Clover disease

In general, isoflavonoids in clovers and other legume pasture plants pose a danger to reproduction in farm animals because they lead to difficult labor, infertility, and lactation in unbred ewes. In Australia, an estimated one million ewes fail to lamb each year because of clover disease (Harborne, 1993). 

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... 

EST-R agonist (2) [oestrogen, causes clover disease (infertility disease) of ewes] EST-R (87)... 

EST-R agonist (yields the more potent oestrogen Equol after ingestion —> clover disease of ewes) [antifungal, hypolipidaemic, phytooestrogen]... 

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. 

Over 300 different plants contain either compounds with estrogenic activity or precursors for the formation of nonsteroidal estrogens. Coumestrol, equol, and zearalenone are examples of phytoestrogens that are found in legumes, tubers, and fungi that infest grains. These substances clearly act as reproductive toxins in sheep (equol in clover disease) and... 

Dale, P.J. and Cheyne, V.A. (1993). The elimination of clover diseases by shoot tip culture. Annals of Applied Biology, 123 25-32. 

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. 

Adams, N.R. (1979). Masculinization of the external genitalia in ewes with clover disease. 

Adams, N.R. (1983). Sexual-behavior of ewes with clover disease treated repeated with estradiol benzoate or testosterone propionate after ovariectomy. Journal of Reproduction cmdFertility, 68,113-117. Adams, N.R. (1990). Permanent infertility in ewes exposed to plant estrogens. Australian Veterinary... 

Adams, N.R. Martin, G.B. (1983). Effects of estradiol on plasma-concentrations of luteinizing-hormone in ovariectomized ewes with clover disease. Australian Journal of Biological Sciences, 36, 295-303. 

Findlay, J.K., Buckmaster, J.M., Goding, J.R., Cuimning, I.A., Chamley, W.A. Hearnshaw, H. (1973). The release of luteinizing hormone by oestradiol-17 and a synthetic gonadotrophin-releasing factor in ewes affected with clover disease. Journal of Reproduction and Fertility, 32, 341-342. 

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