison. In recent years, it has become one of the world's most widely used pesticides. It is typically used as a rodenticide, but is also used to control larger p ...

), a chemical change that causes their half life 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 brandname for

). They are also referred to as "coumarins," in reference to their derivation, although this term also may be deceptive since

itself, as noted, is not active in clotting, and is used mostly as a perfumery agent. Pharmaceutical examples of 4-hydroxycoumarin pharmaceuticals include: *

acenocoumarol Acenocoumarol is an anticoagulant that functions as a vitamin K antagonist (like warfarin). It is a derivative of coumarin Coumarin () or 2''H''-chromen-2-one is an aromatic organic chemical compound with formula . Its molecule can be descri ...

ethyl biscoumacetate Ethyl biscoumacetate is a vitamin K Vitamin K refers to structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-synthesis modification of certain proteins tha ...

phenprocoumon Phenprocoumon (marketed under the brand names Marcoumar, Marcumar and Falithrom) is a long-acting blood thinner drug to be taken by mouth, and a derivative of coumarin. It acts as a vitamin K antagonist and inhibits blood clotting (coagulation) b ...

Compounds in this class have also been used as pesticides, specifically

rodenticide Rodenticides are chemicals made and sold for the purpose of killing rodents. While commonly referred to as "rat poison", rodenticides are also used to kill mice, squirrels, woodchucks, chipmunks, porcupines, nutria, beavers, and voles. Despi ...

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

agents, used only in this fashion as poisons (because their duration of action is too long to be used as pharmaceuticals) include: *

coumatetralyl Coumatetralyl is an anticoagulant of the 4-hydroxycoumarin vitamin K antagonist type used as a rodenticide. Common applications Coumatetralyl is commonly used with grains and other cereals as a rodent poison in conjunction with a tracking po ...

difenacoum Difenacoum is an anticoagulant of the 4-hydroxycoumarin vitamin K antagonist type. It has anticoagulant effects and is used commercially as a rodenticide Rodenticides are chemicals made and sold for the purpose of killing rodents. While co ...

flocoumafen Flocoumafen is a fluorinated, second-generation anticoagulant of the 4-hydroxycoumarin vitamin K antagonist type. It is a second generation (i.e., high potency) chemical in this class, used commercially as a rodenticide. It has a very high toxic ...

bromadiolone Bromadiolone is a potent anticoagulant rodenticide. It is a second-generation 4-hydroxycoumarin derivative and vitamin K antagonist, often called a "super-warfarin" for its added potency and tendency to accumulate in the liver of the poisoned o ...

tioclomarol Tioclomarol is an anticoagulant of the 4-hydroxycoumarin vitamin K antagonist type. It is a second generation drug, used as a rodenticide Rodenticides are chemicals made and sold for the purpose of killing rodents. While commonly referred to ...

d-CON d-CON is an American brand of rodent control products owned and distributed in the United States by the UK-based consumer goods company Reckitt. The d-CON product line includes traps and baits for use around the home for trapping and killing ra ...

" etc.)

Structures

: :

References

External links