title: Towards the discovery of drug-like epigallocatechin gallate analogs as Hsp90 inhibitors.
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.
authors.affiliation: Department of Chemistry and Biochemistry, Montclair State University, Montclair, NJ 07043, United States.
authors.forename: Rohit
authors.initials: R
authors.lastname: Bhat
authors.affiliation: Department of Chemistry and Biochemistry, Montclair State University, Montclair, NJ 07043, United States.
authors.forename: Amna T
authors.initials: AT
authors.lastname: Adam
authors.affiliation: Department of Chemistry and Biochemistry, Montclair State University, Montclair, NJ 07043, United States.
authors.forename: Jungeun Jasmine
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY 14642, United States.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Gasiewicz
authors.affiliation: Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY 14642, United States.
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Henry
authors.affiliation: Department of Chemistry and Biochemistry, Montclair State University, Montclair, NJ 07043, United States. Electronic address: rotellad@mail.montclair.edu.
authors.forename: David P
authors.initials: DP
authors.lastname: Rotella
mesh_terms: D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology; D002392:Catechin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D055808:Drug Discovery; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D001688:Biological Products; D018841:HSP90 Heat-Shock Proteins; D002392:Catechin; C045651:epigallocatechin gallate
keywords: Epigallocatechin gallate; Hsp90 inhibitor; Natural product