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.
| Original language | English |
|---|---|
| Pages (from-to) | 2263-2266 |
| Number of pages | 4 |
| Journal | Bioorganic and Medicinal Chemistry Letters |
| Volume | 24 |
| Issue number | 10 |
| DOIs | |
| State | Published - 15 May 2014 |
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Keywords
- Epigallocatechin gallate
- Hsp90 inhibitor
- Natural product
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Towards the discovery of drug-like epigallocatechin gallate analogs as Hsp90 inhibitors. / Bhat, Rohit; Adam, Amna T.; Lee, Jungeun Jasmine; Gasiewicz, Thomas A.; Henry, Ellen C.; Rotella, David.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 24, No. 10, 15.05.2014, p. 2263-2266.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Towards the discovery of drug-like epigallocatechin gallate analogs as Hsp90 inhibitors
AU - Bhat, Rohit
AU - Adam, Amna T.
AU - Lee, Jungeun Jasmine
AU - Gasiewicz, Thomas A.
AU - Henry, Ellen C.
AU - Rotella, David
PY - 2014/5/15
Y1 - 2014/5/15
N2 - (-)-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.
AB - (-)-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.
KW - Epigallocatechin gallate
KW - Hsp90 inhibitor
KW - Natural product
UR - http://www.scopus.com/inward/record.url?scp=84899506740&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2014.03.088
DO - 10.1016/j.bmcl.2014.03.088
M3 - Article
VL - 24
SP - 2263
EP - 2266
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 10
ER -