Format

Send to

Choose Destination
Bioorg Med Chem Lett. 2014 May 15;24(10):2263-6. doi: 10.1016/j.bmcl.2014.03.088. Epub 2014 Apr 4.

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

Author information

1
Department of Chemistry and Biochemistry, Montclair State University, Montclair, NJ 07043, United States.
2
Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY 14642, United States.
3
Department of Chemistry and Biochemistry, Montclair State University, Montclair, NJ 07043, United States. Electronic address: rotellad@mail.montclair.edu.

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.

KEYWORDS:

Epigallocatechin gallate; Hsp90 inhibitor; Natural product

PMID:
24745965
DOI:
10.1016/j.bmcl.2014.03.088
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center