Design, synthesis, and evaluation of postulated transient intermediate and substrate analogues as inhibitors of 4-hydroxyphenylpyruvate dioxygenase.
An epoxybenzoquinone, 4-hydroxyphenoxypropionic acid, and 2-hydroxy-3-phenyl-3-butenoic acid derivatives have been designed, synthesized, and evaluated for in vitro inhibition activity against 4-hydroxyphenylpyruvate dioxygenase (4-HPPD) from pig liver by the spectrophotometric enol-borate method. The biological data demonstrated that neither epoxybenzoquinone ester nor 2-hydroxy-3-phenyl-3-butenoic acid is an inhibitor of 4-HPPD. The most potent 4-HPPD inhibitor tested was 3-hydroxy-4-phenyl-2(5H)-furanone with an IC(50) value of 0.5 microM, which may serve as a lead compound for further design of more potent 4-HPPD inhibitors.
Lin
Yun-Loung
YL
Department of Chemistry, Tunghai University, 181, Taichung-Kang Rd. Sec. 3, Taichung, Taiwan 40704, Republic of China.
Huang
Jian-Lin
JL
Wu
Chung-Shieh
CS
Liu
Hung-Ge
HG
Yang
Ding-Yah
DY
D015111:4-Hydroxyphenylpyruvate Dioxygenase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D016227:Benzoquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002087:Butyrates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008099:Liver / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D010642:Phenoxyacetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010667:Phenylpyruvic Acids / Q000737:chemistry / Q000378:metabolism; D013552:Swine
D016227:Benzoquinones; D002087:Butyrates; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D007783:Lactones; D010642:Phenoxyacetates; D010667:Phenylpyruvic Acids; C010590:4-hydroxyphenylpyruvic acid; C060827:4-hydroxyphenoxyacetic acid; D015111:4-Hydroxyphenylpyruvate Dioxygenase