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222. Coumarins as anticoagulants
FLAVOURING MATTERS, SOLVENTS AND SWEETENERS
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221. Biosynthesis of eomnarin and herniarin in lavender The mode of formation in plants of 7-hydrocoumarins has given rise to much speculation. Reid (Chem. & Ind. 1959, p. 1439) showed that L-phenylalanine is a general precursor of several compounds of this group, and the present author previously suggested (Browh, Z. Naturf. 1960, 15b, 768) that a cinnamic acid derivative is first formed which then undergoes ortho- or para-hydroxylation to form coumarin or 7-hydroxycoumarin respectively; the cinnamic acid derivative could be formed enzymically from phenylalanine. In this investigation the author studied the formation by lavender plants of coumarin and 7-hydroxyeoumarins from compounds that might be intermediates in the biosynthesis. Lavender roots were immersed in solutions containing the following compounds, which were labelled with 1'C: L-phenylalanine, glucose, o- and p-coumaric acids and o-coumaryl glucoside. The amounts of [1~C] coumarin and its derivatives in ethanol extracts of such plants were determined, after any glycosides had been hydrolyzed by the action of emulsin. Herniarin was released by emulsin-treatment in certain cases. This was evidence for the formation of the glucoside of 4-methoxycoumarinic acid. Additional support was given by the results obtained to the view that L-phenylalanine was a general precursor of coumarin. It was of interest that phenylalanine gave rise to higher amounts of herniarin than of coumarin which suggested that the former was not formed by the introduction of a methoxyl group into coumarin. Relative to glucose, ocoumaric acid and its glucoside were readily converted by the lavender plant into coumarinyl glucoside; p-coumaric acid was transformed predominantly to herniarin. The stage at which o-methylation takes place in the biosynthesis of herniarin is.unknown. In view of the evidence for the formation of the glucoside of 4-methoxycoumarinic acid and of its formation from p- but not o-coumaric acid the author concluded that the first stage was p-hydroxylation of cinnamic acid or some other derivative of phenylpropane. This was probably followed by o-hydroxylation and glucoside formation at the o-hydroxyl group. Hydrolysis of the glucoside into 4-methoxycoumarinic acid, followed by spontaneous dehydration could then give rise to the lactone herniarin. Brown, S. A. (1962). Biosynthesis of coumarin and herniarin in lavender. Science 137, 977. 222. Coumarim as anticoagulants While many clinicians do not realize that coumarin is distinct from dicoumarol, many chemists are apt to overlook the fact that coumarin possesses considerable anticoagulant activity. A comparison of 35 derivatives of coumarin has provided some interesting information on this subject. Taking the relative molar anticoagulant activity of 7-methoxy-3-phenylcoumarin as I, coumarin itself has an activity of 3.2 and dicoumarol 15.2. 3-Hydroxycoumarin, one of the principal metabolites of coumarin, is inactive. 4-Hydroxycoumarin, a minor metabolite has a value of 4.8. Unfortunately the other hydroxycoumarins are not reported upon. Arora, R. B. & Mathur, C. N. (1963). Relationship between structure and anticoagulant activity of coumarin derivatives. Brit. J. Pharmacol. 20, 29. 223.'/The toxicology of saponins ",' Ingestion of a perennial broomweed, Gutierrezia microcephala (I), has been shown (DoUahite & Anthony, J. Amer. vet. med. Ass. 1957, 130, 525) to cause abortion in cattle, sheep, goats and rabbits. In the present paper the effects are described of injecting into pregnant cattle, goats and rabbits a saponin-containing fraction of (I), a toxic saponin prepared from the lechuguiila plant Agave lecheguilla (II), and a pharmaceutical grade commercial saponin alleged to be non-toxic (III). All but one of a group of 18 rabbits died after receiving between 2-75 mg I/kg daily for up to 22 days. Of 18 animals 11 aborted. Goats
271
221. Biosynthesis of eomnarin and herniarin in lavender The mode of formation in plants of 7-hydrocoumarins has given rise to much speculation. Reid (Chem. & Ind. 1959, p. 1439) showed that L-phenylalanine is a general precursor of several compounds of this group, and the present author previously suggested (Browh, Z. Naturf. 1960, 15b, 768) that a cinnamic acid derivative is first formed which then undergoes ortho- or para-hydroxylation to form coumarin or 7-hydroxycoumarin respectively; the cinnamic acid derivative could be formed enzymically from phenylalanine. In this investigation the author studied the formation by lavender plants of coumarin and 7-hydroxyeoumarins from compounds that might be intermediates in the biosynthesis. Lavender roots were immersed in solutions containing the following compounds, which were labelled with 1'C: L-phenylalanine, glucose, o- and p-coumaric acids and o-coumaryl glucoside. The amounts of [1~C] coumarin and its derivatives in ethanol extracts of such plants were determined, after any glycosides had been hydrolyzed by the action of emulsin. Herniarin was released by emulsin-treatment in certain cases. This was evidence for the formation of the glucoside of 4-methoxycoumarinic acid. Additional support was given by the results obtained to the view that L-phenylalanine was a general precursor of coumarin. It was of interest that phenylalanine gave rise to higher amounts of herniarin than of coumarin which suggested that the former was not formed by the introduction of a methoxyl group into coumarin. Relative to glucose, ocoumaric acid and its glucoside were readily converted by the lavender plant into coumarinyl glucoside; p-coumaric acid was transformed predominantly to herniarin. The stage at which o-methylation takes place in the biosynthesis of herniarin is.unknown. In view of the evidence for the formation of the glucoside of 4-methoxycoumarinic acid and of its formation from p- but not o-coumaric acid the author concluded that the first stage was p-hydroxylation of cinnamic acid or some other derivative of phenylpropane. This was probably followed by o-hydroxylation and glucoside formation at the o-hydroxyl group. Hydrolysis of the glucoside into 4-methoxycoumarinic acid, followed by spontaneous dehydration could then give rise to the lactone herniarin. Brown, S. A. (1962). Biosynthesis of coumarin and herniarin in lavender. Science 137, 977. 222. Coumarim as anticoagulants While many clinicians do not realize that coumarin is distinct from dicoumarol, many chemists are apt to overlook the fact that coumarin possesses considerable anticoagulant activity. A comparison of 35 derivatives of coumarin has provided some interesting information on this subject. Taking the relative molar anticoagulant activity of 7-methoxy-3-phenylcoumarin as I, coumarin itself has an activity of 3.2 and dicoumarol 15.2. 3-Hydroxycoumarin, one of the principal metabolites of coumarin, is inactive. 4-Hydroxycoumarin, a minor metabolite has a value of 4.8. Unfortunately the other hydroxycoumarins are not reported upon. Arora, R. B. & Mathur, C. N. (1963). Relationship between structure and anticoagulant activity of coumarin derivatives. Brit. J. Pharmacol. 20, 29. 223.'/The toxicology of saponins ",' Ingestion of a perennial broomweed, Gutierrezia microcephala (I), has been shown (DoUahite & Anthony, J. Amer. vet. med. Ass. 1957, 130, 525) to cause abortion in cattle, sheep, goats and rabbits. In the present paper the effects are described of injecting into pregnant cattle, goats and rabbits a saponin-containing fraction of (I), a toxic saponin prepared from the lechuguiila plant Agave lecheguilla (II), and a pharmaceutical grade commercial saponin alleged to be non-toxic (III). All but one of a group of 18 rabbits died after receiving between 2-75 mg I/kg daily for up to 22 days. Of 18 animals 11 aborted. Goats