Structure-activity relationship of coumarins in xanthine oxidase inhibition.
Esculetin(4), umbelliferone(7-hydroxycoumarin)(3) and 7-hydroxy-4-methyl coumarin(8) are strong xanthine oxidase inhibitors (IC50 = 20.91, 43.65 and 96.70 microM respectively). Based on this observation, the structure of 7-hydroxy coumarin(3) plays a very important role in xanthine oxidase (XO) inhibition. The 6-hydroxy group present in the molecule of 7-hydroxy coumarin, e.g. esculetin(4) enhanced the activity, whereas substitution by the 6-methoxy group, e.g. scopoletin (5), reduced the inhibitory effect. Furthermore, 6-glycoside group present in the molecule of 7-hydroxy coumarin, e.g. esculin (6,7-dihydroxy coumarin 6-glucoside)(12) strongly decreased the inhibitory effect as well as scoparone(6), the fully methylated derivative of esculetin (4). In contrast to 7-hydroxy coumarin(3), however, 4-hydroxy coumarin(13) showed only a weak effect on XO inhibition. 4-Substituent present in the molecule of 7-hydroxycoumarin also reduced the activity but the degree of reduction depended on the substituents: 7-hydroxy-4-methylcoumarin (8) < 7-hydroxycoumarin-4-acetic acid (7) < 7-hydroxy-4-trifluoromethylcoumarin (9). Their percent inhibition at 100 microM was 62.47, 38.46 and 26.84% respectively. 8-substituent present in the molecule of 7-hydroxy coumarin (3), such as 7,8-dihydroxy-6-methoxycoumarin(10) and fraxin(7-hydroxy-6-methoxycoumarin 8-glucoside)(11) reduced the activity as compared with scopoletin (5). Their percent inhibition at 100 microM was 18.4 and 6.9% respectively, which indicated that the more bulky the 8-substituted in the structure, the weaker the inhibitory activity on XO. 3,4,8-Trimethyl-7-hydroxycoumarin(14) which substitution by the methyl at 3,4 & 8 in the structure of 7-hydroxycoumarin(3) also reduced the activity as compared with 7-hydroxycoumarin(3). It seems that the double bond in the structure of coumarin(1) played an important role in the activity as compared with coumarin(dihydrocoumarin)(2). The apparent inhibition constants(Ki) of esculetin(4), umbelliferone (3) and 7-hydroxy-4-methylcoumarin(8) were 2.056, 21.683 and 4.86 microM respectively and induced competitive, uncompetitive and a mixed type of inhibition of the enzyme with respect to the substrate xanthine.
Chang
W S
WS
School of Pharmacy, College of Medicine, National Taiwan University, Taipei, R.O.C.
Chiang
H C
HC
D003374:Coumarins / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
D003374:Coumarins; D014969:Xanthine Oxidase