Development of withaferin A analogs as probes of angiogenesis

Bioorg Med Chem Lett. 2006 May 15;16(10):2603-7. doi: 10.1016/j.bmcl.2006.02.039. Epub 2006 Mar 2.

Abstract

The natural product withaferin A (WFA) is a potent angiogenesis inhibitor and it targets the ubiquitin-proteasome pathway in vascular endothelial cells. We generated a biotinylated affinity analog WFA-LC(2)B for use as a probe to study angiogenesis. WFA-LC(2)B inhibits angiogenic sprouting in vitro and it causes levels of ubiquitinated proteins to increase in tumor necrosis factor-alpha-treated human umbilical vein endothelial cells, confirming the retention of WFA's biological activity. We show that WFA-LC(2)B forms protein adducts in endothelial cells which are competed by free WFA in vivo. This WFA-LC(2)B analog will be useful to isolate the biological target of WFA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / chemistry*
  • Angiogenesis Inhibitors / pharmacology
  • Cells, Cultured
  • Electrophoresis, Polyacrylamide Gel
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Ergosterol / analogs & derivatives*
  • Ergosterol / chemistry
  • Ergosterol / pharmacology
  • Humans
  • Molecular Probes*
  • Withanolides

Substances

  • Angiogenesis Inhibitors
  • Molecular Probes
  • Withanolides
  • withaferin A
  • Ergosterol