3,5,2′,4′-Tetrahydroxychalcone, a new non-purine xanthine oxidase inhibitor

Niu, Yanfen; Zhu, Hua‐Jie; Liu, Jia; Fan, Huafang; Sun, Ling; Lu, Wei; Liu, Xu; Li, Ling

doi:10.1016/j.cbi.2010.12.004

Cited by 46 publications

(33 citation statements)

References 25 publications

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“…The enzymatic activity was measured spectrophotometrically by continuously measuring uric acid formation at 295 nm with xanthine as a substrate (Kong et al 2000;Niu et al 2011). The reaction mixture contained 0.3% sodium pyrophosphate buffer (pH 8.3) and 8.35 U/L xanthine oxidase with or without the test compounds.…”

Section: Xanthine Oxidase Activity Assaymentioning

confidence: 99%

Hypouricaemic action of mangiferin results from metabolite norathyriol via inhibiting xanthine oxidase activity

Niu

Liu

et al. 2016

Pharmaceutical Biology

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Context Mangiferin has been reported to possess a potential hypouricaemic effect. However, the pharmacokinetic studies in rats showed that its oral bioavailability was only 1.2%, suggesting that mangiferin metabolites might exert the action. Objective The hypouricaemic effect and the xanthine oxidase inhibition of mangiferin and norathyriol, a mangiferin metabolite, were investigated. Inhibition of norathyriol analogues (compounds 3-9) toward xanthine oxidase was also evaluated. Materials and methods For a dose-dependent study, mangiferin (1.5-6.0 mg/kg) and norathyriol (0.92-3.7 mg/kg) were administered intragastrically to mice twice daily for five times. For a timecourse study, mice received mangiferin and norathyriol both at a single dose of 7.1 mmol/kg. In vitro, inhibition of test compounds (2.4-2.4 mM) against xanthine oxidase activity was evaluated by the spectrophotometrical method. The inhibition type was identified from Lineweaver-Burk plots. Results Norathyriol (0.92, 1.85 and 3.7 mg/kg) dose dependently decreased the serum urate levels by 27.0, 33.6 and 37.4%, respectively. The action was more potent than that of mangiferin at the low dose, but was equivalent at the higher doses. Additionally, the hypouricaemic action of them exhibited a time dependence. In vitro, norathyriol markedly inhibited the xanthine oxidase activities, with the IC 50 value of 44.6 mM, but mangiferin did not. The kinetic studies showed that norathyriol was an uncompetitive inhibitor by Lineweaver-Burk plots. The structure-activity relationships exhibited that three hydroxyl groups in norathyriol at the C-1, C-3 and C-6 positions were essential for maintaining xanthine oxidase inhibition. Discussion and conclusion Norathyriol was responsible for the hypouricaemic effect of mangiferin via inhibiting xanthine oxidase activity. ARTICLE HISTORY

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Section: Xanthine Oxidase Activity Assaymentioning

confidence: 99%

Hypouricaemic action of mangiferin results from metabolite norathyriol via inhibiting xanthine oxidase activity

Niu

Liu

et al. 2016

Pharmaceutical Biology

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“…In a previous study, we found that 3,5,2′,4′-tetrahydroxychalcone could reduce the uric acid levels in hyperuricemic mice induced by potassium oxonate, implicating that the hypouricemic mechanism is probably related to the inhibition of XOD activity. 13) In the dose-effect study, oral administration of 3,5,2′,4′-tetrahydroxychalcone (1.0, 2.0, 4.0 mg/kg) also significantly inhibited the activity of XOD and XDH in serum or liver of hypoxanthine-induced hyperuricemic mice in a dose-dependent manner. In the time-effect study, after a single 2.0 mg/kg dose of the compound (1, 2, 4, 6 h), the activities of XOD and XDH attenuated in serum, which sustained over 4 h for XOD and 6 h for XDH.…”

Section: Discussionmentioning

confidence: 94%

“…Moreover, intragastric administration of 3,5,2′,4′-tetrahydroxychalcone (2.0 mg/kg) was able to significantly reduce serum uric acid levels and inhibit hepatic XOD activities in potassium oxonate-induced hyperuricemic mice. 13) The results indicate that 3,5,2′,4′-tetrahydroxychalcone reduces the uric acid production by inhibiting the activity of XOD. However, effects of 3,5,2′,4′-tetrahydroxychalcone on other key enzymes involved in the generation of uric acid, such as HGPRT, PRPS and PRPPAT, have not been completely clarified.…”

mentioning

confidence: 97%

Inhibition of 3,5,2′,4′-Tetrahydroxychalcone on Production of Uric Acid in Hypoxanthine-Induced Hyperuricemic Mice

Niu

Zhou

Lin

et al. 2018

Biological & Pharmaceutical Bulletin

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The mechanism of 3,5,2′,4′-tetrahydroxychalcone on lowing urate level is still unknown. Here we investigated the effects of 3,5,2′,4′-tetrahydroxychalcone on urate levels, xanthine oxidase/xanthine dehydrogenase (XOD/XDH) activities in hypoxanthine-induced hyperuricemic mice, as well as the effects of 3,5,2′,4′-tetrahydroxychalcone on the mRNA expression levels and content of phosphoribosyl pyrophosphate synthetase (PRPS), phosphoribosyl pyrophosphate amidotransferase (PRPPAT) and hypoxanthine-guanine phosphoribosyl transferase (HGPRT). Our results demonstrated that 3,5,2′,4′-tetrahydroxychalcone (1.0, 2.0, and 4.0 mg/kg) reduced the uric acid levels in serum of the hyperuricemic mice in dose-and time-dependent manners. The activities of XOD/XDH in serum and liver were also significantly inhibited by 3,5,2′,4′-tetrahydroxychalcone; In addition, 3,5,2′,4′-tetrahydroxychalcone decreased the mRNA expression of HGPRT in brain and content of PRPS and PRPPAT in liver. These findings demonstrated that 3,5,2′,4′-tetrahydroxychalcone suppresses uric acid production by affecting the critical enzymes, XOD/XDH, PRPS, PRPPAT and HGPRT in purine nucleotide metabolism.Key words 3,5,2′,4′-tetrahydroxychalcone; purine metabolism enzyme; hyperuricemia Gout and hyperuricemia are metabolic disorders associated with abnormal amounts of uric acid in the body. The overproduction of uric acid is one of the major factors in most patients with gout. Maintaining uric acid level <6 mg/dL is important for prevention of gout. Many enzymes participated in purine metabolic pathway, such as xanthine oxidase/xanthine dehydrogenase (XOD/XDH), hypoxanthine-guanine phosphoribosyl transferase (HGPRT), phosphoribosyl pyrophosphate synthetase (PRPS), and phosphoribosyl pyrophosphate aminotransferase (PRPPAT).1) The dysfunction of these enzymes increases the production of uric acid, resulting in hyperuricemia.2) Particularly, the XOD has been recognized as one of the promising targets for the treatment of hyperuricemia. Allopurinol, a potent XOD inhibitor with a purine backbone, has been used clinically for more than 50 years.3,4) However, allopurinol induces serious side effects such as renal failure, impaired hepatic function and allergic reactions, 5) limiting its clinical application. Recently, a new non-purine XOD inhibitor, Febuxostat, has been approved for management of gout in the European Union and USA. 6) But a few side effects of febuxostat have been reported, 7) such as liver function abnormalities, nausea, arthralgias, and rash. Therefore, novel alternatives to allopurinol with potent XOD inhibitory activity and less side effects are in great demand.3,5,2′,4′-Tetrahydroxychalcone is one of chalcones (Fig. 1). It has been reported to possess various pharmacological activities, such as antitumor, 8) free radical scavenging, 9) antibiosis, 10) antiulcer 11) and spasmolysis. 12) Currently, there are few reports about their inhibitory effects against the XOD activity. In a previous study, we reported that 3,5,2′,4′-tetrahydroxychalcone had an i...

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“…Recently 3,5,2 0 ,4 0 -tetrahydroxychalcone was found to be potent competitive inhibitor of the enzyme as indicated by the kinetic study. In vivo, intragastric administration of the chalcone was able to significantly reduce serum uric acid levels and inhibited hepatic xanthine oxidase activities of hyperuricemic mice in a dose-dependent manner 32 . Thus, the proved potential of coumarin and chalcones as xanthine oxidase inhibitors and recent success of molecular hybridization technique in drug design 33 tempted us to design such conjugates.…”

Section: Introductionmentioning

confidence: 93%

Design, synthesis and evaluation of 2,4-diarylpyrano[3,2-c]chromen-5(4H)-one as a new class of non-purine xanthine oxidase inhibitors

Virdi

Sharma

Mehndiratta

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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3,5,2′,4′-Tetrahydroxychalcone, a new non-purine xanthine oxidase inhibitor

Cited by 46 publications

References 25 publications

Hypouricaemic action of mangiferin results from metabolite norathyriol via inhibiting xanthine oxidase activity

Hypouricaemic action of mangiferin results from metabolite norathyriol via inhibiting xanthine oxidase activity

Inhibition of 3,5,2′,4′-Tetrahydroxychalcone on Production of Uric Acid in Hypoxanthine-Induced Hyperuricemic Mice

Design, synthesis and evaluation of 2,4-diarylpyrano[3,2-c]chromen-5(4H)-one as a new class of non-purine xanthine oxidase inhibitors

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