Synthesis and Structure–Activity Relationships of EGCG Analogues, a Recently Identified Hsp90 Inhibitor

• Published in: Journal of organic chemistry Vol. 78; no. 16; pp. 7859 - 7884
• Main Authors: Khandelwal, Anuj, Hall, Jessica A, Blagg, Brian S. J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 16.08.2013; Amer Chemical Soc
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Catechin - analogs & derivatives; Catechin - chemical synthesis; Catechin - chemistry; Catechin - pharmacology; Chemistry; Chemistry, Organic; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HSP90 Heat-Shock Proteins - antagonists & inhibitors; Humans; MCF-7 Cells; Molecular Structure; Physical Sciences; Science & Technology; Structure-Activity Relationship; MANIFEST ANTIPROLIFERATIVE ACTIVITY; D-RING; ENANTIOSELECTIVE SYNTHESIS; NATURAL-PRODUCTS; (-)-EPIGALLOCATECHIN GALLATE EGCG; DRUG DISCOVERY; PROTEASOME INHIBITORS; CANCER; NOVOBIOCIN ANALOGS; GREEN TEA EXTRACT
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo401027r

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. Antiproliferative activity of all the analogues was determined against MCF-7 and SKBr3 cell lines and Hsp90 inhibitory activity of the four most potent analogues was further evaluated by Western blot analyses and degradation of Hsp90-dependent client proteins. The prenyl-substituted aryl ester of 3,5-dihydroxychroman-3-ol ring system was identified as a novel scaffold that exhibits Hsp90 inhibitory activity.