title: (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.
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 IC50value 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.affiliation: 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.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Hu
authors.affiliation: School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China; School of Basic Medical Sciences, Nanjing Medical University, Nanjing 210009, PR China.
authors.forename: Mengze
authors.initials: M
authors.lastname: Zhou
authors.affiliation: School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Haoran
authors.initials: H
authors.lastname: Zhu
authors.affiliation: School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Guo
authors.initials: G
authors.lastname: Lu
authors.affiliation: School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Dongsen
authors.initials: D
authors.lastname: Zheng
authors.affiliation: College of Pharmaceutical Science, Soochow University, Suzhou 215123, PR China. Electronic address: huanqiuli@suda.edu.cn.
authors.forename: Huanqiu
authors.initials: H
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Kun
authors.initials: K
authors.lastname: Hao
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D033461:Hyperuricemia / Q000097:blood* / Q000188:drug therapy*; D008297:Male; D051379:Mice; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010091:Oximes / Q000737:chemistry* / Q000627:therapeutic use*; D016896:Treatment Outcome; D014527:Uric Acid / Q000097:blood; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D027361:Organic Anion Transporters; D010091:Oximes; C109687:Slc22a12 protein, mouse; D014527:Uric Acid; D014969:Xanthine Oxidase
keywords: (E)-2-(4-bromophenyl)-1-(2, 4-dihydroxyphenyl)ethanone oxime; Dual inhibitor; Hyperuricemia; Urate transporter 1; Xanthine oxidase