title: Synthesis and evaluation of estradiol derivatives with 16 alpha-(bromoalkylamide), 16 alpha-(bromoalkyl) or 16 alpha-(bromoalkynyl) side chain as inhibitors of 17 beta-hydroxysteroid dehydrogenase type 1 without estrogenic activity.
abstract: To develop inhibitors of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) without residual estrogenic activity, the synthesis of 16 alpha-(bromoalkylamide) derivatives of estradiol was performed starting from a key intermediate aldehyde obtained from commercially available estrone. In addition, series of 16 alpha-(bromoalkyl) and 16 alpha-(bromoalkynyl) derivatives of estradiol were also prepared as model compounds. All new compounds inhibited human placental cytosolic 17 beta-HSD (type 1) with IC50 values ranging from 1.7 to 10.6 microM. From these results, we observed that a primary bromide produces a greater inhibition of 17 beta-HSD activity than secondary bromide, and that a shorter 16 alpha-side chain increases the inhibiting activity. In the estrogen-sensitive ZR-75-1 human breast cancer cell line, the 16 alpha-(bromoalkylamide)-estradiol series had no estrogenic activity at 30 nM, and only the compound with a shorter side chain length showed an estrogenic activity at 1000 nM. Interestingly, at this concentration, the compound with an intermediate side chain length showed an antiestrogenic activity of 74%, whereas the compound with the longer side chain length showed 34% of antiestrogenic activity. In this test, other 17 beta-HSD inhibitors (without bromoalkylamide side chain) were fully estrogenic. Among synthesized compounds, the estradiol derivative 4 (N-butyl, N-methyl, 9-[3',17' beta-(dihydroxy)-1',3',5'(10')-estratrien-16' alpha-yl]-7-bromononamide) was the best compromise for a dual-action inhibitor. This compound inhibited moderately and reversibly the 17 beta-HSD type 1 activity, but possessed no estrogenic activity and exhibited antiestrogenic activity in the ZR-75-1 cell line.
authors.affiliation: Medicinal Chemistry Division, Molecular Endocrinology Laboratory, CHUL Research Center, Ste-Foy, Canada.
authors.forename: J D
authors.initials: JD
authors.lastname: Pelletier
authors.forename: D
authors.initials: D
authors.lastname: Poirier
mesh_terms: D000478:Alkylation; D000577:Amides; D001667:Binding, Competitive; D001965:Bromides; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D011960:Receptors, Estrogen / Q000378:metabolism
chemical_list: D000577:Amides; D001965:Bromides; D004791:Enzyme Inhibitors; D011960:Receptors, Estrogen; D004958:Estradiol; D006913:Hydroxysteroid Dehydrogenases; C035507:3(17)-hydroxysteroid dehydrogenase