title: Estradiol-adenosine hybrid compounds designed to inhibit type 1 17beta-hydroxysteroid dehydrogenase.
abstract: The steroidogenic enzyme type 1 17beta-hydroxysteroid dehydrogenase (17beta-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 17beta-HSD, the hybrid compounds inhibited the reductive activity (E(1) into E(2)) with IC(50) values ranging from 52 to 1,000 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-1,745 complexed with type 1 17beta-HSD showed key interactions with both substrate- and cofactor-binding sites.
authors.affiliation: Oncology and Molecular Endocrinology Research Center, CHUQ-Pavillon CHUL and Université Laval, Québec G1V 4G2, Canada.
authors.forename: Donald
authors.initials: D
authors.lastname: Poirier
authors.forename: Roch P
authors.initials: RP
authors.lastname: Boivin
authors.forename: Martin R
authors.initials: MR
authors.lastname: Tremblay
authors.forename: Marie
authors.initials: M
authors.lastname: Bérubé
authors.forename: Wei
authors.initials: W
authors.lastname: Qiu
authors.forename: Sheng-Xiang
authors.initials: SX
authors.lastname: Lin
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D007668:Kidney / Q000196:embryology / Q000201:enzymology; D008958:Models, Molecular
chemical_list: D004791:Enzyme Inhibitors; D004958:Estradiol; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase; D000241:Adenosine