Towards the discovery of drug-like epigallocatechin gallate analogs as Hsp90 inhibitors

Rohit Bhat, Amna T. Adam, Jungeun Jasmine Lee, Thomas A. Gasiewicz, Ellen C. Henry, David P. Rotella

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Abstract

(-)-Epigallocatechin gallate (EGCG) is the major flavonoid of green tea and has been widely explored for a range of biological activities including anti-infective, anti-inflammatory, anti-cancer, and neuroprotection. Existing structure-activity data for EGCG has been largely limited to exploration of simple ethers and hydroxyl deletion. EGCG has poor drug-like properties because of multiple phenolic hydroxyl moieties and a metabolically labile ester. This work reports a substantial expansion of structure-activity understanding by exploring a range of semi-synthetic and synthetic derivatives with ester replacements and variously substituted aromatic and alicyclic groups containing more drug-like substituents. Structure-activity relationships for these molecules were obtained for Hsp90 inhibition. The results indicate that amide and sulfonamide linkers are suitable ester replacements. Hydroxylated aromatic rings and the cis-stereochemistry in EGCG are not essential for Hsp90 inhibition. Selected analogs in this series are more potent than EGCG in a luciferase refolding assay for Hsp90 activity.

Original languageEnglish
Pages (from-to)2263-2266
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume24
Issue number10
DOIs
StatePublished - 15 May 2014

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Keywords

  • Epigallocatechin gallate
  • Hsp90 inhibitor
  • Natural product

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