Dicoumarol and Warfarin

The cause of fatal haemorrhages in animals fed spoiled sweet clover (Melilotus officinalis; Leguminosae/Fabaceae) was traced to dicoumarol (bishydroxycoumarin) (Figure 4.31). This agent interferes with the effects of vitamin K in blood coagulation (see page 163), the blood loses its ability to clot, and thus minor injuries can lead to severe internal bleeding. Synthetic dicoumarol has been used as an oral blood anticoagulant in the treatment of thrombosis, where the risk of blood clots becomes life threatening. It has been superseded by salts of warfarin and acenocoumarol (nicoumalone) (Figure 4.32), which are synthetic developments from the natural product. An overdose of warfarin may be countered by injection of vitamin K1.

Warfarin was initially developed as a rodenticide, and has been widely employed for many years as the first choice agent, particularly for destruction of rats. After

O "O acenocoumarol (nicoumalone)

O O coumachlor

O "O acenocoumarol (nicoumalone)

O O coumachlor

consumption of warfarin-treated bait, rats die from internal haemorrhage. Other coumarin derivatives employed as rodenticides include coumachlor and coumatetralyl (Figure 4.32). In an increasing number of cases, rodents are becoming resistant to warfarin, an ability which has been traced to elevated production of vitamin K by their intestinal microflora. Modified structures defenacoum and brodifenacoum have been found to be more potent than warfarin, and are also effective against rodents that have become resistant to warfarin.

group in demethylsuberosin is then able to cyclize with the phenol group giving marmesin. This transformation is catalysed by a cytochrome P-450-dependent mono-oxygenase, and requires cofactors NADPH and molecular oxygen. For many years, the cyclization had been postulated to involve an intermediate epoxide, so that nucleophilic attack of the phenol on to the epoxide group might lead to formation of either five-membered furan or six-membered pyran heterocycles as commonly encountered in natural products (Figure 4.34). Although the reactions of Figure 4.34 offer a convenient rationalization for cyclization, epoxide intermediates have not been demonstrated in any of the enzymic systems so far investigated, and therefore some direct oxidative cyclization mechanism must operate. A second cytochrome P-450-dependent mono-oxygenase enzyme then cleaves off the hydroxyisopropyl fragment (as acetone) from marmesin giving the furocoumarin psoralen (Figure 4.35). This does not involve any hydroxylated intermediate, and cleavage is believed to be initiated by a radical abstraction process. Psoralen can act as a precursor for the further substituted furocoumarins bergapten, xanthotoxin, and isopimpinellin (Figure 4.33), such modifications occurring late in the biosynthetic sequence rather than at the cinnamic acid stage. Psoralen, bergapten, etc are termed 'linear' furocoumarins. 'Angular' furocoumarins, e.g. angelicin (Figure 4.33), can arise by a similar sequence of reactions, but these involve dimethylallylation at the alternative position ortho to the phenol. An isoprene-derived furan ring system has already been noted in the formation of khellin (see page 74), though the

DMAPP

DMAPP

umbelliferone

C-alkylation at activated position ortho to phenol

umbelliferone

bergapten

O2 NADPH

demethylsuberosin

O2 NADPH

demethylsuberosin

bergapten

OMe hydroxylation

OMe isopimpinellin

OMe xanthotoxin

xanthotoxol

NADPH

NADPH

O ^O marmesin

I O2 I NADPH

psoralen (linear furocoumarin)

bergaptol

psoralen (linear furocoumarin)

angelicin (angular furocoumarin)

angelicin (angular furocoumarin)

H ® on to epoxide nucleophilic attack

O O marmesin

O2 NADPH

O O marmesin

5-membered furan ring

5-membered furan ring

6-membered pyran ring

Figure 4.34

6-membered pyran ring

Figure 4.34

oxidation leading to radical cleavage of side-chain carbons

side-chain carbons released as acetone

side-chain carbons released as acetone

Figure 4.35

psoralen

psoralen aromatic ring to which it was fused was in that case a product of the acetate pathway. Linear furocoumarins (psoralens)* can be troublesome to humans since they can cause photosensitization towards UV light, resulting in sunburn or serious blistering. Used medicinally, this effect may be valuable in promoting skin pigmentation and treating psoriasis.

Was this article helpful?

0 0
Reducing Blood Pressure Naturally

Reducing Blood Pressure Naturally

Do You Suffer From High Blood Pressure? Do You Feel Like This Silent Killer Might Be Stalking You? Have you been diagnosed or pre-hypertension and hypertension? Then JOIN THE CROWD Nearly 1 in 3 adults in the United States suffer from High Blood Pressure and only 1 in 3 adults are actually aware that they have it.

Get My Free Ebook


Post a comment