Estradiol-adenosine hybrid compounds designed to inhibit type 1 17-β-hydroxysteroid dehydrogenase

The steroidogenic enzyme type 1 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) is involved in the synthesis of estradiol (E-2), a hormone well-known to stimulate the growth of estrogen-sensitive tumors. To obtain compounds able to control E-2 formation, two moieties were linked with a methylene side chain: an adenosine moiety for interacting with the cofactor-binding site and an E-2 moiety for interacting with the substrate-binding site. When tested as inhibitors of type 1 17 beta-HSD, the hybrid compounds inhibited the reductive activity (E-1 into E-2) with IC50 values ranging from 52 to 1000 nM. The optimal side-chain length was determined to be eight methylene groups for a 16 beta-orientation. The presence of two components (E-2 and adenosine) is essential for good inhibition, since 16 beta-nonyl-E-2 and 5-nonanoyl-O-adenosine, two compounds having only one of the components, did not inhibit the enzyme. Moreover, the 3D-structure analysis of EM-1745 complexed with type 1 17 beta-HSD showed key interactions with both substrate- and cofactor-binding sites.