Sweet clover disease

The bis(hydroxycoumarin) derivative dicoumarol (45), which was first identified as the causative agent of sweet clover disease in cattle, is used as an anticoagulant in the treatment of thrombosis. Similar compounds with other linking groups have been used, and warfarin (46), which was first introduced as a rodenticide, is also of value. The hydroxycoumarins interfere with the function of vitamin K in the synthesis of prothrombin and other blood... 

Campbell H A, Link K P 1941 Studies on the haemorrhagic sweet clover disease IV the isolation and crystallisation of the haemorrhagic agent. Journal of Biological Chemistry 138 21. 

Kresge N, Simoni RD, Hill RL. Hemorrhagic sweet clover disease, dicoumarol, and warfarin the work of Karl Paul Link. J Biol Chem 2005 280(8) e5-6. 

BOIA A Vitamin K antagonist This group comprises vitamin K antagonists such as the dicoumarol group. The plant Melilotus officinalis (L.) Pallas, family Fabaceae, that has become mouldy due to microorganisms, caused disease in grazing cows, Sweet Clover Disease , where the cows died ftom internal bleeding. The discovery that this disease was... 

A21. Stahmann, M.A., C.F. Huebner, and K.P. Link Studies on the hemorrhagic sweet clover disease. V. Identification and synthesis of the hemorrhagic agent J. Biol. Chem. 12A01. 

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]. 

Overman RS, Stahmann MA, Hnelmer CF, Sullivan WR, Speio L, Doherty DG, Ikawa M, Graf L, Roseman S, Link KP (1944) Studies on the Htanoirhagic Sweet Clover Disease. XIII. Anticoagulant Activity and Structure in the 4-Hydroxycoumarin Group. J Biol Chem 153 5... 

The aldol condensation of 4-hydroxycoumarin with fonnaldehyde provides an a,p-unsaturated carbonyl compound, which then undergoes a conjugate (1,4-) addition of a second molecule of 4-hydroxycoumarin. This reaction could be catalyzed by either trace base or trace acid the acid-catalyzed reaction is shown and discussed here. The enol portion of 4-hydroxycoumarin is the nucleophile in an aldol reaction with protonated formaldehyde. The resulting product dehydrates to provide the a,p-unsaturated carbonyl compound, which, after protonation renders it a more reactive electrophile, then reacts with another nucleophilic molecule of 4-hydroxycoumarin in a conjugate addition reaction. This product, upon loss of a proton to the aqueous solvent, leads to dicoumarol. This substance is present in moldy sweet clover. It is a blood anticoagulant and its ingestion leads to the hemorrhagic sweet clover disease that kills cattle. 

The addition of oxalate or citrate to blood will chelate calcium ions, and prevent clotting. Addition of a solution of calcium chloride to oxalated normal plasma results in rapid clotting addition of calcium chloride to oxalated plasma from calves with sweet clover disease did not result in clotting. 

Table 9.12 Clotting time of blood from a calf affected by sweet clover disease when treated with the prothrombin fraction from a normal animal or an affected animal...

The discovery of the cause of sweet clover disease opened up an entirely new field. The synthesis of several dicoumarol derivatives followed. These antivitamins, or antagonists, decrease the ability of the blood to clot by inhibiting the synthesis of prothrombin and the other K-dependent blood clotting factors. They are used medically to reduce clotting of the blood in patients with certain circulatory disorders, especially some forms of atherosclerosis, phlebitis, and thrombosis. 

Haemorrhagic agent causing sweet clover disease in cattle vitamin K antagonist. Used as a 0.25-0.5% soln. in EtOH as turbidimetric acid-base indicator (pH range 5.4-5.7). Cryst. (cyclohexanone). Mp 288-289°. 

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