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

被引:22
作者
Bhat, Rohit [1 ]
Adam, Amna T. [1 ]
Lee, Jungeun Jasmine [1 ]
Gasiewicz, Thomas A. [2 ]
Henry, Ellen C. [2 ]
Rotella, David P. [1 ]
机构
[1] Montclair State Univ, Dept Chem & Biochem, Montclair, NJ 07043 USA
[2] Univ Rochester, Dept Environm Med, Med Ctr, Rochester, NY 14642 USA
关键词
Hsp90; inhibitor; Natural product; Epigallocatechin gallate; GREEN TEA POLYPHENOLS; NEURODEGENERATIVE DISEASES; (-)-EPIGALLOCATECHIN-3-GALLATE; DERIVATIVES; EGCG;
D O I
10.1016/j.bmcl.2014.03.088
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
( - )-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. (C) 2014 Elsevier Ltd. All rights reserved.
引用
收藏
页码:2263 / 2266
页数:4
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