Structure-activity relationships of benzbromarone metabolites and derivatives as EYA inhibitory anti-angiogenic agents

PLoS One. 2013 Dec 18;8(12):e84582. doi: 10.1371/journal.pone.0084582. eCollection 2013.

Abstract

The tyrosine phosphatase activity of the phosphatase-transactivator protein Eyes Absent (EYA) is angiogenic through its roles in endothelial cell migration and tube formation. Benzbromarone, a known anti-gout agent, was previously identified as an inhibitor of EYA with anti-angiogenic properties. Here we show that the major metabolite of BBR, 6-hydroxy benzbromarone, is a significantly more potent inhibitor of cell migration, tubulogenesis and angiogenic sprouting. In contrast, other postulated metabolites of BBR such as 5-hydroxy benzbromaorne and 1'-hydroxy benzbromarone are less potent inhibitors of EYA tyrosine phosphatase activity as well as being less effective in cellular assays for endothelial cell migration and angiogenesis. Longer substituents at the 2 position of the benzofuran ring promoted EYA3 binding and inhibition, but were less effective in cellular assays, likely reflecting non-specific protein binding and a resulting reduction in free, bio-available inhibitor. The observed potency of 6-hydroxy benzbromarone is relevant in the context of the potential re-purposing of benzbromarone and its derivatives as anti-angiogenic agents. 6-hydroxy benzbromarone represents a metabolite with a longer half-life and greater pharmacological potency than the parent compound, suggesting that biotransformation of benzbromarone could contribute to its therapeutic activity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analysis of Variance
  • Angiogenesis Inhibitors / chemistry
  • Angiogenesis Inhibitors / metabolism
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Benzbromarone / analogs & derivatives*
  • Benzbromarone / metabolism*
  • Benzbromarone / pharmacology
  • Cell Movement / drug effects
  • DNA-Binding Proteins / antagonists & inhibitors*
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Microtubules / drug effects
  • Molecular Structure
  • Neovascularization, Physiologic / drug effects
  • Protein Tyrosine Phosphatases / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • 6-hydroxybenzbromarone
  • Angiogenesis Inhibitors
  • DNA-Binding Proteins
  • Benzbromarone
  • EYA3 protein, human
  • Protein Tyrosine Phosphatases