Design and SAR of Macrocyclic Hsp90 Inhibitors With Increased Metabolic Stability and Potent Cell-Proliferation Activity

Bioorg Med Chem Lett. 2011 Apr 15;21(8):2278-82. doi: 10.1016/j.bmcl.2011.02.101. Epub 2011 Feb 28.


A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. A basic nitrogen within the tether linking the aniline nitrogen atom to a tetrahydroindolone moiety allowed access to compounds with good physical properties. Important structure-activity relationship information was obtained from this series which led to the discovery of a soluble and stable compound which is potent in an Hsp90 binding and cell-proliferation assay.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Benzamides / chemical synthesis
  • Benzamides / chemistry*
  • Benzamides / pharmacology
  • Binding Sites
  • Cell Line, Tumor
  • Cell Proliferation
  • Computer Simulation
  • Crystallography, X-Ray
  • Drug Design
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Protein Binding
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • Benzamides
  • HSP90 Heat-Shock Proteins
  • benzamide