title: Structure-based design, synthesis and in vitro characterization of potent 17beta-hydroxysteroid dehydrogenase type 1 inhibitors based on 2-substitutions of estrone and D-homo-estrone.
abstract: In search for specific drugs against steroid-dependent cancers we have developed a novel set of potent inhibitors of steroidogenic human 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD 1). The X-ray structure of 17beta-HSD 1 in complex with estradiol served as basis for the design of the inhibitors. 2-Substituted estrone and D-homo-estrone derivatives were synthesized and tested for 17beta-HSD 1 inhibition. The best 17beta-HSD 1 inhibitor, 2-phenethyl-D-homo-estrone, revealed an IC(50) of 15 nM in vitro. The inhibitory potency of compounds is comparable or better to that of previously described inhibitors. An interaction within the cofactor binding site is not necessary to obtain this high binding affinity for substances developed.
authors.affiliation: Helmholtz Zentrum München, Institute of Experimental Genetics, Genome Analysis Center, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Möller
authors.forename: Dominga
authors.initials: D
authors.lastname: Deluca
authors.forename: Christian
authors.initials: C
authors.lastname: Gege
authors.forename: Andrea
authors.initials: A
authors.lastname: Rosinus
authors.forename: Dorota
authors.initials: D
authors.lastname: Kowalik
authors.forename: Olaf
authors.initials: O
authors.lastname: Peters
authors.forename: Peter
authors.initials: P
authors.lastname: Droescher
authors.forename: Walter
authors.initials: W
authors.lastname: Elger
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
authors.forename: Alexander
authors.initials: A
authors.lastname: Hillisch
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004970:Estrone / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D004970:Estrone; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase