Discovery of novel curcumin derivatives targeting xanthine oxidase and urate transporter 1 as anti-hyperuricemic agents.
A series of curcumin derivatives as potent dual inhibitors of xanthine oxidase (XOD) and urate transporter 1 (URAT1) was discovered as anti-hyperuricemic agents. These compounds proved efficient effects on anti-hyperuricemic activity and uricosuric activity in vivo. More importantly, some of them exhibited proved efficient effects on inhibiting XOD activity and suppressing uptake of uric acid via URAT1 in vitro. Especially, the treatment of 4d was demonstrated to improve uric acid over-production and under-excretion in oxonate-induced hyperuricemic mice through regulating XOD activity and URAT1 expression. Docking study was performed to elucidate the potent XOD inhibition of 4d. Compound 4d may serve as a tool compound for further design of anti-hyperuricemic drugs targeting both XOD and URAT1.
Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, PR China.
Gui-Zhen
GZ
Ao
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
Meng-Ze
MZ
Zhou
Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, PR China.
Yu-Yao
YY
Li
Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, PR China.
Si-Ning
SN
Li
Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, PR China.
Hua-Nian
HN
Wang
Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, PR China.
Qian-Wen
QW
Wan
Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, PR China. Electronic address: huanqiuli@suda.edu.cn.
Huan-Qiu
HQ
Li
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: huqh@cpu.edu.cn.
Qing-Hua
QH
Hu
D000818:Animals; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D057809:HEK293 Cells; D006801:Humans; D033461:Hyperuricemia / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008958:Models, Molecular; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014527:Uric Acid / Q000378:metabolism; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C491241:SLC22A12 protein, human; C109687:Slc22a12 protein, mouse; D014527:Uric Acid; D014969:Xanthine Oxidase; D003474:Curcumin
Anti-hyperuricemic; Curcumin derivatives; Urate transporter 1; Uricosuric; Xanthine oxidase