PHARMACOLOGICAL AND BIOCHEMICAL ACTIONS OF SIMPLE COUMARINS - NATURAL-PRODUCTS WITH THERAPEUTIC POTENTIAL

1. More than 1300 coumarins have been identified from natural sources, especially green plants. The pharmacological and biochemical properti es and therapeutic applications of simple coumarins depend upon the pa ttern of substitution. More complex related compounds based on the cou marin nucleus include the dicoumarol/warfarin anticoagulants, aflatoxi ns and the psoralens (photosensitizing agents). 2. Coumarin itself (1, 2-benzopyrone) has long established efficacy in slow onset long-term r eduction of lymphoedema in man, as confirmed in recent double-blind tr ials against elephantiasis and postmastectomy swelling of the arm. The mechanism of action is uncertain, but may involve macrophage induced proteolysis of oedema protein. However, coumarin has low absolute bioa vailability in man (<5%), due to extensive first-pass hepatic conversi on to 7-hydroxycournarin followed by glucuronidation. It may, therefor e, be a prodrug. 3. Scoparone (6,7-dimethoxycoumarin) has been purifie d from the hypolipidaemic Chinese herb Artemisia scoparia and shown to reduce the proliferative responses of human peripheral mononuclear ce lls, to relax smooth muscle, to reduce total cholesterol and triglycer ides and to retard the characteristic pathomorphological changes in hy percholesterolaemic diabetic rabbits. Various properties of scoparone were suggested to account for these findings, including ability to sca venge reactive oxygen species, inhibition of tyrosine kinases and pote ntiation of prostaglandin generation. 4. Osthole (7-methoxy-8-[3-methy lpent-2-enyl]coumarin) from Angelica pubescens, used also in Chinese m edicine, causes hypotension in vivo, and inhibits platelet aggregation and smooth muscle contraction in vitro. It may interfere with calcium influx and with cyclic nucleotide phosphodiesterases. 5. Cloricromene , a synthetic coumarin derivative, also possesses antithrombotic antip latelet actions, inhibits PMN neutrophil function and causes vasodilat ation, Some of these properties of cloricromene have been ascribed to inhibition of arachidonate release from membrane phospholipids. 6. Sim ple coumarins possessing ortho dihydroxy functions, such as fraxetin a nd 4-methyldaphnetin, are potent inhibitors (low micromolar) of lipid peroxidation and scavengers of superoxide anion radicals and of aqueou s alkylperoxyl radicals, but may be pro-oxidant (enhancing generation of hydroxyl radicals ) in the presence of free iron ions. These coumar ins also inhibit the proinflammatory 5-lipoxygenase enzyme at micromol ar concentrations. Another related coumarin, 5, 7-dihydroxy-4-methylco umarin, is of special interest as it inhibits lipid peroxidation, and scavenges alkylperoxyl and superoxide radicals. Unlike most other simp le coumarins studied, 5,7-dihydroxy-4-methylcoumarin also scavenges hy pochlorous chlorous acid, and is a potent inhibitor of cyclo-oxygenase , but is not pro-oxidant. 7. 5,7- and 6,7-dihydroxy-4-methylcoumarin b oth reduced the duration of ventricular fibrillation in postischaemic reperfused isolated perfused rat hearts (in which oxygen derived free radicals are implicated , showing that these antioxidant coumarins pos sess beneficial properties in this pathophysiological model. 8. In vie w of the established low toxicity, relative cheapness, presence in the diet and occurrence in various herbal remedies of coumarins, it appea rs prudent to evaluate their properties and applications further.