title: Design and synthesis of novel hydroxypyridinone derivatives as potential tyrosinase inhibitors.
abstract: Two groups of novel hydroxypyridinone derivatives 6(a-e) and 12(a-c), were designed as potential tyrosinase inhibitors, and synthesized using kojic acid as a starting material. The tyrosinase inhibitory activity of these two groups was demonstrated to be potent, especially compounds 6e and 12a, whose IC50 values for monophenolase activity were 1.95μM and 2.79μM, respectively. Both of these values are lower than that of kojic acid (IC50=12.50μM). Compounds 6e and 12a were investigated for the inhibitory effect on diphenolase activity. The results showed that the inhibitory mechanism of these two compounds was reversible and that the inhibitory type was a competitive-uncompetitive mixed-type. The values of IC50 of 6e and 12a on the diphenolase activity of tyrosinase were determined to be 8.97μM and 26.20μM, respectively. The inhibitory constants (KI and KIS) of 6e were determined as 17.17μM and 22.09μM, respectively; and the KI and KIS values of 12a were 34.41μM and 79.02μM, respectively. Compound 6e showed a greater ability to reduce copper and a stronger copper chelating ability than kojic acid.
authors.affiliation: School of Food Science and Biotechnology, Zhejiang Gongshang University, Xiasha, Hangzhou, Zhejiang 310018, PR China.
authors.forename: De-Yin
authors.initials: DY
authors.lastname: Zhao
authors.affiliation: School of Food Science and Biotechnology, Zhejiang Gongshang University, Xiasha, Hangzhou, Zhejiang 310018, PR China.
authors.forename: Ming-Xia
authors.initials: MX
authors.lastname: Zhang
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China.
authors.forename: Xiao-Wu
authors.initials: XW
authors.lastname: Dong
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China.
authors.forename: Yong-Zhou
authors.initials: YZ
authors.lastname: Hu
authors.affiliation: School of Food Science and Biotechnology, Zhejiang Gongshang University, Xiasha, Hangzhou, Zhejiang 310018, PR China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Dai
authors.affiliation: College of Tourism & Food, Shanghai Business School, Shanghai 200235, PR China.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Wei
authors.affiliation: Division of Pharmaceutical Science, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Hider
authors.affiliation: Chemical Biology Key Laboratory of Hebei Province, Hebei University, Baoding 071002, PR China.
authors.forename: Jin-Chao
authors.initials: JC
authors.lastname: Zhang
authors.affiliation: School of Food Science and Biotechnology, Zhejiang Gongshang University, Xiasha, Hangzhou, Zhejiang 310018, PR China. Electronic address: taozhou@zjgsu.edu.cn.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhou
mesh_terms: D000363:Agaricales / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011725:Pyridines; C014047:hydroxypyridines; D014442:Monophenol Monooxygenase
keywords: 3-Hydroxypyridinone; Inhibitory mechanism; Tyrosinase inhibitor