Inhibition by coumarins

SCHEME 11.3 Postulated mechanisms for the inhibition of serine proteases by coumarin derivatives. NuH nucleophile. Pathway a suicide-type inactivation (suicide substrate). Pathway b transient inactivation by formation of a stable acyl-enzyme (alternate substrate-inhibitor). 

Aliotta, G., Cafiero G., Fiorentino, A. and Strumia, S. (1993). Inhibition of radish germination and root growth by coumarin and phenylpropanoids. Journal of Chemical Ecology 19 175-183. 

Bacterial topoisomerases (called DNA gyrases) are inhibited by several Important classes of antibiotics, including the coumarins, such as novobiocin quinolones, such as nalidixic acid and fluoroquinolones, such as ciprofloxacin. 

This reaction is of interest because of its specific inhibition by such coumarin derivatives as Warfarin ... 

This synthetic compound, as well as natural coumarin anticoagulants (Box 15-F), inhibits both the vitamin K reductase and the epoxide reductase.518 519 The matter is of considerable practical importance because of the spread of warfarin-resistant rats in Europe and the United States. One resistance mutation has altered the vitamin K epoxide reductase so that it is much less susceptible to inhibition by warfarin.519 520... 

Inhibition of chemical carcinogen-induced neoplasia by coumarins and alpha-angelicalactone. Cancer Res. 39, 1651-1654. 

Kaiser, et al. [276] studied another example of inhibition of phosphorylation process by coumarins. In that study, it was shown that imperatorin, a fiiranocoumarin from Imperatoria ostruthium L. and Ammi majus L., inhibited respiration and phosphorylation of isolated mitochondria of the liver in the presence of succinate [276,326]. 

Furanocoumarin 8-methoxypsoralen (8-MOP) (1-100 pg/ml) in the dark showed a protective affect against hypotonic hemolysis of the erythrocyte membrane. However, the effect against heat-induced hemolysis was dependent on the concentration of 8-MOP lower concentrations of 8-MOP showed an inhibiting effect, whereas higher concentrations caused acceleration of hemolysis. The erythrocytes reacted with 8-MOP in the dark were shrunk and had altered shapes. It can be deduced that modification of erythrocyte membrane by 8-MOP is via the reaction with membrane lipids and proteins [295]. From these results, it could be concluded that the effect on the cell membrane by coumarins could have an important role in their bioactivity. 

Coumarin reduced labeled glucose incorporation and carbohydrate and protein content of the cytoplasm of Pythium, but enzymes related to the metabolism of cell wall polysaccharides were not affected [296]. It has been reported that moulds are more sensitive to coumarin when they are cultured on the simple synthetic nutrient medium than on the yeast water [140]. This suggests that coumarin blocks the synthesis of an unknown metabolite of ndamental importance. Coumarin was found to affect the level of a variety of free amino acids present in a cell. In addition, some nucleic acid precursors partially reverse the coumarin-induced inhibition of maize mesocotyle [131]. The stimulation of germination and growth caused by coumarin in low concentrations may be assumed as a supercompensation mechanism. 

Rl. Radio, Z., Reiner, E., and Taylor, P., Role of the peripheral anionic site on acetylcholinesterase Inhibition by substrates and coumarin derivatives. Mol. Pharmacol. 39, 98-104 (1991). 

In vitro studies on the effect of Echinacea purpurea on GYP enzymes have given mixed results. Results from one study on the effects of a preparation of the aerial parts of Echinacea purpurea on CYP3A4 differed according to the model substrate used one substrate (7-benzyloxy-4-trifluoromethyl-coumarin) indicated induction, while the other (resorufin benzyl ether) indicated inhibition (Yale and Gulrich 2005). Another study showed significant inhibition by a "commercial grade extract" (no other description provided) of Echinacea angustifolia root (Budzinski et al. 2000). 

Hopp, H.E., Romero, P.A. Pont-Lezica, R. (1978) On the Inhibition of Cellulose Biosynthesis by Coumarin , FEBS Letters, 86, 259-62... 

TABLE IV. % INHIBITION OF GROWTH OF BLACK SHANK FUNGUS BY COUMARINS... 

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