Design, synthesis, and evaluation of postulated transient intermediate and substrate analogues as inhibitors of 4-hydroxyphenylpyruvate dioxygenase

Bioorg Med Chem Lett. 2002 Jul 8;12(13):1709-13. doi: 10.1016/s0960-894x(02)00291-3.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Hydroxyphenylpyruvate Dioxygenase / antagonists & inhibitors*
  • 4-Hydroxyphenylpyruvate Dioxygenase / chemistry
  • Animals
  • Benzoquinones / chemical synthesis*
  • Benzoquinones / chemistry
  • Benzoquinones / pharmacology
  • Butyrates / chemical synthesis*
  • Butyrates / chemistry
  • Butyrates / pharmacology
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Epoxy Compounds / chemical synthesis
  • Epoxy Compounds / chemistry
  • Epoxy Compounds / pharmacology
  • Inhibitory Concentration 50
  • Lactones / chemical synthesis
  • Lactones / chemistry
  • Lactones / pharmacology
  • Liver / enzymology
  • Magnetic Resonance Spectroscopy
  • Phenoxyacetates / chemical synthesis*
  • Phenoxyacetates / chemistry
  • Phenoxyacetates / pharmacology
  • Phenylpyruvic Acids / chemistry
  • Phenylpyruvic Acids / metabolism
  • Swine

Substances

  • Benzoquinones
  • Butyrates
  • Enzyme Inhibitors
  • Epoxy Compounds
  • Lactones
  • Phenoxyacetates
  • Phenylpyruvic Acids
  • 4-hydroxyphenylpyruvic acid
  • 4-hydroxyphenoxyacetic acid
  • 4-Hydroxyphenylpyruvate Dioxygenase