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Synthesis and Structure activity relationships of EGCG Analogues, A Recently Identified Hsp90 Inhibitor
Khandelwal, Anuj Hall, Jessica Ann Blagg, Brian S. J.
Khandelwal, Anuj
Hall, Jessica Ann
Blagg, Brian S. J.
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Abstract
Epigallocatechin-3-gallate (EGCG), the principal polyphenol isolated from green tea, was recently shown to inhibit Hsp90, however structure-activity relationships for this natural product have not yet been produced. Herein, we report the synthesis and biological evaluation of EGCG analogues to establish structure-activity relationships between EGCG and Hsp90. All four rings as well as the linker connecting the C- and the D-rings were systematically investigated, which led to the discovery of compounds that inhibit Hs90 and display improvement in efficacy over EGCG. Anti-proliferative activity of all the analogues was determined against MCF-7 and SKBr3 cell lines and Hsp90 inhibitory activity of four most potent analogues was further evaluated by western blot analyses and degradation of Hsp90-dependent client proteins. Prenyl substituted aryl ester of 3,5-dihydroxychroman-3-ol ring system was identified as novel scaffold that exhibit Hsp90 inhibitory activity.
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2013-08-16
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American Chemical Society
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Blagg_2013.pdf
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Khandelwal, A., Hall, J., & Blagg, B. S. J. (2013). Synthesis and Structure activity relationships of EGCG Analogues, A Recently Identified Hsp90 Inhibitor. The Journal of Organic Chemistry, 78(16), 7859–7884. http://doi.org/10.1021/jo401027r