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 Rotella

Research output: Contribution to journalArticle

8 Citations (Scopus)

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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Drug Discovery
Esters
Pharmaceutical Preparations
Hydroxyl Radical
Stereochemistry
Ethers
Sulfonamides
Tea
Structure-Activity Relationship
Bioactivity
Luciferases
Flavonoids
Amides
Assays
Anti-Inflammatory Agents
epigallocatechin gallate
Derivatives
Molecules
Neoplasms

Keywords

  • Epigallocatechin gallate
  • Hsp90 inhibitor
  • Natural product

Cite this

Bhat, Rohit ; Adam, Amna T. ; Lee, Jungeun Jasmine ; Gasiewicz, Thomas A. ; Henry, Ellen C. ; Rotella, David. / Towards the discovery of drug-like epigallocatechin gallate analogs as Hsp90 inhibitors. In: Bioorganic and Medicinal Chemistry Letters. 2014 ; Vol. 24, No. 10. pp. 2263-2266.
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Towards the discovery of drug-like epigallocatechin gallate analogs as Hsp90 inhibitors. / Bhat, Rohit; Adam, Amna T.; Lee, Jungeun Jasmine; Gasiewicz, Thomas A.; Henry, Ellen C.; Rotella, David.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 24, No. 10, 15.05.2014, p. 2263-2266.

Research output: Contribution to journalArticle

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