期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 24, 期 10, 页码 2263-2266出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2014.03.088
关键词
Hsp90 inhibitor; Natural product; Epigallocatechin gallate
资金
- Margaret and Herman Sokol Endowment
- NIH [AT006366]
- Center [ES01247]
- Montclair State University
- Sokol Institute for Pharmaceutical Life Sciences
( - )-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.
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