Dicoumarol structure

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. 

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. 

Figure 9.13. (a) Structure of coumarin, dicoumarol and warfarin, (b) Reaction catalysed by the vitamin... 

Coumarinic Acid Compounds. These synthetic phylloquinone 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 cydization. The basic structures of these compounds are shown in Figure 2, and their properties listed in Table 6 (see Coumarin). 

Figure 10.42. Structures of Vitamiu K aud Two Autagouists, Dicoumarol aud Warfariu. 

Figure 10.31 Structures of vitamin K and two antagonists, dicoumarol and warfarin.

The relative stabilities of the tautomers of dicoumarol, which can potentially exist in six tautomeric forms, and its derivatives were studied by the PM3 method (04JST(678)55). The calculations have been carried out both in the gas phase and in a continuum model of water, on isolated tautomers of 10 systems obtained by single proton transfer. In the most cases, the predominance of the a,/-benzopyran tautomeric structure 154a was predicted in the gas phase. In aqueous solution, the calculations imply significant qualitative differences in the relative stabilities of the tautomers and predict the predominance of the tetra-keto structure 154b, even though the a,a -benzopyran structure is the one with the largest dipole moment. 

Schofield first described the sweet clover disease of cattle as a defect in blood clotting [2]. It has been shown since that this disease is connected with prothrombin deficiency [403, 404]. Later, the coumarin structure was recognised as the toxic agent of spoiled sweet clover hay responsible for the anticoagulant activity [34]. The bis-hydroxycoumarin (61) (dicoumarol) as the prototype of these compounds, was isolated from clover [33, 405] and applied in therapy [406-408]. 

Stenflo, J. Vitamin K and the biosynthesis of prothrombin II. Structural comparison of normal and dicoumarol-induced bovine prothrombin. J. biol. Chem. 247, 8167-8175 (1972)... 

DicoumaroL This compound (37) has the empirical formula, CwHijOe, and its structure (154) is ... 

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