Synthesis and structure–activity relationship of 3-O-acylated (–)-epigallocatechins as 5α-reductase inhibitors

A series of 3-O-acylated (–)-epigallocatechins were synthesized and their inhibition of steroid 5α-reductase was studied. They were prepared from the reaction of EGCG with tert-butyldimethylsilyl chloride followed by reductive cleavage of the ester bond. The resultant (–)-epigallocatechins penta-O-tert-butyldimethylsilyl ether was esterified with different fatty acids then desilylated to provide the corresponding products. The activity of 3-O-acylated (–)-epigallocatechins increased with the increasing carbon numbers of the fatty acid moiety, reaching maximum for 16 carbon atoms (compound 4h) with an IC50 of 0.53 μM, which was ∼12-fold more potent than EGCG (IC50 = 6.29 μM). Introduction of monounsaturated fatty acid provided the most potent compound 6 (IC50 = 0.48 μM), which showed moderate anti-tumor activity in vivo.

Graphical abstractIntroduction of fatty acid to the C3-O position of (–)-epigallocatechin increases the potency for the inhibition of steroid 5α-reductase.Figure optionsDownload full-size imageDownload as PowerPoint slideResearch highlights► Synthesis of 3-O-acylated (–)-epigallocatechins is accomplished by use of TBMDSCl as the protecting group. ► 3-O-Acylated (–)-epigallocatechins inhibit 5α-reductase with submicromolar IC50 values. ► 3-O-Acylated (–)-epigallocatechin shows moderate anti-tumor activity in vivo.