Comparative investigation of the in vitro inhibitory potencies of 13-epimeric estrones and D-secoestrones towards 17-hydroxysteroid dehydrogenase type 1

摘要

The inhibitory effects of 13-epimeric estrones, D-secooxime and D-secoalcohol estrone compounds on human placental 17-hydroxysteroid dehydrogenase type 1 isozyme (17-HSD1) were investigated. The transformation of estrone to 17-estradiol was studied by an in vitro radiosubstrate incubation method. 13-Estrone inhibited the enzyme activity effectively with an IC50 value of 1.2M, which indicates that enzyme affinity is similar to that of the natural estrone substrate. The 13 derivatives and the compounds bearing a 3-hydroxy group generally exerted stronger inhibition than the 13 and 3-ether counterparts. The 3-hydroxy-13-D-secoalcohol and the 3-hydroxy-13-D-secooxime displayed an outstanding cofactor dependence, i.e. more efficient inhibition in the presence of NADH than NADPH. The 3-hydroxy-13-D-secooxime has an IC50 value of 0.070M and is one of the most effective 17-HSD1 inhibitors reported to date in the literature.