Towards the Discovery of Drug-Like Epigallocatechin Gallate Analogs As Hsp90 Inhibitors

Authors

Rohit Bhat, Montclair State UniversityFollow
Amna T. Adam, University of RochesterFollow
Jungeun Jasmine Lee, Montclair State UniversityFollow
Thomas A. Gasiewicz, University of Rochester
Ellen C. Henry, University of Rochester
David Rotella, Montclair State UniversityFollow

Document Type

Article

Publication Date

5-15-2014

Journal / Book Title

Bioorganic & Medicinal Chemistry Letters

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.

DOI

10.1016/j.bmcl.2014.03.088

Montclair State University Digital Commons Citation

Bhat, Rohit; Adam, Amna T.; Lee, Jungeun Jasmine; Gasiewicz, Thomas A.; Henry, Ellen C.; and Rotella, David, "Towards the Discovery of Drug-Like Epigallocatechin Gallate Analogs As Hsp90 Inhibitors" (2014). Department of Chemistry and Biochemistry Faculty Scholarship and Creative Works. 14.
https://digitalcommons.montclair.edu/chem-biochem-facpubs/14