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

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.

• Authors: Ram Naresh Pandey, Tim Sen Wang, Emmanuel Tadjuidje, Matthew G McDonald, Allan E Rettie, Rashmi S Hegde
• Journal: PloS one (PLoS One) Vol. 8 Issue 12 Pg. e84582 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24367676 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

• Analysis of Variance
• Angiogenesis Inhibitors (chemistry, metabolism, pharmacology)
• Animals
• Benzbromarone (analogs & derivatives, metabolism, 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