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(E)-2-(4-bromophenyl)-1-(2, 4-dihydroxyphenyl)ethanone oxime is a potential therapeutic agent for treatment of hyperuricemia through its dual inhibitory effects on XOD and URAT1.
Biomed Pharmacother. 2017 Feb; 86:88-94.BP

Abstract

Hyperuricemia is a kind of metabolic disease resulted from imbalance between urate production and excretion. Xanthine oxidase (XOD) or renal urate transporter 1 (URAT1) inhibitors have been applied for hyperuricemia treatment in clinic, but available drugs could not simultaneously target XOD and URAT1 and had various adverse effects. (E)-2-(4-bromophenyl)-1-(2, 4-dihydroxyphenyl)ethanone oxime (BDEO), as a deoxybenzoins oxime analog, was obtained from a cluster of deoxybenzoins derivatives synthesized by our research group with potent anti-hyperuricemic activity, which was expected to be dual inhibitor of XOD and URAT1. This study aimed to investigate effects of BDEO on XOD and URAT1 in vitro, as well as the possible mechanism by which BDEO attenuated hyperuricemia in vivo. In vitro, BDEO obviously inhibited XOD activity with an IC50 value of 3.33μM, moreover, in Human embryonic kidney (HEK)293 cells expressing URAT1, BDEO and benzbromarone blocked uptake of uric acid with a Ki value of 0.145μM. On the other hand, mice were orally administrated by oxonate for seven consecutive days to induce hyperuricemia, BDEO at various doses were administered intragastrically to hyperuricemic and normal mice daily. BDEO dose-dependently decreased serum urate level and uric acid excretion in 24h in hyperuricemic mice. More importantly, BDEO significantly suppressed hepatic XOD activity and down-regulated renal URAT1 protein level in hyperuricemic mice. Notably, BDEO exhibited no effects on all these detected biochemical indicators in normal mice, predicting its safety. Taken together, the data suggested that BDEO may serve as a dual XOD and URAT1 inhibitor for treatment of hyperuricemia.

Authors+Show Affiliations

State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, PR China; School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China; School of Basic Medical Sciences, Nanjing Medical University, Nanjing 210009, PR China.School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.College of Pharmaceutical Science, Soochow University, Suzhou 215123, PR China. Electronic address: huanqiuli@suda.edu.cn.State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: chinacpu1001@163.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27951420

Citation

Hu, Qinghua, et al. "(E)-2-(4-bromophenyl)-1-(2, 4-dihydroxyphenyl)ethanone Oxime Is a Potential Therapeutic Agent for Treatment of Hyperuricemia Through Its Dual Inhibitory Effects On XOD and URAT1." Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, vol. 86, 2017, pp. 88-94.
Hu Q, Zhou M, Zhu H, et al. (E)-2-(4-bromophenyl)-1-(2, 4-dihydroxyphenyl)ethanone oxime is a potential therapeutic agent for treatment of hyperuricemia through its dual inhibitory effects on XOD and URAT1. Biomed Pharmacother. 2017;86:88-94.
Hu, Q., Zhou, M., Zhu, H., Lu, G., Zheng, D., Li, H., & Hao, K. (2017). (E)-2-(4-bromophenyl)-1-(2, 4-dihydroxyphenyl)ethanone oxime is a potential therapeutic agent for treatment of hyperuricemia through its dual inhibitory effects on XOD and URAT1. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, 86, 88-94. https://doi.org/10.1016/j.biopha.2016.12.002
Hu Q, et al. (E)-2-(4-bromophenyl)-1-(2, 4-dihydroxyphenyl)ethanone Oxime Is a Potential Therapeutic Agent for Treatment of Hyperuricemia Through Its Dual Inhibitory Effects On XOD and URAT1. Biomed Pharmacother. 2017;86:88-94. PubMed PMID: 27951420.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - (E)-2-(4-bromophenyl)-1-(2, 4-dihydroxyphenyl)ethanone oxime is a potential therapeutic agent for treatment of hyperuricemia through its dual inhibitory effects on XOD and URAT1. AU - Hu,Qinghua, AU - Zhou,Mengze, AU - Zhu,Haoran, AU - Lu,Guo, AU - Zheng,Dongsen, AU - Li,Huanqiu, AU - Hao,Kun, Y1 - 2016/12/09/ PY - 2016/10/25/received PY - 2016/11/29/revised PY - 2016/12/01/accepted PY - 2016/12/13/pubmed PY - 2017/2/10/medline PY - 2016/12/13/entrez KW - (E)-2-(4-bromophenyl)-1-(2, 4-dihydroxyphenyl)ethanone oxime KW - Dual inhibitor KW - Hyperuricemia KW - Urate transporter 1 KW - Xanthine oxidase SP - 88 EP - 94 JF - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JO - Biomed. Pharmacother. VL - 86 N2 - Hyperuricemia is a kind of metabolic disease resulted from imbalance between urate production and excretion. Xanthine oxidase (XOD) or renal urate transporter 1 (URAT1) inhibitors have been applied for hyperuricemia treatment in clinic, but available drugs could not simultaneously target XOD and URAT1 and had various adverse effects. (E)-2-(4-bromophenyl)-1-(2, 4-dihydroxyphenyl)ethanone oxime (BDEO), as a deoxybenzoins oxime analog, was obtained from a cluster of deoxybenzoins derivatives synthesized by our research group with potent anti-hyperuricemic activity, which was expected to be dual inhibitor of XOD and URAT1. This study aimed to investigate effects of BDEO on XOD and URAT1 in vitro, as well as the possible mechanism by which BDEO attenuated hyperuricemia in vivo. In vitro, BDEO obviously inhibited XOD activity with an IC50 value of 3.33μM, moreover, in Human embryonic kidney (HEK)293 cells expressing URAT1, BDEO and benzbromarone blocked uptake of uric acid with a Ki value of 0.145μM. On the other hand, mice were orally administrated by oxonate for seven consecutive days to induce hyperuricemia, BDEO at various doses were administered intragastrically to hyperuricemic and normal mice daily. BDEO dose-dependently decreased serum urate level and uric acid excretion in 24h in hyperuricemic mice. More importantly, BDEO significantly suppressed hepatic XOD activity and down-regulated renal URAT1 protein level in hyperuricemic mice. Notably, BDEO exhibited no effects on all these detected biochemical indicators in normal mice, predicting its safety. Taken together, the data suggested that BDEO may serve as a dual XOD and URAT1 inhibitor for treatment of hyperuricemia. SN - 1950-6007 UR - https://www.unboundmedicine.com/medline/citation/27951420/_E__2__4_bromophenyl__1__2_4_dihydroxyphenyl_ethanone_oxime_is_a_potential_therapeutic_agent_for_treatment_of_hyperuricemia_through_its_dual_inhibitory_effects_on_XOD_and_URAT1_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0753-3322(16)32045-5 DB - PRIME DP - Unbound Medicine ER -