芒果苷代谢产物的合成及黄嘌呤氧化酶抑制活性研究

Synthesis and Xanthine Oxidase Inhibition Activity of Mangiferin Metabolites

以2,4,5-三甲氧基苯甲酸和2,5-二甲氧基苯甲酸为原料合成芒果苷的两个主要代谢产物1,3,6,7-四羟基氧杂蒽酮（2）和1,3,7-三羟基氧杂蒽酮（3），同时获得四个合成中间体（4～7），利用^1H NMR和^13C NMR鉴定结构。活性研究表明代谢产物2能浓度依赖性地抑制黄嘌呤氧化酶活性，其IC50为10.89 μM；代谢产物3及中间体5、7也有抑制作用，但弱于2，而中间体4、6和芒果苷则没有明显的抑制作用；灌胃给予小鼠等分子剂量的芒果苷及2后，均明显降低氧嗪酸钾诱导的高尿酸血症小鼠的血尿酸水平，两者效价相似，提示芒果苷的降尿酸作用与其代谢产物抑制黄嘌呤氧化酶活性的作用有关。

Mangiferin,a natural glucosyl xanthone,has been reported to possess a potential hypouricemic effect.However,the pharmacokinetic studies in rats showed that its oral bioavailability was only 1.2%,suggesting that mangiferin metabolites might exert the action.To screen the active constituent of mangiferin for hypouricemic action,two metabolites （2,3） and four precursors （4,5,6,7） were synthesized using 2,4,5-trimethoxybenzoic acid and 2,5-dimethoxybenzoic acid as starting material.Their structures were characterized by ^1H NMR and ^13C NMR.Of the tested compounds,compound 2 （1,3,6,7-tetrahydroxyxanthone） exhibited a significant inhibitory activity on xanthine oxidase with an IC50 value of 10.89 μM.Compound 3 （1,3,7-trihydroxyxanthone）,the precursors 5 and 7 also inhibited the enzymatic activities at a concentration of 87.3 μM,with the inhibitory rates of 45.8%,52.1% and 32.1%,respectively.However,the inhibition effects of other precursors and mangiferin was not observed. In vivo,intragastric administration of mangiferin （1） and compound 2 significantly reduced the serum urate levels in hyperuricemic mice induced by potassium oxonate,compared with the untreated hyperuricemic mice （P〈0.05）.The hypouricemic action of compound 2 was similar in potency to mangiferin （1） at a same molar dose.These findings suggested that the hypouricemic effect of mangiferin was related to its metabolites,at least partly resulting from compound 2,via inhibiting xanthine oxidase activity.