Dicoumarol

The antagonisms that exist between unsaturated fatty acids, and carotene and vitamin E are compHcated and largely undefined. Linoleic acid acts as an antivitamin to i7/-a-tocopherol [59-02-9, 1406-18-9, 10191-41-0] (vitamin E) by reducing availabiHty through direct intestinal destmction. Various Hpoxidases destroy carotenes and vitamin A (73). Dicoumarol [66-76-2] (3,3 -methylenebis(4-hydroxycoumarin)) is a tme antimetaboHte of vitamin K [12001 -79-5] but seems to occur only in clover and related materials that are used primarily as animal feeds (74). 

Coum rinic Acid Compounds. These synthetic phyUoquinone derivatives and congeners have been employed as anticoagulants since the isolation of 3,3 -methylenebis(4-hydroxy-2H-l-benzopyran-2-one) [66-76-2] (bis-4-hydroxycoumarin or dicoumarol) (1) from spoiled sweet clover in 1939. The ingestion of the latter was responsible for widespread and extensive death of bovine animals at that time. The parent compound for the synthesis of many congeners is 4-hydrocoumarin, which is synthesized from methyl salicylate by acetylation and internal cyclization. The basic stmctures of these compounds are shown in Figure 2, and their properties Hsted in Table 6 (see Coumarin). 

Hydroxycoumarin [1076-38-6] can be synthesized by cyclization of acetyl methyl salicylate. It is a coumatin metaboHte occurring in spoiled hay. Derivatives of 4-hydroxycoumarin such as dicoumarol [66-76-2] warfarin [81-81-2] cyclocoumarol [518-20-7] ethylbis—coumaracetate [548-00-5] and bis-4-hydroxycoumarin [25892-93-7] are synthetic blood anticoagulants (see Blood, coagulants and anticoagulants). 

Dicoumarol [66-76-2] (5) was isolated from spoiled sweet clover hay. It is prepared synthetically by reaction of 4-hydroxycoumarin with formaldehyde (85). It is used in anticoagulant therapy often associated with heparin. 

Dicoumarol — see Coumarin, 3,3 -methylenebis(4-hydroxy-Dictamnine biosynthesis, 4, 992 occurrence, 4, 989 pharmacology, 4, 992 synthesis, 4, 990 Dicyanocobyrinic acid heptamethyl ester, 4, 422 Dicycloalkaselenophenes synthesis, 4, 968 Dicyclohexa-1,4-diselenins thermolysis, 4, 968 Dieckmann condensation chroman-3-one synthesis by, 3, 854 isochroman-4-one synthesis by, 3, 859 oxoindolizidine synthesis by, 4, 471... 

Anticoagulant therapy was developed with the adventitious discovery of dicoumarol (8). A fuller discussion of the rationale for the use of such compounds is found in the chapter on Five-Mem-bered Heterocycles Fused to One Benzene Ring. The reader s attention is directed, however, at the fact that dicoumarol is a polycarbonyl compound containing a very acidic hydrogen. A series of similarly acidic 1,3-indandiones have been found to constitute an additional class of anticoagulant agents. 

Dicoumarol is found in sweet clover and can cause hemorrhaging in cattle because of its anticoagulant action. It acts as a vitamin K antagonist and has served as a model for the development of warfarin and related anticoagulant rodenticides. 

The formulas of some ARs are given in Figure 11.1, where it can be seen that they have some structural resemblance to both dicoumarol and vitamin K in its quinone form. All possess quinone rings linked to unsubstituted phenyl rings. The phenyl rings of the rodenticides confer hydrophobicity, especially in the relatively large and complex molecules of brodifacoum and flocoumafen. The chemical properties of some ARs are given in Table 11.1... 

Warfarin and the second-generation superwarfarins are ARs that have a structural resemblance to dicoumarol and vitamin K. They act as vitamin K antagonists, thereby retarding or stopping the carboxylation of clotting proteins in the hepatic endoplasmic reticulum. The buildup of nonfunctional, undercarboxylated clotting proteins in the blood leads eventually to death by hemorrhaging. 

Dicoumarol and related molecules are generally used over prolonged periods, whereas heparin is used over shorter periods. Hirudin has recently been approved for general medical use, while ancrod remains under clinical investigation. 

The last of the fat-soluble vitamins to be identified was vitamin K, found by Dam to be an anti-hemorrhagic factor for young chicks, distinct from vitamin C. Its structure was determined by Dam in collaboration with Karrer. Interest in the vitamin was intensified when it was discovered (Link, 1941) that dicoumarol, present in spoiled sweet clover, was the agent producing hypothrombinemia (giving prolonged blood-clotting time) in cattle. Since vitamin K is structurally similar to dicoumarol, the vitamin was presumptively implicated in thrombin formation. This has been fully substantiated by recent work on the role of vitamin K in the synthesis of prothrombin in the liver. 

Coumarin glycosides are found throughout the plant kingdom (Burrows and Tyrl, 2001). Seeds of Aesculus glabra (Ohio buckeye) contain the coumarin esculin, which is a mild neurotoxin. Sweet clovers Melilotus spp.) contain coumarins that are considered harmless unless moldy conditions exist, in which fungal activity produces the double coumarin dicoumarol. Dicoumarol is a... 

Warfarin provides us with a slightly incongruous state of affairs it is used as a drug and also as a rat poison. It was developed from a natural product, dicoumarol, and provides us with a nice example of how pyrone chemistry resembles that of conjugated lactones rather than aromatic systems. 

Many plants produce coumarins coumarin itself is found in sweet clover and contributes to the smell of new-mown hay. However, if sweet clover is allowed to ferment, oxidative processes initiated by the microorganisms lead to the formation of 4-hydroxycoumarin rather than coumarin. 4-Hydroxycoumarin then reacts with formaldehyde, also produced via the microbial degradative reactions, and provides dicoumarol. 

Animals fed spoiled sweet clover were prone to fatal haemorrhages. The canse was traced to the presence of dicoumarol. This compound interferes with the effects of vitamin K in blood coagulation, the blood loses its ability to clot, and minor injnries can lead to severe internal bleeding. Synthetic dicoumarol has been nsed as an oral blood anticoagnlant in the treatment of thrombosis, where the risk of blood clots becomes life threatening. It has since been snperseded by warfarin, a synthetic development based on the natnral prodnct. 

Other NADH dehydrogenases include NADH dehydrogenase (quinone) [EC 1.6.99.5] which catalyzes the reaction of NADH with an acceptor to produce NAD+ and the reduced acceptor. Menaquinone can serve as the acceptor substrate. This dehydrogenase is inhibited by AMP and 2,4-dinitrophenol but not by dicoumarol or folic acid derivatives. 

This enzyme [EC 1.6.99.2] (also known as NAD(P)H quinone reductase, DT diaphorase, quinone reductase, azoreductase, phylloquinone reductase, and menadione reductase) catalyzes the reaction of NAD(P)H with an acceptor to produce NAD(P) and the reduced acceptor. This FAD-dependent enzyme is inhibited by dicoumarol. 

Deserpldine, 320, 321 Desimlpramine, 402 Desmethylmorphine, 289 Desulfurization, 130, 166 Dexamethosone, 199 Dexbrompheniramine, 77 Dexchlorpheniramine, 77 Dextroamphetamine, 70 Dextromoramide, 82 Dextromorphan, 293 Dextrothyroxine, 92 Diabetes, 136 Dianlthazole, 327 Diazepam, 365, 366 Diazoxide, 355 Dibenamine, 55 Dibenzepine, 405 Dibucaine, 15 Dicarbocyanine dye, 327 Dichlorisone, 203 Dichloroisoproteronol, 65, 66 Dichlorophenamide, 133 Dicloxacillin, 413 Dicoumarol, 147 Dicyclonine, 36... 

CI2. Cucinell, S. A., Conney, A. H., Sansor, M., and Bums, J. J., Drug interactions in man lowering effect of phenobarbital on plasma levels of dicoumarol and diphenylhydantoin. Clin. Pharmacol. Thcr. 6, 420-429 (1965). 

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