Abstract A89: Synthesis and structure-activity relationship of 3-O-acylated (−)-epigallocatechins as 5α-reductase inhibitors

Abstract

Abstract A series of 3-O-acylated (−)-epigallocatechins were synthesized and their inhibition of steroid 5α-reductase was studied. They were prepared by 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 using DCC and DMAP and then desilylated with aqueous HF to provide the corresponding products. For 3-O-acylated (−)-epigallocatechins with saturated fatty acids, the 5α-reductase inhibitory activity increased with the increasing numbers of carbon atoms at the C3-O position, reaching maximum for 16 carbon atoms (compound 4h, with palmitic acid) with an IC50 of 0.53 µM, which was ∼12-fold more potent than EGCG (IC50 = 6.29 M). Introduction of monounsaturated fatty acid to the C3-O position of (−)-epigallocatechins enhanced the activity, providing the most potent compound 6 (IC50 = 0.48 µM, with palmitoleic acid), which showed moderate anti-tumor activity in a PC-3 prostate cancer xenograft model. Replacement of the ester moiety at C3-O with carbamate, or permethylation or peracylation of hydroxyl groups diminished 5α-reductase inhibitory activity. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A89.