Abstract
Dryopteris crassirhizoma rhizomes are used as a traditional medicine in Asia. The EtOAc extract of these roots has shown potent xanthine oxidase (XO) inhibitory activity. However, the main phloroglucinols in D. crassirhizoma rhizomes have not been analyzed. Thus, we investigated the major constituents responsible for this effect. Bioassay-guided purification isolated four compounds: flavaspidic acid AP (1), flavaspidic acid AB (2), flavaspidic acid PB (3), and flavaspidic acid BB (4). Among these, 1 showed the most potent inhibitory activity with a half-maximal inhibitory concentration (IC50) value of 6.3 µM, similar to that of allopurinol (IC50 = 5.7 µM) and better than that of oxypurinol (IC50 = 43.1 µM), which are XO inhibitors. A comparative activity screen indicated that the acetyl group at C3 and C3′ is crucial for XO inhibition. For example, 1 showed nearly 4-fold higher efficacy than 4 (IC50 = 20.9 µM). Representative inhibitors (1–4) in the rhizomes of D. crassirhizoma showed reversible and noncompetitive inhibition toward XO. Furthermore, the potent inhibitors were shown to be present in high quantities in the rhizomes by a UPLC-QTOF-MS analysis. Therefore, the rhizomes of D. crassirhizoma could be used to develop nutraceuticals and medicines for the treatment of gout.
Highlights
Hyperuricemia is caused by the overproduction and/or underexcretion of uric acid [1,2]
Isolated compounds were identified as flavaspidic acid AP (1), flavaspidic acid AB (2), flavaspidic acid PB (3), and flavaspidic acid BB (4)
For the first time, the potent inhibitors were identified as flavaspidic acid AP (1) and its derivatives (2−4), with inhibitory activity against Xanthine oxidase (XO) at low micromolar concentrations (IC50 = 6.3−20.9 μM)
Summary
Hyperuricemia is caused by the overproduction and/or underexcretion of uric acid [1,2]. The increased uric acid levels cause the precipitation of urate crystals in the joints and kidneys, causing gout and gouty arthritis [5]. The use of allopurinol, a representative XO inhibitor that blocks uric acid synthesis in the body, is one of the therapeutic approaches for the clinical treatment of hyperuricemia and chronic gout [6]. It can cause a number of adverse side effects, such as allergic and hypersensitivity reactions, skin rash, gastrointestinal distress, renal failure, and renal toxicity [7]. The development of potential XO-inhibitory agents from natural sources with greater efficacy, fewer side effects, and a better safety profile is highly desirable
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