Synthesis, Chemical, and Biological Properties of Vinylogous Hydroxamic Acids: Dual Inhibitors of 5-lipoxygenase and IL-1 Biosynthesis

J Med Chem. 1992 Oct 30;35(22):4061-8. doi: 10.1021/jm00100a011.

Abstract

Vinylogous hydroxamic acids (3-(N-hydroxy-N-alkylamino)-2-propen-1-ones, VHA) were prepared as antiinflammatory agents. The synthesis, chemical properties, and in vitro biological activities of these relatively unexplored compounds are described. The VHAs were prepared by condensation of the appropriate N-substituted hydroxylamine with any of the three reagents: a 1,3-dicarbonyl compound (method A); a vinylogous amide (method B); or an alkynone (method C). The VHAs exist as one or more tautomers in solution with the relative proportions of each being dependent upon the structure of the VHA, solvent, and pH. VHAs undergo some of the typical reactions of hydroxamic acids as well as those of vinylogous amides. VHAs are active as inhibitors of 5-lipoxygenase and of IL-1 biosynthesis in vitro, which do not inhibit other enzymes of the arachidonic acid cascade. They have been shown by ESR studies to bring about inhibition of soybean type 1 15-lipoxygenase by reduction of the active site iron.

MeSH terms

  • Animals
  • Humans
  • Hydroxamic Acids / chemical synthesis*
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / pharmacology
  • In Vitro Techniques
  • Interleukin-1 / biosynthesis*
  • Lipoxygenase Inhibitors / chemical synthesis*
  • Lipoxygenase Inhibitors / chemistry
  • Lipoxygenase Inhibitors / pharmacology
  • Rats
  • Soybeans
  • Structure-Activity Relationship
  • Tumor Cells, Cultured
  • Vinyl Compounds / chemical synthesis*
  • Vinyl Compounds / chemistry
  • Vinyl Compounds / pharmacology

Substances

  • Hydroxamic Acids
  • Interleukin-1
  • Lipoxygenase Inhibitors
  • Vinyl Compounds