Compounds containing trace element copper or zinc exhibit as potent hyperuricemia inhibitors via xanthine oxidase inactivation

高尿酸血症 化学 黄嘌呤氧化酶 尿酸 痛风 黄嘌呤 次黄嘌呤 黄嘌呤脱氢酶 药理学 生物化学 有机化学 医学
作者
Lan‐Zhu Li,Guo-Xiu Zhou,Jia Li,Wei Jiang,Baolin Liu,Wen Zhou
出处
期刊:Journal of Trace Elements in Medicine and Biology [Elsevier]
卷期号:49: 72-78 被引量:21
标识
DOI:10.1016/j.jtemb.2018.04.019
摘要

Compounds containing trace elements copper or zinc are potential gout and hyperuricemia suppressant by virtue of their inhibiting effect on xanthine oxidase/xanthine dehydrogenase (XOD/XDH) and anti-inflammatory and anti-oxidative function. In this study, compounds Cu(hmy-paa)·SO4·H2O (simplified as CuHP) and Zn(hmy-paa)·SO4·H2O (simplified as ZnHP) are synthesized, where hmy-paa stands for 3-(4-hydroxy-3-methoxyphenyl)-N-(1H-pyrazol-3-yl)acrylamide). The ligand hmy-paa is composed of functional ferulic acid and 3-aminopyrazole. The XOD and XDH activity of the mouse liver homogenate could efficiently be inhibited by CuHP and ZnHP. XOD has been recognized as one of the promising targets for the treatment of hyperuricemia. Fluorescence spectrometry study indicates that the interaction between the compound and XOD could be strengthened by the introduction of metals. In vitro drug efficacy study illustrates that metals copper and zinc distinctly improves the uric acid reducing efficacy by suppressing XOD activation. Hyperuricemia mouse model is induced by co-treatment of hypoxanthine and oteracil potassium. Intraperitoneal injection of CuHP and ZnHP to hyperuricemia mice exhibits a significant effect on reducing serum uric acid. The serum creatinine value detection indicates that the side effect of CuHP and ZnHP on renal function is weak. The computational docking simulation exhibits the tightly binding mode between the compound and XOD. Consequently, compounds CuHP and ZnHP are new type candidates for the treatment of gout and hyperuricemia.
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