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

• Published in: Bioorganic & medicinal chemistry letters 2014-05, Vol.24 (10), p.2263-2266
• Main Authors: Bhat, Rohit, Adam, Amna T., Lee, Jungeun Jasmine, Gasiewicz, Thomas A., Henry, Ellen C., Rotella, David P.
• Format: Article
• Language: English
• Subjects: Biological Products - chemistry; Biological Products - pharmacology; Catechin - analogs & derivatives; Catechin - chemistry; Catechin - pharmacology; Drug Discovery; Epigallocatechin gallate; HSP90 Heat-Shock Proteins - antagonists & inhibitors; Hsp90 inhibitor; Natural product; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.03.088

(−)-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.